METHODS OF MODULATING THE ACTIVITY OF THE MC5 RECEPTOR AND TREATMENT OF CONDITIONS RELATED TO THIS RECEPTOR

FIELD OF THE INVENTION

The present invention relates to methods of modulating the activity of the melanocortin-5 receptor. In particular the present invention relates to the use of a family of 1,4-diazepan-2-ones and derivatives thereof to modulate the activity of the melanocortin-5 receptor. The invention also relates to methods and uses of the compounds in the treatment of conditions in which antagonism of the melanocortin-5 receptor is beneficial.

BACKGROUND OF THE INVENTION

The melanocortin-5 receptor (MC5R) is a G-protein coupled receptor (GPCR) belonging to the family of melanocortin receptors. There are five melanocortin receptors that have been isolated and cloned to date: MC1R, MC2R, MC3R, MC4R and MC5R. The melanocortin receptors participate in a variety of physiologic functions, providing a number of opportunities for therapeutic intervention in physiologic processes through alteration (i.e., a statistically significant increase or decrease) or modulation (e.g., up-regulation or down-regulation) of melanocortin receptor signalling activity.

Reviews of the melanocortin receptors, and their potential as targets for therapy have been published (Wikberg 2001; Bohm 2006). The melanocortin receptor family members are regulated by natural peptide agonists such as ACTH and the melanocyte-stimulating hormones (α-, β-, γ-MSH) derived from pro-opiomelanocortin (POMC) and by peptide antagonists such as Agouti signal protein (ASP) and Agouti-related peptide (AGRP). The MC1R is widely expressed and is associated with pigmentation in melanocytes and with inflammation responses in many cells involved in the immune system. The MC2R differs from the other melanocortin receptors in that it binds only ACTH but not MSH ligands. It is highly expressed in the adenal gland and controls corticosteroid synthesis. The MC3R is found in the brain, but also elsewhere in the body, and appears to play a role in the regulation of energy homeostasis, and possibly sexual dysfunction. The MC4R is found almost exclusively in the brain, with some reports of its presence elsewhere. It has been strongly associated with feeding control, and also implicated with sexual desire. The MC5R is widely expressed in peripheral tissues, particularly in the exocrine glands, with some receptor also expressed in the brain. Given the breadth of activity associated with the melanocortin receptors it is desirable when seeking to target one of these receptors to do so selectively in order to avoid side effects associated with antagonism or agonism of another receptor in this family.

The MC5R has been cloned and expressed from multiple species, including humans in 1993 (though called MC2 in this paper) (Chhajlani 1993), rat in 1994 (Griffon 1994) mice in 1994 (Gantz 1994; Labbe 1994) and in 1995 (Fathi 1995), canine (Houseknecht 2003), rhesus monkey (Huang 2000), sheep (Barrett 1994), zebrafish (Ringholm 2002), goldfish (Cerdá-Reverter 2003), spiny dogfish (Klovins 2004), rainbow trout (Haitina 2004), and chicken (Ling 2004), with the MC5R gene also identified in pig (Kim 2000). Patents covering the MC5R sequence in humans (Wikberg 2002), mice (Yamada 1997), rhesus monkey (Fong 2003) and dogs (Houseknecht 2003) have been published.

The MC5R has been implicated in regulating sebum secretion by a number of studies, as summarized in 2006 (Zhang 2006). Mice lacking MC5R have reduced sebum production, as evidenced by a marked inability to shed water from their fur, and a reduced quantity of sebum isolated from their hair. Significantly, these mice were otherwise generally healthy, with no readily visible abnormalities (appearance, behaviour, growth, muscle mass, adipose mass, reproduction, basal and stress-induced corticosterone, glucose and insulin levels) (Chen 1997). Further studies have identified reductions in pheromones, causing alterations in aggressive behaviours between mice (Caldwell 2002; Morgan 2004a; Morgan 2004b; Morgan 2006). Mice in which the POMC-derived peptide native ligands of MC5R have been knocked out show a similar phenotype (Yaswen 1999). Rats injected with α-MSH had 30-37% increased rates of sebum production, while removal of the neurointermediate lobe (the source of MSH) caused a 35% decrease in sebum secretion, which was restored upon administration of α-MSH (Thody 1973). A synergistic effect between α-MSH and testosterone was observed in rats, with testosterone increasing sebaceous gland and cell volumes (presumably via increased proliferation), α-MSH increasing dermal lipogenesis, and the combination increasing sebum secretion (Thody 1975a; Thody 1975b).

At a cellular level human sebocytes have been shown to express MC5R, via detection of MC5R transcripts in micro-dissected sebaceous glands (Thiboutot 2000), detection of MC5R in human facial sebaceous glands by immunostaining (Hatta 2001), detection of MC5R mRNA and MC5R in human sebaceous glands, cultured human sebocytes and rat preputial cells (Thiboutot 2000) and detection of MC5R as punctate particles within sebaceous glands by staining with polyclonal antibodies, seen in differentiated but not undifferentiated sebocytes (Zhang 2006). MC5R mRNA was also detected in sebaceous glands from the skin of wild-type mice, but not in skin sections of the MC5R-knockout mice (Chen 1997). Treatment of human sebocytes with cholera toxin (ChT), bovine pituitary extract (BPE), α-MSH or NDP-MSH increases lipid droplet formation, squalene synthesis, and MC5R expression (Zhang 2003; Zhang 2006), While both MC1R and MC5R have been detected in sebaceous cells, treatment of primary human sebocyte cell culture with NDP-MSH or BPE caused a substantial increase in human MC5R expression compared to serum-free conditions, correlating with sebocyte differentiation. Immortalized sebaceous cell lines (SZ-95, TSS-1 and SEB-1) also show MC5R expression (Jeong 2007; Smith 2007a; Phan 2007). These studies suggest that MC5R antagonists could be useful in reducing sebum secretion in mammals and hence in treating conditions associated with excess sebum secretion.

A family of 1,2,4-thiadiazole derivatives with MC5R antagonist activity (138-320 nM) were found to reduce sebum formation both in human sebocyte cell cultures and when applied topically to human skin grafted onto immunodeficient mice (Eisinger 2003a-d; 2006a,b).

Excessive sebum secretion, or seborrhoea, is a common affliction. Sebaceous glands occur over most of the body, with dense concentrations of large glands on the face, scalp and upper trunk (Simpson and Cunliffe p 43.1). Sebaceous secretion is dependent in part on androgenic hormones, possibly partly mediated by 5α-reductase processing of testosterone to 5α-DHT (dihydrotestosterone). Sebum consists of a species-specific mixture of lipids. In humans this consists of approximately 58% glycerides, 26% wax esters, 12% squalene, and 4% cholesterol/cholesterol esters (Simpson and Cunliffe p 43.5). The presence of squalene is almost exclusively characteristic of human sebum. The function of sebum is not well defined, but it is believed to have fungistatic properties, and play a role in moisture loss from, and water repellence of, the epidermis (Simpson and Cunliffe p 43.6; Danby 2005; Porter 2001; Shuster 1976; Kligman 1963).

Excessive sebum secretion has been associated with the development of acne vulgaris. Acne vulgaris is a common disease affecting an estimated 80% of the world's population at some stage in their lives. A person is more likely to develop acne than any other disease, although the severity varies greatly (Simpson and Cunliffe p 43.16). Acne peaks in prevalence and severity in adolescents aged 14-19 years old, with approximately 35-40% affected, but in a significant number of patients (7-24%) it persists beyond 25 years of age (Simpson and Cunliffe p 43.15). Of patients treated for acne, one study found 80% still had symptoms at 30-40 years of age (Simpson and Cunliffe p 43.16). While acne is not a life-threatening disease it can have a severe impact on a patient's quality of life (Follador 2006), with one study of severe acne patients showing similar impact as much more serious chronic medical conditions such as asthma, epilepsy, diabetes, back pain or arthritis (Mallon 1999).

Four major factors are believed to be involved in the pathogenesis of acne: (i) increased sebum production (seborrhoea), (ii) hypercornification/blockage of the pilosebaceous duct (comedogenesis), (iii) infection of the duct with P. acnes, and (iv) inflammation of the pilosebaceous duct (Simpson and Cunliffe p 43.15; Williams 2006). A number of studies have demonstrated a clear link between increased production of sebum, and the presence and severity of acne (Simpson and Cunliffe p 43.17; Youn 2005; Piérard 1987; Harris 1983; Cotterill 1981; Thody 1975c; Pochi 1964). A 2007 study found a correlation between sebum excretion and development of acne in preadolescent children (Mourelatos 2007). Sebum is the main nutrient of P. acnes, thus reduction of sebum will reduce the subsequent bacterial infection and inflammation response.

Androgenic sex hormones appear to play a role in the development of acne, with strong correlations with sebum production (Makrantonaki 2007). Two oral contraceptive pills are approved by the FDA for the treatment of acne vulgaris (Harper 2005), and these compounds appear to act by reducing androgen mediated sebum formation. Diet (Cordain 2005; Smith 2007b), stress (Zouboulis 2004) and genetic factors (Goulden 1999; Bataille 2006) also may play a role in acne, again potentially via increased sebum production.

Current treatments for acne vulgaris focus predominantly on treating the infection and inflammation stages of the disease, with a large number of different formulations of topical antibiotics (e.g. benzoyl peroxide, tetracycline, erythromycin, clindamycin) and retinoids (e.g. retinoic acid, isotretinoin, adapalene, tazarotene) in use, either alone or in combination; some of these also possess anti-inflammatory action (Simpson and Cunliffe p 43.36-43.38). Many of these treatments are of limited efficacy, particularly for severe cases of acne. A growing problem is the development of antibiotic-resistant strains of P. acnes (Simpson and Cunliffe p 43.37, 43.46; Williams 2006). Both topical retinoids and benzoyl peroxide cause skin irritation, and retinoids can cause photosensitivity (Williams 2006). Oral therapies include isotretinoin, antibiotics, hormones, and steroids. In females, antiandrogens have been shown to reduce sebum production (by approximately 40-80%, though with no placebo control group) and improve acne (Simpson and Cunliffe p 43.44; Burke 1984; Goodfellow 1984). Laser and UV-based therapies are gaining acceptance, and are believed to act through heating of the sebaceous gland followed by reduction in sebum formation; with reductions in both sebum formation and acne lesions measured (Jih 2006; Bhardwaj 2005). Of the many therapies available for acne, only oral isotretinoin and hormonal therapies act by regulating the sebaceous gland to reduce sebum secretion (Clarke 2007).

The most effective acne treatment, oral isotretinoin (13-cis-retinoic acid, Roaccutane, Accutane) was introduced in 1983 and still remains the most clinically effective anti-acne therapy. It is the only known treatment with strong sebusuppressive activity, reducing sebum excretion by up to 90% after 8-12 weeks of therapy (60-70% by 2 weeks) (Simpson and Cunliffe p 43.47; Jones 1983; Goldstein 1982; King 1982). Topical retinoids, in contrast, have no effect on sebum production. Oral isotretinoin is also anti-inflammatory, reduces comedogenesis, and reduces P. acnes infection. The mechanism of action is still unclear, and metabolites of isotretinoin appear to play a significant role. Isotretinoin induces apoptosis and cell cycle arrest in human immortalized SEB-1 sebocyte cell culture (Nelson 2006). Unfortunately, oral isotretinoin has serious side effects; most significantly it is a teratogen and requires a registration program for use in the USA. The FDA has issued a warning against online purchases of isotretinoin. Blood testing for fasting lipids and liver function is also recommended during treatment (Williams 2006). Isotretinoin has been implicated (though not substantively) with adverse psychological effects, including suicide and depression (Marqueling 2005).

Other forms of acne, such as acne conglobata or acne fulminans, may also respond to a sebum-reducing agent. Seborrhoea, or excessive skin oil production, is often associated with severe acne. Seborrheic dermatitis (SD) is a skin disease associated with sebum-rich areas of the scalp, face and trunk with scaly, flaky, itchy red skin affecting 3-5% of the population; dandruff represents a mild form of this dermatitis affecting 15-20% of the population. Seborrhoea and SD appear more common in patients with Parkinson's disease or mood disorders (facial paralysis, supraorbital injury, poliomyelitis, syringomyelia, quadriplegia, unilateral injury to the ganglion Gasser and those with HIV/AIDS) (Plewig 1999). Studies have shown that seborrheic dermatitis is also associated with chronic alcoholic pancreatitis, hepatitis C virus and various cancers. It is also common in patients with genetic disorders, such as Down's syndrome, Hailey-Hailey disease and cardio-facio cutaneous syndrome (Gupta 2004). MC5R antagonists may be useful for treating these indications.

Although rare, a variety of tumours involving sebaceous glands or sebaceous cells have been described (e.g. Ide 1999; Mariappan 2004; Kruse 2003). Muir-Torre syndrome consists of sebaceous gland adenomas associated with an internal adenocarcinoma (usually colon, breast, ovary or prostate). Preventing sebaceous cell differentiation may provide an effective treatment for arresting tumour growth. Oral isotretinoin has been used for this purpose (Graefe 2000). Sebaceous hyperplasia is a benign hyperplasia of the sebaceous glands, generating yellowish small papules on the skin surface, usually the face. The disease is associated with excessive undifferentiated sebocyte proliferation, but not excessive sebum formation. Ectopic sebaceous glands (Fordyce spots) are similar yellow papules found in the mouth or on the penile shaft. Both respond to oral isotreinoin. A compound that reduced sebocyte proliferation could be an effective treatment.

α-MSH shows immunosuppressive effects in humans, suppressing a variety of inflammation responses, and the MC5R has been implicated in these immunomodulating activities. MC5R mRNA was found to be expressed at high levels in human CD4+ T helper (Th) cells and in moderate levels in other human peripheral blood leukocytes (Andersen 2005). In mice, MC5R was detected in the lymphoid organs (Labbé, 1994), and MC5R was found on the surface of mouse pro-B-lymphocyte cells where it appears to mediate α-MSH activation of the JAK2 signalling pathway, enhancing cellular proliferation (Buggy 1998). Induction of CD25+ CD4+ regulatory T-cells by α-MSH also appears to be through MC5R (Taylor 2001).

For the reasons described above it would be desirable to provide MC5R antagonists that could be used in a number of therapeutic areas. Therapeutic regulation of biological signal transduction includes modulation of MC5R-mediated cellular events including, inter alia, inhibition or potentiation of interactions among MC5R-binding and activating or deactivating molecules, or of other agents that regulate MC5R activities. An increased ability to so regulate MC5R may facilitate the development of methods for modulating sebum secretion or other biological processes, and for treating conditions associated with such pathways such as acne as described above.

Accordingly there is still the need to develop improved methods of modulating the activity of MC5R which would facilitate the treatment of MC5R related conditions.

SUMMARY OF THE INVENTION

The present invention provides a method of down-regulating the activity of MC5R or a fragment, analogue or functional equivalent thereof comprising exposing the MC5R or a fragment or analogue or functional equivalent thereof to a compound of the formula (I):

wherein

Y is a group of formula —(CR⁹R¹⁰)_n—;

X is selected from the group consisting of —C(═O)—, —OC(═O)—, —NHC(═O)—, —(CR¹¹R¹²)_s, and —S(═O)₂—;

R is an amino acid side chain group;

R¹is selected from the group consisting of H, optionally substituted C₁-C₁₂alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionally substituted C₁-C₁₂heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₆-C₁₈aryl, and optionally substituted C₁-C₁₈heteroaryl;

R²and R³are each independently selected from the group consisting of H, optionally substituted C₁-C₁₂alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionally substituted C₁-C₁₂heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₆-C₁₈aryl, and optionally substituted C₁-C₁₈heteroaryl;

each R^5aand R^5bare independently selected from the group consisting of H, halogen, C₁-C₁₂alkyl, C₁-C₁₂hydroxyalkyl and C₁-C₁₂haloalkyl, or

one or more of R^5aand R^5bwhen taken together with one or more of R⁶, R⁷and R⁸and the atoms to which they are attached form a moiety selected from the group consisting of an optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₆-C₁₈aryl, and optionally substituted C₁-C₁₈heteroaryl;

R⁶, R⁷and R⁸are each independently selected from the group consisting of H, halogen, hydroxy, optionally substituted C₁-C₁₂alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionally substituted C₁-C₁₂heteroalkyl, optionally substituted C₁-C₁₀heteroalkenyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₆-C₁₈aryl, optionally substituted C₁-C₁₈heteroaryl, optionally substituted amino, optionally substituted carboxy, C₁-C₁₂alkyloxy, and optionally substituted thio, or

(a) when taken together with the carbon atom to which they are attached two or more of R⁶, R⁷and R⁸form a moiety selected from the group consisting of optionally substituted C₂-C₁₂alkenyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₆-C₁₈aryl, and optionally substituted C₁-C₁₈heteroaryl, or

(b) one or more of R⁶, R⁷and R⁸when taken together with one or more of R^5aand R^5band the atoms to which they are attached form a moiety selected from the group consisting of an optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₆-C₁₈aryl, and optionally substituted C₁-C₁₈heteroaryl;

each R⁹and R¹⁰is independently selected from the group consisting of H, optionally substituted C₁-C₁₂alkyl, optionally substituted C₆-C₁₈aryl, and optionally substituted C₁-C₁₈heteroaryl;

each R¹¹and R¹²is independently selected from the group consisting of H, and optionally substituted C₁-C₁₂alkyl;

n is an integer selected from the group consisting of 1, 2, 3 and 4;

r is an integer selected from the group consisting of 1, 2, 3, and 4;

s is an integer selected from the group consisting of 1, 2, 3, and 4;

or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment the MC5R or fragment or analogue or functional equivalent thereof is in a cell and the method comprises exposing the cell to a compound of formula (I). In one embodiment the invention provides a method of down-regulating the activity of MC5R or fragment or analogue or functional equivalent thereof in a mammal comprising administering a MC5R-modulating amount of a compound of the invention to the mammal.

In yet a further aspect the invention provides the use of a compound of the formula (I) in down-regulating the activity of MC5R or a fragment, analogue or functional equivalent thereof.

In yet a further aspect the invention provides the use of a compound of formula (I) in the preparation of a medicament for down-regulating the activity of MC5R or fragment or analogue or functional equivalent thereof in a mammal.

In yet an even further aspect the invention provides a method of treating, preventing, or controlling a condition associated with the activity of MC5R or a fragment, analogue or functional equivalent thereof in a mammal the method comprising administering a therapeutically effective amount of a compound of formula (I). The compound may be administered in any way known in the art although in one aspect the compound is administered topically. In another aspect the compound is administered orally. In another aspect the compound is administered parenterally. In one embodiment of the method the condition is selected from the group consisting of acne, seborrhoea, and seborrheic dermatitis. In one embodiment the condition is acne vulgaris. In one embodiment the compound of formula (I) is administered in combination with a second active agent. In one embodiment the second active agent is selected from the group consisting of antibiotics, retinoids, anti-androgens, and steroids.

In yet an even further aspect the invention provides the use of a compound of formula (I) in the preparation of a medicament for treating, preventing, or controlling a condition associated with the activity of MC5R or a fragment, analogue or functional equivalent thereof in a mammal. In one aspect the medicament is adapted to be administered topically. In another aspect the medicament is adapted to be administered orally. In another aspect the compound is administered parenterally. In one embodiment of the method the condition is selected from the group consisting of acne, seborrhoea, and seborrheic dermatitis. In a specific embodiment of the invention the condition is acne vulgaris.

In yet an even further aspect the invention provides a method of reducing sebum secretion by a mammal the method comprising administering a therapeutically effective amount of a compound of formula (I) to the mammal. The compound of the invention may be administered in any way known in the art although in one aspect the compound is administered topically. In another aspect the compound is administered orally. In another aspect the compound is administered parenterally.

In yet an even further aspect the invention provides the use of a compound of formula (I) in the preparation of a medicament for reducing sebum secretion in a mammal. In one embodiment the medicament is adapted to be administered topically. In another embodiment the medicament is adapted to be administered orally. In another embodiment the compound is administered parenterally.

DETAILED DESCRIPTION OF THE INVENTION

In this specification a number of terms are used which are well known to a skilled addressee. Nevertheless for the purposes of clarity a number of terms will be defined.

As used herein, the term “unsubstituted” means that there is no substituent or that the only substituents are hydrogen.

The term “optionally substituted” as used throughout the specification denotes that the group may or may not be further substituted or fused (so as to form a condensed polycyclic system), with one or more non-hydrogen substituent groups. In certain embodiments the substituent groups are one or more groups independently selected from the group consisting of halogen, ═O, ═S, —CN, —NO₂, —CF₃, —OCF₃, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, alkyloxycycloalkyl, alkyloxyheterocycloalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkyloxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, —C(═O)OH, —C(═O)R^a, —C(═O)OR^a, C(═O)NR^aR^b, C(═NOH)R^a, C(═NR^a)NR^bR^c, NR^aR^b, NR^aC(═O)R^b, NR^aC(═O)OR^b, NR^aC(═O)NR^bR^c, NR^aC(═NR^b)NR^cR^d, NR^aSO₂R^b,—SR^a, SO₂NR^aR^b, —OR^a, OC(═O)NR^aR^b, OC(═O)R^aand acyl,

wherein R^a, R^b, R^cand R^dare each independently selected from the group consisting of H, C₁-C₁₂alkyl, C₁-C₁₂haloalkyl, C₂-C₁₂alkenyl, C₂-C₁₂alkynyl, C₁-C₁₀heteroalkyl, C₃-C₁₂cycloalkyl, C₃-C₁₂cycloalkenyl, C₁-C₁₂heterocycloalkyl, C₁-C₁₂heterocycloalkenyl, C₆-C₁₈aryl, C₁-C₁₈heteroaryl, and acyl, or any two or more of R^a, R^b, R^cand R^d, when taken together with the atoms to which they are attached form a heterocyclic ring system with 3 to 12 ring atoms.

In one embodiment each optional substituent is independently selected from the group consisting of: halogen, ═O, ═S, —CN, —NO₂, —CF₃, —OCF₃, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, —COOH, —SH, and acyl.

Examples of particularly suitable optional substituents include F, Cl, Br, I, CH₃, CH₂CH₃, OH, OCH₃, CF₃, OCF₃, NO₂, NH₂, and CN.

The term “amino acid side chain group” represents a natural or unnatural side chain group present in a protein. The term includes side chain moieties present in naturally occurring proteins including the naturally occurring amino acid side chain moieties identified in table 1 below.

TABLE 1

Amino Acid Side Chain Moieties

Amino Acid Side

Chain Moiety
Amino Acid

H
Glycine

CH₃
Alanine

CH(CH₃)₂
Valine

CH₂CH(CH₃)₂
Leucine

CH(CH₃)CH₂CH₃
Isoleucine

(CH₂)₄NH₃⁺
Lysine

(CH₂)₃NHC(NH₂)NH₂₊
Arginine

CH₂-(imidazol-4-yl)
Histidine

CH₂COO⁻
Aspartic Acid

CH₂CH₂COO⁻
Glutamic acid

CH₂CONH₂
Asparagine

CH₂CH₂CONH₂
Glutamine

CH₂Ph
Phenylalanine

CH₂C₆H₄OH
Tyrosine

CH₂(Indolin-3-yl)
Tryptophan

CH₂SH
Cysteine

CH₂CH₂SCH₃
Methionine

CH₂OH
Serine

CH(OH)CH₃
Threonine

In addition to naturally occurring amino acid side chain groups as identified above the term also includes derivatives or analogs thereof. As used herein the term derivative or analogue of an amino acid side chain group includes modifications and variations to naturally occurring side chain groups. With reference to the table above most of the naturally occurring amino acid side chain groups may be classified as alkyl, aryl, arylalkyl or heteroalkyl moieties. As such derivatives of amino acid side chain groups include straight or branched, cyclic or non-cyclic alkyl, aryl, heteroaryl, heteroarylalkyl, arylalkyl or heteroalkyl moieties.

Amino acid side chain groups as discussed above also include optionally substituted derivatives of alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heteroalkyl moieties. The optional substituents may be selected from the group defined above. For example, the optional substituents may be selected from but are not limited to OH, Cl, Br, F, COOH, COOR^Z, CONH₂, NH₂, NHR^Z, NR^ZR^Z, SH, SR^Z, SO₂R^Z, SO₂H and SOR^Zwherein R^Zis an alkyl, aryl or arylalkyl moiety.

In the definitions of a number of substituents below it is stated that “the group may be a terminal group or a bridging group”. This is intended to signify that the use of the term is intended to encompass the situation where the group is a linker between two other portions of the molecule as well as where it is a terminal moiety. Using the term alkyl as an example, some publications would use the term “alkylene” for a bridging group and hence in these other publications there is a distinction between the terms “alkyl” (terminal group) and “alkylene” (bridging group). In the present application no such distinction is made and most groups may be either a bridging group or a terminal group.

Several terms are prefaced by the a modifier indicating the number of carbon atoms present in the moiety. For example, the modifier “C₁-C₆” in front of the term “alkyl” indicates that the alkyl moiety has from 1 to 6 carbon atoms. Further, the modifier “C₁-C₁₈” in front of the term “heteroaryl” indicates that the heteroaromatic ring may have from 1 to 18 carbon atoms as part of the total number of atoms in the ring system.

“Acyl” means an R—C(═O)— group in which the R group may be an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group as defined herein. Examples of acyl include acetyl and benzoyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.

“Acylamino” means an R—C(═O)—NH— group in which the R group may be an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.

“Alkenyl” as a group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched preferably having 2-14 carbon atoms, more preferably 2-12 carbon atoms, most preferably 2-6 carbon atoms, in the normal chain. The group may contain a plurality of double bonds in the normal chain and the orientation about each is independently E or Z. Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl. The group may be a terminal group or a bridging group.

“Alkenyloxy” refers to an alkenyl-O— group in which alkenyl is as defined herein. Preferred alkenyloxy groups are C₁-C₆alkenyloxy groups. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.

“Alkyl” as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group, preferably a C₁-C₁₄alkyl, more preferably a C₁-C₁₀alkyl, most preferably C₁-C₆unless otherwise noted. Examples of suitable straight and branched C₁-C₆alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like. The group may be a terminal group or a bridging group.

“Alkylamino” includes both mono-alkylamino and dialkylamino, unless specified. “Mono-alkylamino” means a Alkyl-NH— group, in which alkyl is as defined herein. “Dialkylamino” means a (alkyl)₂N— group, in which each alkyl may be the same or different and are each as defined herein for alkyl. The alkyl group is preferably a C₁-C₆alkyl group. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.

“Alkylaminocarbonyl” refers to a group of the formula (Alkyl)_x(H)_yNC(═O)— in which x is 1 or 2, and the sum of x+y=2. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.

“Alkyloxy” refers to an alkyl-O— group in which alkyl is as defined herein. Preferably the alkyloxy is a C₁-C₆alkyloxy. Examples include, but are not limited to, methoxy and ethoxy. The group may be a terminal group or a bridging group.

“Alkyloxyalkyl” refers to an alkyloxy-alkyl- group in which the alkyloxy and alkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.

“Alkyloxyary” refers to an alkyloxy-aryl- group in which the alkyloxy and aryl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the aryl group.

“Alkyloxycarbonyl” refers to an alkyl-O—C(═O)— group in which alkyl is as defined herein. The alkyl group is preferably a C₁-C₆alkyl group. Examples include, but are not limited to, methoxycarbonyl and ethoxycarbonyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.

“Alkyloxycycloalkyl” refers to an alkyloxy-cycloalkyl- group in which the alkyloxy and cycloalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the cycloalkyl group.

“Alkyloxyheteroary” refers to an alkyloxy-heteroaryl- group in which the alkyloxy and heteroaryl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroaryl group.

“Alkyloxyheterocycloalkyl” refers to an alkyloxy-heterocycloalkyl- group in which the alkyloxy and heterocycloalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heterocycloalkyl group.

“Alkylsulfinyl” means an alkyl-S—(═O)— group in which alkyl is as defined herein. The alkyl group is preferably a C₁-C₆alkyl group. Exemplary alkylsulfinyl groups include, but not limited to, methylsulfinyl and ethylsulfinyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.

“Alkylsulfonyl” refers to an alkyl-S(═O)₂— group in which alkyl is as defined above. The alkyl group is preferably a C₁-C₆alkyl group. Examples include, but not limited to methylsulfonyl and ethylsulfonyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.

“Alkynyl” as a group or part of a group means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched preferably having from 2-14 carbon atoms, more preferably 2-12 carbon atoms, more preferably 2-6 carbon atoms in the normal chain. Exemplary structures include, but are not limited to, ethynyl and propynyl. The group may be a terminal group or a bridging group.

“Alkynyloxy” refers to an alkynyl-O— group in which alkynyl is as defined herein. Preferred alkynyloxy groups are C₁-C₆alkynyloxy groups. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.

“Aminoalkyl” means an NH₂-alkyl- group in which the alkyl group is as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.

“Aminosulfonyl” means an NH₂—S(═O)₂— group. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.

“Aryl” as a group or part of a group denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) preferably having from 5 to 12 atoms per ring. Examples of aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C_5-7cycloalkyl or C_5-7cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl. The group may be a terminal group or a bridging group. Typically an aryl group is a C₆-C₁₈aryl group.

“Arylalkenyl” means an aryl-alkenyl- group in which the aryl and alkenyl are as defined herein. Exemplary arylalkenyl groups include phenylallyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.

“Arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl moieties are as defined herein. Preferred arylalkyl groups contain a C_1-5alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl, 1-naphthalenemethyl and 2-naphthalenemethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.

“Arylalkyloxy” refers to an aryl-alkyl-O— group in which the alkyl and aryl are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.

“Arylamino” includes both mono-arylamino and di-arylamino unless specified. Mono-arylamino means a group of formula arylNH—, in which aryl is as defined herein. di-arylamino means a group of formula (aryl)₂N— where each aryl may be the same or different and are each as defined herein for aryl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.

“Arylheteroalkyl” means an aryl-heteroalkyl- group in which the aryl and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.

“Aryloxy” refers to an aryl-O— group in which the aryl is as defined herein. Preferably the aryloxy is a C₆-C₁₈aryloxy, more preferably a C₆-C₁₀aryloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.

“Arylsulfonyl” means an aryl-S(═O)₂— group in which the aryl group is as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.

A “bond” is a linkage between atoms in a compound or molecule. The bond may be a single bond, a double bond, or a triple bond.

“Cyclic group” refers to saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or polycyclic ring system. Examples of cyclic groups include cycloalkyl, cycloalkenyl and aryl.

“Cycloalkenyl” means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. The cycloalkenyl group may be substituted by one or more substituent groups. The group may be a terminal group or a bridging group.

“Cycloalkyl” refers to a saturated monocyclic or fused or spiro polycyclic, carbocycle preferably containing from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane. The group may be a terminal group or a bridging group.

“Cycloalkylalkyl” means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as defined herein. Exemplary monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.

“Cycloalkylalkenyl” means a cycloalkyl-alkenyl- group in which the cycloalkyl and alkenyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.

“Cycloalkylheteroalkyl” means a cycloalkyl-heteroalkyl- group in which the cycloalkyl and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.

“Cycloalkyloxy” refers to a cycloalkyl-O— group in which cycloalkyl is as defined herein. Preferably the cycloalkyloxy is a C₁-C₆cycloalkyloxy. Examples include, but are not limited to, cyclopropanoxy and cyclobutanoxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.

“Cycloalkenyloxy” refers to a cycloalkenyl-O— group in which the cycloalkenyl is as defined herein. Preferably the cycloalkenyloxy is a C₁-C₆cycloalkenyloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.

“Haloalkyl” refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine. A haloalkyl group typically has the formula C_nH_(2n+1−m)X_mwherein each X is independently selected from the group consisting of F, Cl, Br and I. In groups of this type n is typically from 1 to 10, more preferably from 1 to 6, most preferably 1 to 3. m is typically 1 to 6, more preferably 1 to 3. Examples of haloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl.

“Haloalkenyl” refers to an alkenyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, Cl, Br and I.

“Haloalkynyl” refers to an alkynyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, Cl, Br and I.

“Halogen” represents chlorine, fluorine, bromine or iodine.

“Heteroalkyl” refers to a straight- or branched-chain alkyl group preferably having from 2 to 14 carbons, more preferably 2 to 10 carbons in the chain, one or more of which has been replaced by a heteroatom selected from S, O, P and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like. The group may be a terminal group or a bridging group.

“Heteroaryl” either alone or part of a group refers to groups containing an aromatic ring (preferably a 5 or 6 membered aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulphur. Examples of heteroaryl include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane, phenoxazine, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5-, or 8-quinolyl, 1-, 3-, 4-, or 5-isoquinolinyl 1-, 2-, or 3-indolyl, and 2-, or 3-thienyl. The group may be a terminal group or a bridging group.

“Heteroarylalkyl” means a heteroaryl-alkyl group in which the heteroaryl and alkyl moieties are as defined herein. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.

“Heteroarylalkenyl” means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.

“Heteroarylheteroalkyl” means a heteroaryl-heteroalkyl- group in which the heteroaryl and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.

“Heteroaryloxy” refers to a heteroaryl-O— group in which the heteroaryl is as defined herein. Preferably the heteroaryloxy is a C₁-C₁₂heteroaryloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.

“Heterocyclic” refers to saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or polycyclic ring system containing at least one heteroatom selected from the group consisting of nitrogen, sulfur and oxygen as a ring atom. Examples of heterocyclic moieties include heterocycloalkyl, heterocycloalkenyl and heteroaryl.

“Heterocycloalkenyl” refers to a heterocycloalkyl as defined herein but containing at least one double bond. The group may be a terminal group or a bridging group.

“Heterocycloalkyl” refers to a saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10 membered, more preferably 4 to 7 membered. Examples of suitable heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane, and 1,4-oxathiapane. The group may be a terminal group or a bridging group.

“Heterocycloalkylalkyl” refers to a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as defined herein. Exemplary heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.

“Heterocycloalkylalkenyl” refers to a heterocycloalkyl-alkenyl- group in which the heterocycloalkyl and alkenyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.

“Heterocycloalkylheteroalkyl” means a heterocycloalkyl-heteroalkyl- group in which the heterocycloalkyl and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.

“Heterocycloalkyloxy” refers to a heterocycloalkyl-O— group in which the heterocycloalkyl is as defined herein. Preferably the heterocycloalkyloxy is a C₁-C₆heterocycloalkyloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.

“Heterocycloalkenyloxy” refers to a heterocycloalkenyl-O— group in which heterocycloalkenyl is as defined herein. Preferably the heterocycloalkenyloxy is a C₁-C₆heterocycloalkenyloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.

“Hydroxyalkyl” refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with an OH group. A hydroxyalkyl group typically has the formula C_nH_(2n+1−x)(OH)_x. In groups of this type n is typically from 1 to 10, more preferably from 1 to 6, most preferably 1 to 3. x is typically 1 to 6, more preferably 1 to 3.

“Lower alkyl” as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 6 carbon atoms in the chain, more preferably 1 to 4 carbons such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl). The group may be a terminal group or a bridging group.

“Sulfinyl” means an R—S(═O)— group in which the R group may be OH, alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.

“Sulfinylamino” means an R—S(═O)—NH— group in which the R group may be OH, alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.

“Sulfonyl” means an R—S(═O)₂— group in which the R group may be OH, alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.

“Sulfonylamino” means an R—S(═O)₂—NH— group. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.

It is understood that included in the family of compounds of Formula (I) are isomeric forms including diastereoisomers, enantiomers, tautomers, and geometrical isomers in “E” or “Z” configurational isomer or a mixture of E and Z isomers. It is also understood that some isomeric forms such as diastereomers, enantiomers, and geometrical isomers can be separated by physical and/or chemical methods and by those skilled in the art.

Some of the compounds of the disclosed embodiments may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and /or diastereomers. All such single stereoisomers, racemates and mixtures thereof, are intended to be within the scope of the subject matter described and claimed.

The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of formula (I) wherein one or more atoms have the same atomic number as, but an atomic mass or mass number different from, the atomic mass or mass number usually found in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as ³⁵S.

Certain isotopically-labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.

Additionally, Formula (I) is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds. Thus, each formula includes compounds having the indicated structure, including the hydrated as well as the non-hydrated forms.

The term “pharmaceutically acceptable salts” refers to salts that retain the desired biological activity of the above-identified compounds, and include pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of compounds of Formula (I) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, Pa. 1995. In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.

“Prodrug” means a compound that undergoes conversion to a compound of formula (I) within a biological system, usually by metabolic means (e.g. by hydrolysis, reduction or oxidation). For example an ester prodrug of a compound of formula (I) containing a hydroxyl group may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of compounds of formula (I) containing a hydroxyl group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-β-hydroxynaphthoates, gestisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates. As another example an ester prodrug of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule. (Examples of ester prodrugs are those described by F. J. Leinweber, Drug Metab. Res.,18:379, 1987). Similarly, an acyl prodrug of a compound of formula (I) containing an amino group may be convertible by hydrolysis in vivo to the parent molecule (Many examples of prodrugs for these and other functional groups, including amines, are described in Prodrugs: Challenges and Rewards (Parts 1 and 2); Ed V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag and J Tilley; Springer, 2007).

The term “therapeutically effective amount” or “effective amount” is an amount sufficient to effect beneficial or desired clinical results. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.

The term “functional equivalent” is intended to include variants of the specific receptor described herein. It will be understood that receptors may have isoforms, such that while the primary, secondary, tertiary or quaternary structure of a given receptor isoform is different to the prototypical receptor; the molecule maintains biological activity as a receptor. Isoforms may arise from normal allelic variation within a population and include mutations such as amino acid substitution, deletion, addition, truncation, or duplication. Also included within the term “functional equivalent” are variants generated at the level of transcription.

In the methods and uses of the invention it is observed that certain of the compounds of the Formula (I), are more active than others and therefore it is desirable to use these compounds in the methods and uses of the present invention.

In the methods and uses of the invention the preferred stereochemistry at the 3 and 5 positions of the ring of the compounds of formula (I) is the 3S, 5S diastereomer. Accordingly, in one embodiment of the methods and uses of the invention the compound of formula (I) used is a compound of formula (Ia):

wherein R, R¹, R², R³, R^5a, R^5b, R⁶, R⁷, R⁸, X, Y and r are as defined in formula 1, or a pharmaceutically acceptable salt or prodrug thereof.

In the methods and uses of the invention a particularly useful subset of compounds of formula (I) are compounds of formula (Ib) as shown below.

wherein

R¹, R², R³, R^5a, R^5b, R⁶, R⁷, R⁸, X, Y and r are as defined above,

Z is a group of formula —(CR¹³R¹⁴)_q—;

R⁴is selected from the group consisting of H, C₁-C₁₂alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₆-C₁₈aryl, optionally substituted C₁-C₁₈heteroaryl, NR^4aR^4b, C(═O)R¹⁵, C(═O)NR¹⁶R¹⁷, —C(═NR¹⁶)NR¹⁷R¹⁸, SR²⁰, SC(═O)R²⁰, SO₂R²⁰, OR²⁰, ONR¹⁶R¹⁷, OCR¹⁷R¹⁸R²⁰, OC(═O)R²⁰, OC(═O)OR²⁰, OC(═O)NR¹⁶R¹⁷, and ONR¹⁶C(═NR¹⁷)NR¹⁸R¹⁹.

R^4ais selected from the group consisting of H, optionally substituted C₁-C₁₂alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionally substituted C₁-C₁₂heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₆-C₁₈aryl, optionally substituted C₁-C₁₈heteroaryl, C(═O)R^15a, C(═O)NR^15aR^16a, C(═O)OR^15a, SO₂R^15a, C(═O)H, —C(═NR^15a)—NR^16aR^17aand OR^15a,

R^4bis selected from the group consisting of H, optionally substituted C₁-C₁₂alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionally substituted C₁-C₁₂heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₆-C₁₈aryl, optionally substituted C₁-C₁₈heteroaryl, C(═O)R^15a, C(═O)NR^15aR^16a, C(═O)OR^15a, or

R^4aand R^4bwhen taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic moiety, or

one of R^4aand R^4bwhen taken together with any R¹³or R¹⁴and the atoms to which they are attached forms an optionally substituted heterocyclic moiety;

R¹³and R¹⁴are each independently selected from the group consisting of H, halogen, OH, C₁-C₁₂alkyl, C₆-C₁₈aryl, C₁-C₁₂hydroxyalkyl, C₁-C₁₂haloalkyl, C₁-C₁₂alkyloxy and C₁-C₁₂haloalkyloxy, or

when taken together with the carbon to which they are attached R¹³and R¹⁴form an optionally substituted C₃-C₁₂cycloalkyl, or an optionally substituted C₁-C₁₂heterocycloalkyl group, or

one of R¹³and R¹⁴when taken together with one of R^4a, and R^4band the atoms to which they are attached form an optionally substituted heterocyclic moiety, or

one of R¹³and R¹⁴when taken together with one of R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹or R²⁰and the atoms to which they are attached form an optionally substituted cyclic moiety;

each R¹⁵, R^15a, R¹⁶, R^16a, R¹⁷, R^17a, R¹⁸, R¹⁹and R²⁰is independently selected from the group consisting of H, optionally substituted C₁-C₁₂alkyl, optionally substituted C₁-C₁₂heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₆-C₁₈aryl, and optionally substituted C₁-C₁₈heteroaryl, or

any two of R¹⁵, R^15a, R¹⁶, R^16a, R¹⁷, R^17a, R¹⁸, R¹⁹and R²⁰when taken together with the atoms to which they are attached form an optionally substituted cyclic group, or

one of R¹⁵, R¹, R¹⁷, R¹⁸, R¹⁹and R²⁰when taken together with one of R¹³and R¹⁴and the atoms to which they are attached form an optionally substituted cyclic moiety;

q is an integer selected from the group consisting of 0, 1, 2, 3, 4, and 5;

or a pharmaceutically acceptable salt or prodrug thereof.

In the methods and uses of the invention a particularly useful subset of compounds of formula (I) are compounds where Y is a group of the formula —(CR⁹R¹⁰)_n—. In one embodiment of the suitable compounds n is 1 and Y is —CR⁹R¹⁰—. In another embodiment of the suitable compounds n is 2 and Y is —CR⁹R¹⁰CR⁹R¹⁰—.

In one embodiment of the compounds suitable for use in the invention each R⁹and R¹⁰is independently selected from H and CH₃. In one specific embodiment R⁹and R¹⁰are both H. Accordingly in one embodiment of the compounds suitable for use in the invention Y is —CH₂—. In another embodiment of compounds suitable for use in the invention Y is —CH₂CH₂—. In yet an even further embodiment of compounds suitable for use in the invention Y is —C(CH₃)₂—.

In one embodiment of the compounds suitable for use in the invention R²is H or C₁-C₆alkyl. In a specific embodiment R²is H.

In one embodiment of the compounds suitable for use in the invention R³is H or C₁-C₆alkyl. In a specific embodiment R³is H.

In one embodiment of the compounds suitable for use in the invention X is selected from the group consisting of —C(═O)— and —(CR¹¹R¹²)_s—. In one specific embodiment X is —C(═O)—. In one embodiment of the compounds suitable for use in the invention X is —(CR¹¹R¹²)_s—, s is 1. In another embodiment of compounds suitable for use in the invention X is —(CR¹¹R¹²)_s—, s is 2. In one form of each of these embodiments R¹¹and R¹²are each independently selected from the group consisting of H and C₁-C₆alkyl. In a specific embodiment both R¹¹and R¹²are H, and s is 1 such that X is —CH₂—.

In one embodiment of the compounds suitable for use in the present invention R²═H, R³═H, X═C(═O) and Y═CH₂. This provides compounds of formula (Ic).

wherein R¹, R⁴, R^5a, R^5b, R⁶, R⁷, R⁸and r are as defined above.

In one embodiment of the compounds suitable for use in the invention and in particular the compounds of formula (Ib) and (Ic) R⁴is selected from the group consisting of H, C₁-C₁₂alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, C₃-C₁₂cycloalkyl, optionally substituted C₆-C₁₈aryl, optionally substituted C-linked C₁-C₁₈heteroaryl, C(═O)R¹⁵, C(═O)NR¹⁶R¹⁷, —C(═NR¹⁶)NR¹⁷R¹⁸, SR²⁰, SC(═O)R²⁰, SO₂R²⁰, OR²⁰, ONR¹⁶R¹⁷, OCR¹⁷R¹⁸R²⁰, OC(═O)R²⁰, OC(═O)OR²⁰, OC(═O)NR¹⁶R¹⁷, and ONR¹⁶C(═NR¹⁷)NR¹⁸R¹⁹.

In one specific embodiment R⁴is optionally substituted C₁-C₁₈heteroaryl. In another embodiment R⁴is optionally substituted C₃-C₁₂cycloalkyl. In another embodiment R⁴is C₁-C₁₂alkyl

In another specific embodiment R⁴is C(═O)NR¹⁶R¹⁷.

In another specific embodiment R⁴is C(═O)NR¹⁶R¹⁷and R¹⁶and R¹⁷, when taken together with the nitrogen atom to which they are attached, form an optionally substituted C₂-C₁₂heterocycloalkyl group. In specific embodiments R¹⁵and R¹⁶when taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl group selected from the group consisting of piperidin-1-yl, pyrrolidin-1-yl, azetidin-1-yl, morpholin-4-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl and 1-azepanyl.

In one embodiment of the compounds suitable for use in the invention R¹⁶is selected from the group consisting of H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH(CH₃)CH₂CH₃, CH₂CH(CH₃)₂, C(CH₃)₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivative thereof.

In one embodiment of the compounds suitable for use in the invention R¹⁷is selected from the group consisting of H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH(CH₃)CH₂CH₃, CH₂CH(CH₃)₂, C(CH₃)₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivative thereof.

In one embodiment of the methods and uses of the invention the compound of formula (I) used is one in which R⁴═NR^4aR^4b. Accordingly a useful subset of compounds for use in the methods and uses of the present invention are compounds of formula (Id):

wherein R¹, R^4a, R^4b, R^5a, R^5b, R⁶, R⁷, R⁸, Z and r are as defined for formula (I).

In one embodiment of the compounds suitable for use in the invention, r is selected from the group consisting of 1, 2, 3, and 4. In one specific embodiment r is 1. In another specific embodiment r is 2. In yet a further specific embodiment r is 3. In an even further specific embodiment r is 4.

In one embodiment of the compounds suitable for use in the invention, R^5aand R^5bare independently selected from H and C₁-C₆alkyl. In one embodiment R^5aand R^5bare each independently selected from H and CH₃. In one specific embodiment R^5aand R^5bare both H. In yet another embodiment at least one of R^5aand R^5bwhen taken together with at least one of R⁶, R⁷and R⁸and the atoms to which they are attached form an optionally substituted cycloalkyl group. In one specific embodiment at least one of R^5aand R^5bwhen taken together with at least one of R⁶, R⁷and R⁸and the atoms to which they are attached forms a cyclohexyl group.

In one embodiment of the compounds of the invention, Y is CH₂, R²is H, R³is H, R^5aand R^5bare H, and X is —C(═O)—, and r is 1. This provides compounds of formula (II).

wherein R¹, R⁴, R⁶, R⁷, R⁸and Z are as defined for formula (I).

In one embodiment of the compounds of the invention, Y is CH₂, R²is H, is H, R^5aand R^5bare H, X is —C(═O)—, R⁴is NR^4aR^4b, and r is 1. This provides compounds of formula (IIa).

wherein R¹, R^4a, R^4b, R⁶, R⁷, R⁸, and Z are as defined for formula (I).

In the compounds of the invention Z is a group of formula —(CR¹³R¹⁴)_q—. In one embodiment of the compounds suitable for use in the invention, and in particular the compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (II) and Formula (IIa) R¹³and R¹⁴are independently selected from H and C₁-C₆alkyl. In one embodiment R¹³and R¹⁴are each independently selected from H and CH₃. In one specific embodiment R¹³and R¹⁴are both H. In yet another embodiment at least one of R¹³and R¹⁴when taken together with at least one of R^4aand R^4band the atoms to which they are attached form an optionally substituted heterocycloalkyl group. In one embodiment Z is —(CH₂)_q—

In one embodiment of the compounds suitable for use in the invention q is an integer selected from the group consisting of 0, 1, 2, 3, 4, and 5. In one specific embodiment q is 1. In another specific embodiment q is 2, in yet an even further specific embodiment q is 3, and in yet an even further specific embodiment q is 4.

Compounds in which R⁷, R¹³and R¹⁴are H and q is from 1 to 4 lead to compounds (IIIa), (IIIb), (IIIc) and (IIId) respectively.

wherein R¹, R^4a, R^4b, R⁶, and R⁸are as defined for formula (I).

In one form of the compounds suitable for use in the invention R^4ais selected from the group consisting of H, —C(═N)NH₂, —C(═N)N(CH₃)₂, —C(═N)NCH(CH₃)₂, —C(═O)CH₃, —C(═O)cyclohexyl, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH(CH₃)CH₂CH₃, CH₂CH(CH₃)₂, C(CH₃)₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivative thereof. In one form of the compounds suitable for use in the invention R^4bis selected from the group consisting of H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH(CH₃)CH₂CH₃, CH₂CH(CH₃)₂, C(CH₃)₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivative thereof.

In another form of the compounds suitable for use in the invention R^4aand R^4bwhen taken together with the nitrogen atom to which they are attached form an optionally substituted C₂-C₁₂heterocycloalkyl group, an optionally substituted C₂-C₁₂heterocycloalkenyl group or an optionally substituted C₁-C₁₈heteroaryl group.

In a particular embodiment of the compounds suitable for use in the invention R^4aand R^4bwhen taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl group selected from the group consisting of piperidin-1-yl, pyrrolidin-1-yl, azetidin-1-yl, piperazin-1-yl, morpholin-4-yl and 1-azepanyl.

In one embodiment of the methods and uses of the invention, the compound of formula (I) is one in which one of R^4aand R^4bwhen taken together with the nitrogen atom to which it is attached and one of R¹³and R¹⁴and the carbon atom to which it is attached form an optionally substituted C₂-C₁₂heterocycloalkyl group. In a particular embodiment one of R^4aand R^4bwhen taken together with the nitrogen atom to which it is attached and one of R¹³and R¹⁴and the carbon atom to which it is attached form an optionally substituted heterocycloalkyl group selected from the group consisting of piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl, and azepanyl.

Specific examples of NR^4aR^4bin the compounds which are useful in the methods and uses of the invention include:

In one embodiment of the compounds suitable for use in the invention, R⁷is H.

In one embodiment of the compounds suitable for use in the invention, R⁶and R⁸are each independently selected from the group consisting of H, optionally substituted C₁-C₁₂alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₆-C₁₈aryl and optionally substituted C₁-C₁₈heteroaryl.

In one specific embodiment of the compounds suitable for use in the invention R⁶is selected from the group consisting of H, methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, isopropenyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, 2-methylbutyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, optionally substituted phenyl and optionally substituted C₁-C₅heteroaryl

In one specific embodiment of the compounds suitable for use in the invention R⁶is optionally substituted phenyl or optionally substituted C₁-C₁₈heteroaryl.

In one specific embodiment of the compounds suitable for use in the invention R⁸is selected from the group consisting of H, methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, isopropenyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, 2-methyl-butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl, optionally substituted phenyl and optionally substituted C₁-C₅heteroaryl.

In one specific embodiment of the compounds suitable for use in the invention R⁸is methyl, ethyl, phenyl or optionally substituted C₁-C₅heteroaryl.

In one specific embodiment of the compounds suitable for use in the invention R⁶, R⁷and R⁸when taken together with the carbon to which they are attached form a moiety selected from the group consisting of optionally substituted C₂-C₁₂alkenyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₆-C₁₈aryl, and optionally substituted C₁-C₁₈heteroaryl.

In one specific embodiment of the compounds suitable for use in the invention R⁶, R⁷and R⁸when taken together with the carbon to which they are attached form an optionally substituted C₆-C₁₈aryl group.

In one specific embodiment of the compounds of the invention and specifically of the compounds of formula (I), (II) (IIa) (IIIa), (IIIb), (IIIc), and (IIId), R⁶, R⁷and R⁸when taken together with the carbon atom to which they are attached form a disubstituted phenyl group. In one embodiment the disubstituted phenyl group is a 2,4-disubstituted phen-1-yl group or a 3,5-disubstituted phen-1-yl group. A wide variety of substituents may be present on the disubstituted phenyl group as defined above. Examples of particularly suitable substituents include, but are not limited to, F, Br, Cl, methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl, phenyl, NH₂, cyano, phenoxy, hydroxy, methoxy, ethoxy, methylenedioxy, pyrrol-1-yl, and 3,5-dimethyl-pyrazol-1-yl. In one specific embodiment the disubstituted phenyl group is a 3,5-dichlorophen-1-yl group.

In one specific embodiment of the compounds suitable for use in the invention R¹is selected from the group consisting of optionally substituted C₂-C₁₂alkenyl, optionally substituted C₆-C₁₈aryl and optionally substituted C₁-C₁₈heteroaryl.

In one specific embodiment of the compounds suitable for use in the invention R¹is optionally substituted C₆-C₁₈aryl. The C₆-C₁₈aryl may be a monocyclic, bicyclic or polycyclic moiety. In certain embodiments the C₆-C₁₈aryl is a monocyclic moiety. In certain embodiments the C₆-C₁₈aryl is a bicyclic moiety.

In one specific embodiment R¹is an optionally substituted C₆-C₁₈aryl selected from the group consisting of optionally substituted phenyl, biphenyl, and optionally substituted naphthyl. The moieties may be unsubstituted or may be substituted with one or more optional substituents. A wide variety of optional substituents may be used as defined above. Examples of particularly suitable optional substituents include, but are not limited to, F, Br, Cl, methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl, phenyl, NH₂, cyano, phenoxy, hydroxy, methoxy, ethoxy, pyrrol-1-yl, and 3,5-dimethyl-pyrazol-1-yl.

The substituents may be located at any substitutable position around the aryl ring available for substitution as would be clear to a skilled addressee. Examples of suitable optionally substituted phenyl compounds include, but are not limited to, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 4-bromo-phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 4-hydroxy-phenyl, 4-phenyl-phenyl, 4-methyl-phenyl, 2,4-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-dichloro-phenyl, 2,6-difluoro-phenyl, 2-chloro-6-fluoro-phenyl, 3-fluoro-4-chloro-phenyl, 3-methyl-4-chloro-phenyl, 3-chloro-4-fluoro-phenyl, 3-chloro-4-methyl-phenyl, 2-hydroxy-phenyl, 3-hydroxy-phenyl, 4-hydroxy-phenyl, 4-ethoxy-phenyl, 3-phenoxy-phenyl, 4-phenoxy-phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 4-isopropyl-phenyl, 4-cyano-phenyl 3,4-dimethyl-phenyl, 2,4-dimethyl-phenyl, 4-t-butyl-phenyl, 2,4-dimethoxy-phenyl, and 3,4-methylenedioxy-phenyl.

When R¹is optionally substituted biphenyl the point of attachment of R¹to the remainder of the molecule may be at the 2-, 3- or 4-position relative to the point of attachment of the second phenyl ring. As such the biphenyl may be an optionally substituted biphen-2-yl, or an optionally substituted biphen-3-yl, or an optionally substituted biphen-4-yl. In general the optionally substituted biphenyl is an optionally substituted biphen-4-yl. The optionally substituted biphenyl may be substituted in any suitable position.

When R¹is optionally substituted naphthyl the point of attachment of R¹to the remainder of the molecule may be at the 1 or 2 position. As such the naphthyl may be an optionally substituted naphth-1-yl, or an optionally substituted naphth-2-yl. In general the optionally substituted naphthyl is an optionally substituted naphth-2-yl. The optionally substituted naphthyl may be substituted in any suitable position. Examples of suitable optionally substituted naphth-2-yls include, but are not limited to, 6-fluoro-naphth-2-yl, 6-bromo-naphth-2-yl, 6-chloro-naphth-2-yl, 1-methoxy-naphth-2-yl, 3-methoxy-naphth-2-yl, 6-methoxy-naphth-2-yl, 1-hydroxy-naphth-2-yl, and 6-amino-naphth-2-yl.

In one specific embodiment of the compounds suitable for use in the invention R¹is optionally substituted C₁-C₁₈heteroaryl. The C₁-C₁₈heteroaryl may be a monocyclic, bicyclic or polycyclic moiety. In certain embodiments the C₁-C₁₈heteroaryl is a monocyclic moiety. In certain embodiments the C₁-C₁₈heteroaryl is a bicyclic moiety. Examples of suitable heteroaryl moieties include, but are not limited to, indol-2-yl, indol-3-yl quinolin-2-yl quinolin-3-yl, isoquinolin-3-yl, quinoxaline-2-yl, benzo[b]furan-2-yl, benzo[b]thiophen-2-yl, benzo[b]thiophen-5-yl, thiazole-4-yl, benzimidazole-5-yl, benzotriazol-5-yl, furan-2-yl, benzo[d]thiazole-6-yl, pyrazole-1-yl, pyrazole-4-yl and thiophen-2-yl. These may also be optionally substituted as discussed above.

In one specific embodiment of the compounds suitable for use in the invention R¹is an optionally substituted C₂-C₁₂alkenyl. The optionally substituted alkenyl may contain one or more double bonds with each of the double bonds being independently in the E or Z configuration. In one embodiment of the invention the alkenyl contains a single double bond which is in the E configuration.

In one specific form of this embodiment R¹is an optionally substituted C₂-C₁₂alkenyl of the formula:

R^1ais selected from the group consisting of H, halogen and optionally substituted C₁-C₁₂alkyl;

R^1band R^1care each independently selected from the group consisting of H, halogen, optionally substituted C₁-C₁₂alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionally substituted C₁-C₁₂heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₆-C₁₈aryl, and optionally substituted C₁-C₁₈heteroaryl.

In one form of this embodiment R^1ais H. In one form of this embodiment R^1bis H. This provides compounds where R¹is of the formula:

In one embodiment of the compounds of the invention R^1cis optionally substituted C₆-C₁₈aryl. The C₆-C₁₈aryl may be monocyclic, bicyclic or polycyclic moiety. In certain embodiments the C₆-C₁₈aryl is a monocyclic moiety. In certain embodiments the C₆-C₁₈aryl is a bicyclic moiety.

In one specific embodiment R^1cis an optionally substituted C₆-C₁₈aryl selected from the group consisting of optionally substituted phenyl and optionally substituted naphthyl. The moieties may be unsubstituted or may be substituted with one or more optional substituents. A wide variety of optional substituents may be used as defined above. Examples of particularly suitable optional substituents include, but are not limited to, F, Br, Cl, methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl, phenyl, NH₂, cyano, phenoxy, hydroxy, methoxy, ethoxy, methylenedioxy, pyrrol-1-yl, and 3,5-dimethyl-pyrazol-1-yl.

Specific compounds suitable for use in the methods and uses of the invention include the following:

or a pharmaceutically acceptable salt or prodrug thereof.

In order to assist the reader the names of compounds suitable for use in the invention as discussed above are as follows:

(14) N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(25) N-(((3S,5S)-3-(2-(diethylamino)ethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide
(31) N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide
(33) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
(37) N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-(2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(38) N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(39) N-(((3S,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(49) N-(((3S,5S)-3-(2-aminoethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(50) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)naphthalene-2-sulfonamide
(54) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(60) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-bromo-N-methyl-2-naphthamide
(62) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-4-methyl-2-oxo-1,4-diazepan-5-yl)methyl)-6-bromo-2-naphthamide
(63) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(64) N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(65) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-(isopropylamino)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(67) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-(3-methylguanidino)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(71) (E)-N-(((3S,5S)-3-butyl-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
(79) N—((S)-1-((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethyl)acetamide
(81) (S)-2-acetamido-N-—(S)-1-((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethyl)-3-(1H-imidazol-5-yl)propanamide
(83) propyl (S)-1-((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethylcarbamate
(85) N—((R)-1-((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethyl)acetamide
(86) (S)-2-acetamido-N—((R)-1-((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethyl)-3-(1H-imidazol-4-yl)propanamide
(87) propyl (R)-1-((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethylcarbamate
(102) N-(((3R,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(103) N-(((3R,5R)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(104) N-(((3S,5R)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(105) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(106) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)biphenyl-4-carboxamide
(107) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1H-indole-2-carboxamide
(108) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)biphenyl-4-carboxamide
(109) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1H-indole-2-carboxamide
(110) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(naphthalen-2-yl)acetamide
(111) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide
(112) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)quinoline-3-carboxamide
(113) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)quinoxaline-2-carboxamide
(114) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)isoquinoline-3-carboxamide
(115) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
(116) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5yl)methyl)quinoline-2-carboxamide
(117) N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalen-1-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(118) N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalen-1-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(naphthalen-2-yl)acetamide
(119) N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalen-1-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1-naphthamide
(120) N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalen-1-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(1H-indol-3-yl)acetamide
(121) N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalen-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(biphenyl-4-yl)acetamide
(122) N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalen-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(123) N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalen-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(naphthalen-2-yl)acetamide
(124) N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalen-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1-naphthamide
(125) N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalen-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(naphthalen-1-yl)acetamide
(126) N-(((3S,5S)-3-(4-aminobutyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(127) (S)—N-(((3S,5S)-3-(4-aminobutyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
(128) (R)—N-(((3S,5S)-3-(4-aminobutyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
(129) N-(((3S,5S)-3-(4-aminobutyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzofuran-2-carboxamide
(130) (R)—N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-(3-methylguanidino)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
(131) (S)—N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
(132) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzofuran-2-carboxamide
(133) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2,3-dihydro-1H-indene-2-carboxamide
(134) (R)—N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
(135) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzo[b]thiophene-2-carboxamide
(136) 2,4-dichloro-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
(137) 2,5-dichloro-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
(138) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
(139) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)cyclohexanecarboxamide
(140) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-phenoxybenzamide
(141) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-4-phenoxybenzamide
(142) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1H-indole-2-carboxamide
(143) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-phenylpropanamide
(144) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dimethylbenzamide
(145) 4-tert-butyl-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
(146) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2,4-dimethoxybenzamide
(147) 2-cyclohexyl-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)acetamide
(148) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide
(149) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1H-benzo[d]imidazole-5-carboxamide
(150) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1H-benzo[d][1,2,3]triazole-5-carboxamide
(151) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)cyclopentanecarboxamide
(152) 3,4-dichloro-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
(153) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)cinnamamide
(154) 3,5-dichloro-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
(155) 2-(2,4-dichlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)acetamide
(156) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1-methoxy-2-naphthamide
(157) 2-(3,4-dichlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)acetamide
(158) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-methoxy-2-naphthamide
(159) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(2-(guanidinooxy)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(160) (E)-3-(2,4-dichlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidino-propyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
(161) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-adamantane-1-carboxamide
(162) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-phenoxyacetamide
(163) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-methoxy-2-naphthamide
(164) 4-bromo-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
(165) (S)—N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxine-2-carboxamide
(166) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
(167) (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(thiophen-2-yl)acrylamide
(168) (R)—N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxine-2-carboxamide
(169) (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-hydroxyphenyl)acrylamide
(170) (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2-methoxyphenyl)acrylamide
(171) (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-p-tolylacrylamide
(172) (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2-(trifluoromethyl)phenyl)acrylamide
(173) (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(3-fluorophenyl)acrylamide
(174) (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-methyl-3-phenylacrylamide
(175) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-phenylcyclopropanecarboxamide
(176) 2-(2,4-dichlorophenoxy)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)acetamide
(177) (E)-3-(3-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
(178) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzo[d]thiazole-6-carboxamide
(179) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-5-phenylfuran-2-carboxamide
(180) (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(3-methoxyphenyl)acrylamide
(181) 6-bromo-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(182) N-(((3S,5S)-3-(3-guanidinopropyl)-2-oxo-1-phenethyl-1,4-diazepan-5-yl)methyl)-2-naphthamide
(183) N-(((3S,5S)-1-(3,4-dichlorophenethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(184) N-(((3S,5S)-1-(2,4-dichlorophenethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(185) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzo[b]th iophene-5-carboxamide
(186) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide
(187) (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-methoxyphenyl)acrylamide
(188) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide
(189) (E)-3-(2-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
(190) (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2-hydroxyphenyl)acrylamide
(191) (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-m-tolylacrylamide
(192) (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(3-(trifluoromethyl)phenyl)acrylamide
(193) (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(3-hydroxyphenyl)acrylamide
(194) (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2-fluorophenyl)acrylamide
(195) (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-o-tolylacrylamide
(196) (Z)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-fluoro-3-phenylacrylamide
(197) N-((1-(2,2-diphenylethyl)-2-oxo-3-(piperidin-4-yl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(198) N-((1-(2,2-diphenylethyl)-2-oxo-3-(piperidin-4-ylmethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(199) (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide
(200) (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-(trifluoromethyl)phenyl)acrylamide
(201) N-(((3S,5S)-1-(2,2-diphenylpropyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(202) N-(((3S,5S)-1-(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(203) N-(((3S,5S)-1-(1-adamantylmethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(204) N-(((3S,5S)-1-((S)-1,1-diphenylpropan-2-yl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(205) N-(((3S,5S)-1-((R)-1,1-diphenylpropan-2-yl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(206) N-(((3S,5S)-1-cyclohexyl-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(207) N-(((3S,5S)-1-((R)-1-fluoro-1,1-diphenylpropan-2-yl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(208) (E)-3-(2,6-difluorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
(209) (E)-3-(2-chloro-6-fluorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
(210) (E)-3-(4-bromophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
(211) (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-ethoxyphenyl)acrylamide
(212) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-bromo-2-naphthamide
(213) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)cinnamamide
(214) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
(215) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1,4-dimethoxy-2-naphthamide
(216) N-(((3S,5S)-3-(3-(3,3-dimethylguanidino)propyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(217) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-hydroxy-2-naphthamide
(218) 6-amino-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(219) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-p-tolylacrylamide
(220) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide
(221) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide
(222) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-ethylhexanamide
(223) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dimethylbenzamide
(224) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide (225) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-ethylhexanamide
(226) N-(((3S,5S)-3-(3-(cyclohexylamino)propyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(227) N-(((3S,5S)-3-(3-guanidinopropyl)-1-(naphthalen-2-yl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(228) N-(((3S,5S)-1-((9H-fluoren-9-yl)methyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(229) N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(pyridin-3-yl methyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(230) N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(pyridin-4-ylmethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(231) (E)-N-(((3S,5S)-3-(3-(cyclohexylamino)propyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide
(232) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(4-(isopropylamino)butyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(233) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2,4-difluorophenyl)acrylamide
(234) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-cyanophenyl)acrylamide
(235) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(naphthalen-2-yl)acrylamide
(236) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(4-fluorophenoxy)acetamide
(237) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-5-(4-chlorophenyl)furan-2-carboxamide
(238) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-4-(1H-pyrrol-1-yl)benzamide
(239) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-oxo-1-phenylpyrrolidine-3-carboxamide
(240) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-5-(4-chlorophenyl)isoxazole-3-carboxamide
(241) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-5-(furan-2-yl)isoxazole-3-carboxamide
(242) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-phenylthiazole-4-carboxamide
(243) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-4-(3,5-dimethyl-1H-pyrazol-1-yl)benzamide
(244) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide
(245) N-(((3S,5S)-1-(2-cyclohexylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(246) N-(((3S,5S)-1-(2-(bicyclo[2.2.1]heptan-2-yl)ethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(247) N-(((3S,5S)-1-(2,2-bis(4-methoxyphenyl)ethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(248) N-(((3S,5S)-3-(3-(benzylamino)propyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(249) N-(((3S,5S)-3-(3-(cyclopentylamino)propyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(250) N-(((3S,5S)-3-(3-(cyclobutylamino)propyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(251) N-(((3S,5S)-3-(3-(dicyclobutylamino)propyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(252) N-(((3S,5S)-1-benzyl-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(253) N-(((3S,5S)-1-(2,2-bis(4-fluorophenyl)ethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(254) N-(((3S,5S)-3-(3-guanidinopropyl)-1-(naphthalen-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(255) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(5-methylthiophen-2-yl)acrylamide
(256) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-phenyl-1H-pyrazole-5-carboxamide
(257) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)-N-methylacrylamide
(258) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-4-methyl-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide
(259) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-4-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzamide
(260) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-bromophenyl)acrylamide
(261) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-(pyrrolidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)acrylamide
(262) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)acrylamide
(263) N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(264) N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-(pyrrolidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(265) N-(((3S,5S)-3-(3-(azetidin-1-yl)propyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(266) N-(((3S,5S)-3-(3-guanidinopropyl)-1-(naphthalen-1-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(267) N-(((3S,5S)-3-(3-guanidinopropyl)-1-(2-(naphthalen-2-yl)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(268) N-(((3S,5S)-1-((S)-2-acetamido-2-phenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(269) N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)cinnamamide
(270) N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-3,4-dimethylbenzamide
(271) 3,4-dichloro-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)benzamide
(272) N-(((3S,5S)-1-((S)-2-(cyclobutanecarboxamido)-2-phenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(273) N-(((3S,5S)-1-((S)-2-(cyclohexanecarboxamido)-2-phenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(274) N-(((3S,5S)-3-(aminomethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(275) (E)-N-(((3S,5S)-3-(aminomethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
(276) (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide
(277) (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-p-tolylacrylamide
(278) N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(piperidin-1-ylmethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(279) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(piperidin-1-ylmethyl)-1,4-diazepan-5-yl)methyl)acrylamide
(280) N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
(281) N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dimethylbenzamide
(282) N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)cinnamamide
(283) (E)-N-(((3S,5S)-3-(2-aminoethyl)-l-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
(284) 3,4-dichloro-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
(285) N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3,4-dimethylbenzamide
(286) N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)cinnamamide
(287) (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide
(288) (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-p-tolylacrylamide
(289) N-(((3S,5S)-1-(3,5-dimethylbenzyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(290) N-(((3S,5S)-1-((S)-2-benzamido-2-phenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(291) N-(((3S,5S)-1-((R)-2-benzamido-2-phenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(292) N-(((3S,5S)-3-(3-guanidinopropyl)-1-(2-methoxy-2-phenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(293) N-(((3S,5S)-3-(3-guanidinopropyl)-2-oxo-1-(2-phenyl-2-propoxyethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(294) N-(((3S,5S)-1-(2-(benzyloxy)-2-phenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(295) N-(((3S,5S)-1-(2-(allyloxy)-2-phenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(296) N-(((3S,5S)-3-butyl-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(297) (E)-N-(((3S,5S)-3-butyl-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
(298) (E)-N-(((3S,5S)-3-(3-amino-3-oxopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
(299) N-(((3S,5S)-3-(3-amino-3-oxopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(300) (E)-N-(((3S,5S)-3-(3-acetamidopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-p-tolylacrylamide
(301) N-(3-((2S,7S)-4-(2,2-diphenylethyl)-3-oxo-7-(((E)-3-p-tolylacrylamido)methyl)-1,4-diazepan-2-yl)propyl)cyclohexanecarboxamide
(302) N-(((3S,5S)-3-(3-guanidinopropyl)-2-oxo-1-(2-phenoxy-2-phenylethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(303) ethyl 3-((3S,5S)-5-((2-naphthamido)methyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-1-yl)-2-phenylpropanoate
(304) N-(((3S,5S)-1-(2-ethylbutyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(305) N-(((3S,5S)-1-((3,5-dimethylcyclohexyl)methyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(306) N-(2-((2S,7S)-7-(((E)-3-(4-chlorophenyl)acrylamido)methyl)-4-(2,2-diphenylethyl)-3-oxo-1,4-diazepan-2-yl)ethyl)cyclohexanecarboxamide
(307) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-3-(2-(2-cyclohexylacetamido)ethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
(308) N-(2-((3S,5R)-1-(2,2-diphenylethyl)-2-oxo-3-(2-aminoethyl)-1,4-diazepan-5-yl)ethyl)benzamide
(309) 3,4-dichloro-N-(2-((3S,5R)-1-(2,2-diphenylethyl)-2-oxo-3-(2-aminoethyl)-1,4-diazepan-5-yl)ethyl)benzamide
(310) N-(2-((3S,5R)-1-(2,2-diphenylethyl)-2-oxo-3-(2-aminoethyl)-1,4-diazepan-5-yl)ethyl)-2-naphthamide
(311) N-(2-((3S,5R)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)ethyl)benzamide
(312) 3,4-dichloro-N-(2-((3S,5R)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)ethyl)benzamide
(313) N-(2-((3S,5R)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)ethyl)-2-naphthamide
(314) N-(((3S,5S)-1-(3-(dimethylamino)-3-oxo-2-phenylpropyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(315) N-(((3S,5S)-3-(cyclohexylmethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(316) N-(((3S,5S)-3-(2-aminoethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(317) N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-oxo-3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(318) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-oxo-3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)acrylamide
(319) N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-phenethyl-1,4-diazepan-5-yl)methyl)-2-naphthamide
(320) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-phenethyl-1,4-diazepan-5-yl)methyl)acrylamide
(321) N-(((3S,5S)-3-(2-cyclohexylethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(322) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-3-(2-cyclohexylethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
(323) N-(((3S,5S)-3-benzyl-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(324) (E)-N-(((3S,5S)-3-benzyl-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
(325) N-(((3S,5S)-3-(2-aminoethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
(326) (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
(327) N-(((3S,5S)-1-(3-chloro-5-fluorobenzyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(328) N-(((3S,5S)-1-(3,5-difluorobenzyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(329) N-(((3S,5S)-3-(3-aminopropyl)-1-(3-chloro-5-fluorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(330) N-(((3S,5S)-3-(3-aminopropyl)-1-(3,5-difluorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(331) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(332) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,6-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(333) N-(((3S,5S)-3-(3-aminopropyl)-1-(3,5-dimethoxybenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(334) N-(((3S,5S)-3-(3-aminopropyl)-1-(2-chlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(335) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,3-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(336) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,4-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(337) N-(((3S,5S)-3-(3-aminopropyl)-1-(3,4-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(338) N-(((3S,5S)-3-(3-aminopropyl)-1-(3-fluoro-5-methylbenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(339) N-(((3S,5S)-3-(3-aminopropyl)-1-(3-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(340) N-(((3S,5S)-3-(3-aminopropyl)-1-(4-chlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(341) N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-(2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(342) N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-((1-phenylcyclohexyl)methyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(343) 3,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide 4
(344) N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(345) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
(346) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
(347) (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
(348) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
(349) 3,4-dichloro-N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
(350) N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(351) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-4-chloro-3-fluorobenzamide
(352) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-4-chloro-3-methylbenzamide
(353) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-chloro-4-fluorobenzamide
(354) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-chloro-4-methylbenzamide
(355) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(piperidin-1-ylmethyl)-1,4-diazepan-5-yl)methyl)acrylamide
(356) N-(2-((3S,5R)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)-1,4-diazepan-5-yl)ethyl)-2-naphthamide
(357) N-(((3S,5S)-3-(3-aminopropyl)-1-(3,5-bis(trifluoromethyl)benzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(358) N-(((3S,5S)-3-(3-aminopropyl)-1-(3-chlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(359) N-(((3S,5S)-2-oxo-1-(2-phenylbutyl)-3-(3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(360) N-(((3S,5S)-3-(3-guanidinopropyl)-2-oxo-1-(3-oxo-2-phenyl-3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(361) N-(((3S,5S)-3-(3-guanidinopropyl)-2-oxo-1-(3-oxo-2-phenyl-3-(phenylamino)propyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(362) 3,4-dichloro-N-(2-((3S,5R)-1-(2,2-diphenylethyl)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)ethyl)benzamide
(363) 3,4-dichloro-N-(2-((3S,5R)-3-(2-(diisopropylamino)ethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)ethyl)benzamide
(364) N-(((3S,5S)-3-(aminomethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
(365) N-(((3S,5S)-3-(aminomethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(366) (E)-N-(((3S,5S)-3-(aminomethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
(367) 3,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(piperidin-1-ylmethyl)-1,4-diazepan-5-yl)methyl)benzamide
(368) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(piperidin-1-ylmethyl)-1,4-diazepan-5-yl)methyl)acrylamide
(369) N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-(2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
(370) (E)-N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-(2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
(371) 3,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(pyrrolidin-1-ylmethyl)-1,4-diazepan-5-yl)methyl)benzamide
(372) N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(pyrrolidin-1-ylmethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(373) N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-((S)-2-phenylpropyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(374) N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-((R)-2-phenyl propyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(375) N-(((3S,5S)-3-(2-(dimethylamino)ethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(376) N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide
(377) N-(((3S,5S)-3-(3-aminopropyl)-1-(3,5-diethynylbenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(378) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-3-(2-(diethylamino)ethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
(379) N-(((3S,5S)-3-(2-(diethylamino)ethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(380) 3,4-dichloro-N-(((3S,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
(381) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
(382) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
(383) N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide
(384) N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(385) N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(386) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide
(387) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide
(388) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-bromo-2-naphthamide
(389) N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide
(390) 6-chloro-N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(391) 6-bromo-N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(392) N-(((3S,5S)-3-(2-aminoethyl)-1-((3,5-dimethylcyclohexyl)methyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
(393) N-(((3S,5S)-3-(2-aminoethyl)-1-((3,5-dimethylcyclohexyl)methyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(394) (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-((3,5-dimethylcyclohexyl)methyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
(395) 6-chloro-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(396) N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide
(397) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
(398) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
(399) N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(400) 3,4-dichloro-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
(401) N-(((3S,5S)-3-(3-aminopropyl)-1-((2,6-dimethylcyclohexyl)methyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(402) N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-l -((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(403) 3,4-dichloro-N-(((3S,5S)-1-((3,5-dimethylcyclohexyl)methyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
(404) 3,4-dichloro-N-(((3S,5S)-1-((3,5-dimethylcyclohexyl)methyl)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
(405) N-(((3S,5S)-3-(2-aminoethyl)-1-(3-methyl-2-phenylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(406) N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(407) N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-((R)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(408) (E)-N-(((3S,5S)-3-((1H-imidazol-4-yl)methyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
(409) 3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)propanamide
(410) N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)propanamide
(411) N-(((2S,7S)-7-(((E)-3-(4-chlorophenyl)acrylamido)methyl)-4-(2,2-diphenylethyl)-3-oxo-1,4-diazepan-2-yl)methyl)picolinamide
(412) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(pyridin-2-ylmethyl)-1,4-diazepan-5-yl)methyl)acrylamide
(413) N-(((3S,5S)-1-((R)-3-methyl-2-phenylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(414) N-(((3S,5S)-1-((S)-3-methyl-2-phenylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(415) (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-(4-isopropyl phenyl)acrylamide
(416) (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-isopropylphenyl)acrylamide
(417) (E)-3-(2,4-dimethylphenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
(418) (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2,4-dimethylphenyl)acrylamide
(419) (E)-3-(2,4-difluorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
(420) (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2,4-difluorophenyl)acrylamide
(421) N-(((2S,7S)-7-(((E)-3-(4-chlorophenyl)acrylamido)methyl)-4-(2,2-diphenylethyl)-3-oxo-1,4-diazepan-2-yl)methyl)cyclohexanecarboxamide
(422) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(2-morpholinoethyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
(423) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-3-(2-(2,5-dimethyl-1H-pyrrol-1-yl)ethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
(424) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-3-(2-(2,5-dimethylpyrrolidin-1-yl)ethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
(425) 6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(426) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(pyrrolidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
(427) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-3-(2-(isopropylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)acrylamide
(428) 6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(pyrrolidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(429) 3,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
(430) 3,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(pyrrolidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
(431) benzyl ((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methylcarbamate
(432) (E)-3-(4-bromophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
(433) 5-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)isoxazole-3-carboxamide
(434) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-oxo-2-(pyridin-2-ylamino)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
(435) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-oxo-2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
(436) 6-chloro-N-(((3S,5S)-2-oxo-3-(3-oxo-3-(piperidin-1-yl)propyl)-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(437) 3,4-dichloro-N-(((3S,5S)-2-oxo-3-(3-oxo-3-(piperidin-1-yl)propyl)-1-((S)-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide
(438) 6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(piperidin-1-ylmethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(439) 3,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(piperidin-1-ylmethyl)-1,4-diazepan-5-yl)methyl)benzamide
(440) 6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(441) 3,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)benzamide
(442) (E)-N-(2-((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)propan-2-yl)-3-(4-chlorophenyl)acrylamide
(443) (E)-3-(4-chlorophenyl)-N-(2-((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)propan-2-yl)acrylamide
(444) N-(((3S,5S)-3-(2-aminoethyl)-1-((R)-2-(4-chlorophenyl)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(445) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-(4-chlorophenyl)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(446) N-(((3S,5S)-1-((R)-2-(4-chlorophenyl)propyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(447) N-(((3S,5S)-1-((S)-2-(4-chlorophenyl)propyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(448) 3,4-dichloro-N-(((3S,5S)-3-(2-(methyl(phenyl)amino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide
(449) 3,4-dichloro-N-(((3S,5S)-3-(2-(diethylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide
(450) 3,4-dichloro-N-(((3S,5S)-3-(2-morpholinoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide
(451) 3,4-dichloro-N-(((3S,5S)-2-oxo-3-(2-(phenylamino)ethyl)-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide
(452) N-(((3S,5S)-3-(2-(benzylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
(453) (5S,9aS)-5-(2-aminobenzyl)-2-((E)-3-(4-chlorophenyl)acryloyl)-7-(2,2-diphenylethyl)hexahydro-1H-imidazo[1,5-d][1,4]diazepin-6(5H)-one
(454) N-(((3S,5S)-3-(2-(tert-butylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
(455) 3,4-dichloro-N-(((3S,5S)-3-(2-(4-methyl piperazin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide
(456) N-(((3S,5S)-2-oxo-1-((R)-2-phenylpentyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(457) N-(((3S,5S)-2-oxo-1-((S)-2-phenyl pentyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(458) N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-4-(trifluoromethyl)benzamide
(459) N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-4-(trifluoromethyl)benzamide
(460) N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-(trifluoromethyl)benzamide
(461) N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(trifluoromethyl)benzamide
(462) 6-chloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(463) 3,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
(464) 6-chloro-N-(((3S,5S)-3-(2-(isopropylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(465) N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide
(466) N-(((3S,5S)-3-(2-aminobenzyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(467) N-(((3S,5S)-3-(2-(benzyl(methyl)amino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
(468) 3,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperazin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
(469) 3,4-dichloro-N-(((3S,5S)-3-(2-(methyl (pentyl)amino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide
(470) 3,4-dichloro-N-(((3S,5S)-3-(2-(diisopropylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide
(471) 3,4-dichloro-N-(((3S,5S)-3-(2-(4-methylpiperidin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide
(472) (S)-6-chloro-N-((2-oxo-1-(2-phenylbutyl)-3-(piperidin-4-yl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(473) (S)-6-chloro-N-(3-(1-isopentylpiperidin-4-yl)-2-oxo-1-(2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(474) N-(((3S,5S)-3-butyl-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide
(475) 6-chloro-N-(((3S,5S)-3-isopentyl-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(476) 3,4-dichloro-N-(((3S,5S)-3-(2-(3,5-dimethylpiperidin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide
(477) 3,4-dichloro-N-(((3S,5S)-3-(2-(4-hydroxypiperidin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide
(478) 1-(2-((2S,7S)-7-((3,4-dichlorobenzamido)methyl)-3-oxo-4-((S)-2-phenylbutyl)-1,4-diazepan-2-yl)ethyl)piperidine-4-carboxylic acid
(479) N-(((3S,5S)-3-(2-(azepan-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
(480) 3,4-dichloro-N-(((3S,5S)-3-(2-((S)-2-methylpiperidin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide
(481) N-(((3S,5S)-3-(2-(tert-butyl(methyl)amino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
(482) N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)benzyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(483) N-(((3S,5S)-3-(3-(butyl(methyl)amino)-3-oxopropyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(484) N-(((3S,5S)-3-(3-(cyclohexylamino)-3-oxopropyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(485) 6-chloro-N-((3-(1-ethylpiperidin-4-yl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(486) (3S,5S)-5-((3,4-dichlorobenzylamino)methyl)-1-(2,2-diphenylethyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-2-one
(487) 6-chloro-N-(((3S,5S)-3-(2-guanidinoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(488) 6-chloro-N-(((3S,5S)-3-(2-(3-methylguanidino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(489) N-(((3S,5S)-3-(2-aminoethyl)-1-((R)-2-ethyl-3-methylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
(490) N-(((3S,5S)-3-(2-aminoethyl)-1-((S)-2-ethyl-3-methylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
(491) 3,4-dichloro-N-(((3S,5S)-1-((R)-2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
(492) 3,4-dichloro-N-(((3S,5S)-1-((S)-2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
(493) N-(((3S,5S)-3-(2-amino-2-methylpropyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide
(494) N-(((3R,5R)-3-(2-amino-2-methylpropyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide
(495) N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
(496) 3,4-dichloro-N-(((3S,5S)-3-(2-(isopropylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide
(497) N-(((3S,5S)-3-(2-aminoethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide
(498) 6-chloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(499) 6-chloro-N-(((3S,5S)-3-(2-methyl-2-(piperidin-1-yl)propyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(500) 6-chloro-N-(((3R,5R)-3-(2-methyl-2-(piperidin-1-yl)propyl)-2-oxo-1-((S)-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(501) N-(((3S,5S)-3-(2-aminoethyl)-1-((R)-2-ethyl-3-methylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide
(502) N-(((3S,5S)-3-(2-aminoethyl)-1-((S)-2-ethyl-3-methylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide
(503) 6-chloro-N-(((3S,5S)-1-((R)-2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(504) 6-chloro-N-(((3S,5S)-1-((S)-2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(505) 6-chloro-N-(((3S,5S)-3-(2-cyclohexylethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(506) 6-chloro-N-(((3S,5S)-3-hexyl-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(507) 6-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methylcarbamoyl)-2-naphthoic acid
(508) 6-chloro-N-(((3S,5S)-3-(2-(3-isopropylguanidino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(509) 6-chloro-N-(((3S,5S)-3-(4-hydroxybutyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(510) 6-chloro-N-(((3S,5S)-3-(2-methoxyethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(511) N-(((3S,5S)-3-(2-(benzyloxy)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide
(512) 6-chloro-N-(((3S,5S)-3-isobutyl-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(513) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethyl-3-methylbut-3-enyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
(514) 3,4-dichloro-N-(((3S,5S)-1-(2-ethyl-3-methylbut-3-enyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
(515) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethyl-3-methylbut-3-enyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide
(516) 6-chloro-N-(((3S,5S)-1-((R)-2-ethyl-3-methylbut-3-enyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(517) 6-chloro-N-(((3S,5S)-1-((S)-2-ethyl-3-methylbut-3-enyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(518) N-(((3S,5S)-1-(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)biphenyl-4-carboxamide
(519) N-(((3S,5S)-1-(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(1H-indol-3-yl)acetamide
(520) N-(((3S,5S)-1-(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)quinoline-3-carboxamide
(521) 3,4-dichloro-N-(((3S,5S)-3-(2-(4,4-difluoropiperidin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide
(522) 3,4-dichloro-N-(((3S,5S)-3-(2-hydroxyethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide
(523) 3,4-dichloro-N-(((3S,5S)-3-(2-(3,3-difluoropiperidin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide
(524) (3S,5S)-5-((3,4-dichlorobenzylamino)methyl)-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-2-one
(525) 3,4-dichloro-N-(((3S,5S)-1-(2-cyclopropylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
(526) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-cyclopropylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide
(527) 6-chloro-N-(((3S,5S)-1-(2-cyclopropylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(528) 3,4-dichloro-N-(((3S,5S)-3-(2-(2,5-dioxopyrrolidin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide
(529) 6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(3-ureidopropyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(530) 3,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(1,1,1-trifluoropropan-2-ylamino)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
(531) 3,4-dichloro-N-(((3S,5S)-3-(2-(3,3-dimethyl-2,5-dioxopyrrolidin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide
(532) N-(((3S,5S)-3-(2-(azepan-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide
(533) 6-chloro-N-(((3S,5S)-3-(2-(3-isopropylureido)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(534) N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)biphenyl-4-carboxamide
(535) N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-phenylthiazole-4-carboxamide
(536) 4′-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)biphenyl-2-carboxamide
(537) 6-chloro-N-(((3S,5S)-3-(2-(N-isopropylacetamido)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(538) 6-chloro-N-(((3S,5S)-3-((isopropylamino)methyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(539) 6-chloro-N-(((3S,5S)-3-(guanidinomethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(540) 2-(2,4-dichlorophenyl)-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acetamide
(541) N-(((3S,5S)-3-(2-aminoethyl)-1-(2,4-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
(542) 3,4-dichloro-N-(((3S,5S)-1-(2,4-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
(543) 3,4-dichloro-N-(((3S,5S)-1-(2,4-dichlorobenzyl)-3-(2-(methylsulfonamido)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
(544) 3,4-dichloro-N-(((3S,5S)-1-(2,4-dichlorobenzyl)-3-(2-(4-methylphenylsulfonamido)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
(545) N-(((3S,5S)-3-(2-((S)-2-amino-3-methylbutanamido)ethyl)-1-(2,4-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
(546) N-(((3S,5S)-3-(2-aminoethyl)-1-(2,4-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide
(547) 6-chloro-N-(((3S,5S)-1-(2,4-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(548) N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-(2-(thiophen-3-yl)butyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide
(549) 6-chloro-N-(((3S,5S)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1-((R)-2-(thiophen-3-yl)butyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(550) 6-chloro-N-(((3S,5S)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1-((S)-2-(thiophen-3-yl)butyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(551) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethyl-2-methylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide
(552) 6-chloro-N-(((3S,5S)-1-(2-ethyl-2-methylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(553) 6-chloro-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(2-morpholinoethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(554) 6-chloro-N-(((3S,5S)-3-(2-morpholinoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(555) 6-chloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(2-morpholinoethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide
(556) 3,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(2-morpholinoethyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
(557) N-(3,4-dichlorobenzyl)-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acetamide
(558) 1-(4-chlorobenzyl)-3-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)urea
(559) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethyl-2-methylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
(560) 3,4-dichloro-N-(((3S,5S)-1-(2-ethyl-2-methylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
(561) 6-chloro-N-(((3S,5S)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1-(2,3,5-trichlorobenzyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(562) 6-chloro-N-(((3S,5S)-3-(2-(1-methylethylsulfonamido)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(563) butyl 2-((2S,7S)-7-((6-chloro-2-naphthamido)methyl)-3-oxo-4-((S)-2-phenylbutyl)-1,4-diazepan-2-yl)ethylcarbamate
(564) (S)-6-chloro-N-((3-(1-isopropylpiperidin-4-yl)-2-oxo-1-(2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(565) 6-chloro-N-(((3S,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(566) 5-(4-chlorophenyl)-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)isoxazole-3-carboxamide
(567) 2,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
(568) N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-6-methoxy-2-naphthamide
(569) 6-chloro-N-(([5-¹³C,4-¹⁵N](3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)[¹³C]methyl)-2-naphthamide
(570) N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-1-methoxy-2-naphthamide
(571) (E)-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)acrylamide
(572) 5-(4-chlorophenyl)-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)isoxazole-3-carboxamide
(573) 2,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
(574) 5,6-dichloro-2-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)isoindoline-1,3-dione
(575) (E)-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-(3-fluoro-4-(trifluoromethoxy)phenyl)acrylamide
(576) 6-methoxy-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(577) 1-methoxy-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(578) (E)-3-(3-fluoro-4-(trifluoromethoxy)phenyl)-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
(579) 6-chloro-N-(([5,6,6-²H₃](3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)[²H₂]methyl)-2-naphthamide
(580) 6-chloro-N-(((3R,5R)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(581) 6-chloro-N-(((3S,5R)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(582) 6-chloro-N-(((3R,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(583) 6-chloro-N-(((3S,5R)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(584) 6-chloro-N-(((3R,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide
(585) 6-chloro-N-(((3R,5R)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide

As stated previously the compounds of formula (I) are antagonists of the MC5R and therefore may be used to modulate the activity of MC5R or a fragment or analogue or functional equivalent thereof by exposing MC5R or a fragment or analogue or functional equivalent thereof to a compound of the invention. This can occur in vitro in assays where the downregulation of MC5R activity is desirable, however it is typically more beneficial when utilised in downregulation of MC5R activity in a patient. The amount of downregulation provided by the compounds of the invention will vary from compound to compound and will also be affected by the amount of compound administered. In one embodiment the amount of downregulation is at least 10%. In another embodiment the amount of downregulation is at least 20%. In an even further embodiment the amount of downregulation is at least 50%.

Accordingly the methods of the present invention may be used in the treatment of any condition in which modulation of the activity of MC5R or a fragment or analogue or functional equivalent thereof would lead to a beneficial effect on that condition. As such the compounds suitable for use in the present invention may be used in methods of treating, preventing, or controlling a condition associated either directly or indirectly with the activity of MC5R or a fragment or analogue or functional equivalent thereof in a mammal wherein an MC5R modulating amount of the compound of the invention is administered to the mammal. One condition associated with MC5R activity is excess sebum secretion and conditions related thereto. In one embodiment of the method the condition is selected from the group consisting of acne, seborrhoea, and seborrheic dermatitis. In one embodiment the acne is selected from the group consisting of acne vulgaris, acne, acne conglobata and acne fulminans. In one specific embodiment the condition is acne vulgaris.

For example, downregulation of MC5R leads to a reduction of sebum secretion and can thus be used in the treatment or prophylaxis of a number of conditions in which excess sebum secretion is observed such as acne, seborrhoea and seborrheic dermatitis.

The methods of the invention may also be useful in the treatment, prevention or control of a number of conditions that relate to biological processes controlled by MC5R, such as diseases related to inflammation. The compounds of formula (I) may also be useful for the treatment or prevention of cancers, such as Muir-Torre syndrome or other cancers of the sebaceous gland.

Due to their impact on sebum secretion the compounds of formula (I) may also find application in treatments where reduced sebum secretion is desirable such as in cosmetic treatments. The compounds may thus be used in methods of reducing sebum secretion by a mammal, the method comprising administering an effective amount of a compound of formula (I).

The compounds of formula (I) may be used in the treatment of conditions in any species in which MC5R is present, most typically mammals. Examples of species in which MC5R is found and hence species in which the compounds may be used include humans, rats, mice, dogs, rhesus monkey, sheep, zebrafish, goldfish, spiny dogfish, rainbow trout and chickens. In a specific embodiment the mammal is a human.

Administration of compounds within Formula (I) to a patient such as humans can be by topical administration, by any of the accepted modes for enteral administration such as oral or rectal, or by parenteral administration such as subcutaneous, intramuscular, intravenous and intradermal routes. Injection can be bolus or via constant or intermittent infusion. The active compound is typically included in a pharmaceutically acceptable carrier or diluent and in an amount sufficient to deliver to the patient a therapeutically effective dose.

In using the compounds of formula (I) they can be administered in any form or mode which makes the compound bioavailable. One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the condition to be treated, the stage of the condition to be treated and other relevant circumstances. We refer the reader to Remingtons Pharmaceutical Sciences, 19^thedition, Mack Publishing Co. (1995) for further information.

The compounds of formula (I) can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent or excipient. The compounds of formula (I), while effective themselves, are typically formulated and administered in the form of their pharmaceutically acceptable salts as these forms are typically more stable, more easily crystallised and have increased solubility.

The compounds are, however, typically used in the form of pharmaceutical compositions which are formulated depending on the desired mode of administration. The compositions are prepared in manners well known in the art.

A compound of formula (I) is typically combined with the carrier to produce a dosage form suitable for the particular patient being treated and the particular mode of administration. For example, a formulation intended for the oral administration to humans may contain from about 0.5 mg to about 5 g of the compound of the invention, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 99.95 percent of the total composition. Representative dosage forms will generally contain between from about 1 mg to about 500 mg of a compound of the invention, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg. Compounds of the present invention may also be formulated for topical delivery in formulations such as solutions, ointments, lotions, gels, creams, microemulsions or transdermal patches. For example, these topical formulations may contain from 0.005 to 5% (wt/wt or wt/vol) of a compound of the invention.

The compounds of formula (I) may be used or administered in combination with one or more additional drug(s). The compounds of the present invention may be used in combination with one or more other pharmaceutically-active compounds, such as other anti-acne treatments. In one embodiment the other pharmaceutically active agent is selected from the group consisting of antibiotics, retinoids, anti-androgens, and steroids. Examples of other pharmaceutically active compounds that may be combined with a compound of formula (I) and administered in concurrent or sequential combination therewith may include, by way of non-limiting example, other anti-acne agents such as oral retinoids (e.g. isotretinoin), topical retinoids (e.g. isotretinoin, adapalene, tazarotene), oral or topical antibiotics (e.g. clindamycin, erythromycin, minocycline, tetracycline, benzoyl peroxide), or hormonal therapies (e.g. drospirenone, norgestimate-ethinyl estradiol, cyproterone acetate). As stated these components can be administered in the same formulation or in separate formulations. If administered in separate formulations the compounds of the invention may be administered sequentially or simultaneously with the other drug(s).

Pharmaceutical compositions suitable for use in the invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or non aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and non aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of micro-organisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin.

If desired, and for more effective distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

If desired, and for more effective distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.

The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

For topical administration, the active agent may be in the form of an ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol or oil. Alternatively, the composition may be delivered via a liposome, nanosome, rivosome, or nutri-diffuser vehicle. Alternately, a formulation may comprise a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. Methods for producing formulations for topical administration are known in the art.

The compositions used for topical administration typically contain a pharmaceutically acceptable carrier which may be any vehicle that is toxicologically and pharmaceutically acceptable. Typical pharmaceutically acceptable carriers that can be used in compositions of the present invention include water, ethanol, acetone, isopropyl alcohol, stearyl alcohol, freons, polyvinyl pyrrolidone, propylene glycol, polyethlyene glycol, fragrances, gel-producing materials, mineral oil, stearic acid, spermaceti, sorbitan, monoleate, polysorbates, “Tweens,” sorbitol, methyl cellulose, petrolatum, a mineral oil (vaseline oil), which may be any petroleum based product; modified or unmodified vegetable oils such as peanut oil, wheatgerm oil, linseed oil, jojoba oil, apricot kernel oil, walnut oil, palm oil, pistachio oil, sesame oil, colza oil, cade oil, corn germ oil, peach kernel oil, poppyseed oil, pine oil, castor oil, soya oil, safflower oil, coconut oil, hazelnut oil, grapeseed oil, avocado oil, soy oil, sweet almond oil, calophyllum oil, castor oil, olive oil, sunflower oil, or animal oils such as whale oil, seal oil, menhaden oil, halibut liver oil, cod liver oil, cod, tuna, turtle tallow, horse's hoof, sheep's foot, mink, otter, marmot oil and the like; synthetic oils such as silicon oil such as dimethylpolysiloxane; alkyl and alkenyl esters of fatty acids, such as isopropyl esters of myristic, palmitic and stearic acids and fatty esters which are solid at room temperature; waxes such as lanolin wax, candelilla wax, spermaceti, cocoa butter, karite butter, silicon waxes, hydrogenated oils which are solid at room temperature, sucro-glycerides, oleates, myristates, linoleates, stearates, paraffin, beeswax, carnauba wax, ozokerite, candelilla wax, microcrystalline wax; fatty alcohols such as lauryl, cetyl, myristyl, stearyl, palmityl and oleyl alcohols; polyoxyethylated fatty alcohols; and wax esters, lanolin and its derivatives, perhydrosqualene and saturated esters, ethyl palmitate, isopropyl palmitate, alkyl myristates such as isopropyl myristate, butyl myristate and decyl myristate, hexyl stearate, triglyceride esters, triglycerides of octanoic and decanoic acid, cetyl ricinoleate, stearyl octanoate (Purcellin oil), fatty acids, polyhydric alcohols, polyether derivatives, fatty acid monoglycerides, polyethylene gylcol, propylene glycol, alkyl ethoxy ether sulfonates, ammonium alkyl sulfates, fatty acid soaps, and hydrogenated polyisobutene, and mixtures of waxes and oils.

The compositions for topical administration may be formulated in numerous forms. However, the composition may often take the form of an aqueous or oily solution or dispersion or emulsion or a gel or a cream. An emulsion may be an oil-in-water emulsion or a water-in-oil emulsion.

The oil phase of water-in-oil or oil-in-water emulsions may comprise for example: a) hydrocarbon oils such as paraffin or mineral oils; b) waxes such as beeswax or paraffin wax; c) natural oils such as sunflower oil, apricot kernel oil, shea butter or jojoba oil; d) silicone oils such as dimethicone, cyclomethicone or cetyldimethicone; e) fatty acid esters such as isopropyl palmitate, isopropyl myristate, dioctylmaleate, glyceryl oleate and cetostearyl isononanoate; f) fatty alcohols such as cetyl alcohol or stearyl alcohol and mixtures thereof (eg cetearyl alcohol); g) polypropylene glycol or polyethylene glycol ethers, eg PPG-14 butyl ether; or h) mixtures thereof.

Emulsifiers used may be any emulsifiers known in the art for use in water-in-oil or oil-in-water emulsions. Known cosmetically acceptable emulsifiers include: a) sesquioleates such as sorbitan sesquioleate, available commercially for example under the trade name Arlacel 83 (ICI), or polyglyceryl-2-sesquioleate; b) ethoxylated esters of derivatives of natural oils such as the polyethoxylated ester of hydrogenated castor oil available commercially for example under the trade name Arlacel 989 (ICI); c) silicone emulsifiers such as silicone polyols available commercially for example under the trade name ABIL WS08 (Th. Goldschmidt AG); d) anionic emulsifiers such as fatty acid soaps e.g. potassium stearate and fatty acid sulphates e.g. sodium cetostearyl sulphate available commercially under the trade name Dehydag (Henkel); e) ethoxylated fatty alcohols, for example the emulsifiers available commercially under the trade name Brij (ICI); f) sorbitan esters, for example the emulsifiers available commercially under the trade name Span (ICI); g) ethoxylated sorbitan esters, for example the emulsifiers available commercially under the trade name Tween (ICI); h) ethoxylated fatty acid esters such as ethoxylated stearates, for example the emulsifiers available commercially under the trade name Myrj (ICI); i) ethoxylated mono-, di-, and tri-glycerides, for example the emulsifiers available commercially under the trade name Labrafil (Alfa Chem.); j) non-ionic self-emulsifying waxes, for example the wax available commercially under the trade name Polawax (Croda); k) ethoxylated fatty acids, for example, the emulsifiers available commercially under the trade name Tefose (Alfa Chem.); l) methylglucose esters such as polyglycerol-3 methyl glucose distearate available commercially under the name Tegocare 450 (Degussa Goldschmidt); or m) mixtures thereof.

Gels for topical administration may be aqueous or non-aqueous. Aqueous gels are preferred. The gel will contain a thickening agent or gelling agent in order to give sufficient viscosity to the gel. A variety of thickening agents may be used according to the nature of the liquid carrier and the viscosity required and these are recited hereinafter. A particularly suitable thickener is a copolymer of acryloyl dimethyl tauric acid (or a salt thereof), preferably a copolymer of that monomer with another vinylic monomer. For example, the thickening agent is a copolymer of a salt of acryloyl dimethyl tauric acid with another vinylic monomer. The salt may be a salt of a Group I alkali metal, but is more preferably an ammonium salt. Examples of suitable copolymer thickening agents are: i) Ammonium acryloyl dimethyl taurate I vinyl pyrrolidone copolymer, ie a copolymer of ammonium acryloyl dimethyl taurate and vinyl pyrrolidone (1-vinyl-2-pyrrolidone).

The composition may additionally comprise other skincare active agents which are well known in the art which may be effective to aid the normal functioning of the skin. One group of preferred compositions comprise hydrolysed milk protein to regulate sebum production.

The composition may additionally comprise other components which will be well known to those skilled in the art such as emollients, humectants, emulsion stabilising salts, preservatives, chelating agents or sequestering agents (sequestrants), abrasives, anti-oxidants, stabilisers, pH adjusters, surfactants, thickeners, diluents, perfumes and colourings.

The topical formulations may desirably include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.

The amount of compound administered will preferably treat and reduce or alleviate the condition. A therapeutically effective amount can be readily determined by an attending diagnostician by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective amount a number of factors are to be considered including but not limited to, the species of animal, its size, age and general health, sex, diet, the specific condition involved, the severity of the condition, the response of the patient to treatment, the particular compound administered, the mode of administration, the bioavailability of the preparation administered, the dose regime selected, the use of other medications and other relevant circumstances.

A preferred dosage will be a range from about 0.01 to 300 mg per kilogram of body weight per day. A more preferred dosage will be in the range from 0.1 to 100 mg per kilogram of body weight per day, more preferably from 0.2 to 80 mg per kilogram of body weight per day, even more preferably 0.2 to 50 mg per kilogram of body weight per day. A suitable dose can be administered in multiple sub-doses per day.

Synthesis of Compounds for Use in the Invention

The general synthetic route to the compounds for use in the invention proceeds through the key intermediate A, produced as outlined in Schemes 1 or 2.

In Scheme 1, an amino acid derivative V—N(R²)—Y—CO₂H (V═R¹X or an amine protecting group P¹) is converted to a Weinreb amide via activation of the carboxyl group and amidation with N-methyl methoxyamine. Addition of a vinyl Grignard reagent produces the aminoalkyl vinyl ketone, which undergoes conjugate addition by the R⁶R⁷R⁸C—(CR^5aR^5b)_rNH₂amine component (shown as WNH₂for simplicity). The resulting secondary amine is acylated under standard peptide coupling conditions with the protected amino acid, P²—NHCH(U)—CO₂H, where U represents either the final R side chain, a protected final side chain R—P³, or a precursor that requires chemical modification to form the final R side chain. Deprotection of the P²protecting group is followed by intramolecular reductive amination of the ketone using standard reduction conditions, such as H₂/Pd catalyst, NaBH₄, NaBH₃CN, or NaBH(OAc)₃, forming key intermediate A. If Y═CH₂or CH₂CH₂, A is formed as the predominant diastereomer. If V═R¹X and U═R, A is the final product.

In Scheme 2, an alternate route to the desired intermediate A begins with the same Weinreb amide formation, vinyl Grignard addition, and amine conjugate addition. At this point, the secondary amine is protected with an amine protecting group P⁴. The ketone is then reductively aminated with a protected amino ester, H₂NCH(U)—CO₂P⁵, producing a mixture of diastereomers that are carried through the next reaction steps. The ring system is generated by deprotection of the P⁴and P⁵protecting groups, followed by amide bond formation using standard peptide coupling reagents. Alternatively, the P⁴protecting group is removed and cyclization achieved by thermal or base-induced cyclization with the P⁵-protected ester. The cyclization produces a mixture of two diastereomers, A and B, from which the preferred diastereomers A can be separated by chromatography.

The key intermediate A may be the final product if U═R and V═R¹X, but otherwise is converted into the final product as illustrated in Schemes 3, 4 and 5.

In Scheme 3, where V═R¹X, the final product is obtained by modification of the U side chain, such as removal of a P³protecting group, or removal of a P³protecting group followed by further chemical modification.

In Scheme 4, where V═P¹, the final product is obtained by removal of the P1 protecting group followed by introduction of the R¹X substituent. If U═R, this produces the final product. Alternatively, the U side chain is then modified to produce the final R group as in Scheme 3.

In Scheme 5, where V═P¹, the final product is obtained by first modifying the U side chain to produce the final R group as in Scheme 3. This is followed by removal of the P1 protecting group followed by introduction of the R¹X substituent.

It is also possible to modify the W substituent, if desired, during these reaction sequences.

EXAMPLES

The following examples are intended to illustrate the embodiments disclosed and are not to be construed as being limitations thereto. Additional compounds, other than those described below, may be prepared using the following described reaction schemes as discussed above or appropriate variations or modifications thereof. All starting materials described in the Examples below are commercially available or readily synthesized by those skilled in the art.

Instrumentation

HPLC analyses were carried out on an Agilent 1100 Series Purification System with a Phenomenex Synergi 4μ Max-RP 80A, 50×2.00 mm analytical HPLC column, with peak detection by UV. The standard analysis employed a 1 mL/min flow rate of 0.05% trifluoroacetic acid (TFA) in water (Solvent A) and 0.05% TFA in 90:10 acetonitrile:water (Solvent B), using a gradient of 5% B (initial) to 95% B over 9 min. Mass spectra were run on an Applied Biosystems MDS Sciex API 2000 LC/MS/MS triple quadrupole mass spectrometer and analyzed by ion spray mass spectrometry (ISMS). Preparative scale HPLC was carried out on a Waters Delta Prep 3000 HPLC system with peak detection by UV (Waters model 486 tunable absorbance detector), using Phenomenex Luna 10μ C5 100A, 250×21.20 mm (20 mg scale), Phenomenex Luna 15μ C8(2) 100A, 250×30.00 mm (50 mg scale), or Phenomenex Luna 15μ C8(2) 100A, 250×50.00 mm (100 mg scale) HPLC columns. The solvent system employed various gradients of 0.05% TFA in water (Solvent A) and 0.05% TFA in 90:10 acetonitrile:water (Solvent B).

The following examples 1 to 7 provide general synthetic procedures that may be followed in order to carry out the transformations described in schemes 1 to 5. In order to make different end products using these procedures it is necessary to either vary a variable group on the starting material or to vary a variable group on one of the reagents depending upon the nature of the reaction. It will be apparent to a skilled addressee from a reading of the general procedures how to vary either the starting material or the reagents used in the procedure to produce differing end products. In addition depending upon the starting materials and the reagents it may be necessary and/or desirable to make slight modifications to the described general procedures in order to provide the most facile synthesis of the desired end product.

Example 1
General Procedure—Weinreb Amide Formation

BOP reagent (100 mmol) and diisopropylethylamine (DIPEA) (100 mmol) is added to a stirred solution of the amino acid (1) (100 mmol) in dichloromethane (DCM) (100 mL). The solution is then stirred at room temperature for 10 mins, before addition of a premixed solution of N,O-dimethylhydroxylamine hydrochloride (100 mmol) and DIPEA (100 mmol) followed by stirring at room temperature overnight. The DCM is then removed by rotary evaporation and the residue taken up in ethyl acetate (EtOAc) (200 mL). The organic phase is then washed with 1N HCl (3×100 mL), H₂O (3×100 mL), saturated NaHCO₃aqueous solution (3×100 mL) and brine (1×10 mL). The organic phase is then dried (MgSO₄) and the EtOAc removed to give the Weinreb amide (2) as a white solid or an oil.

Example 2
General Procedure—Vinyl Grignard Addition to Weinreb Amide to Form α,β-Unsaturated Ketones of Formula (3)

To the Weinreb amide (2) (15 mmol) in DCM (10 mL) at 0° C. is added vinyl magnesium bromide (45 mmol) in THF (45 mL). The reaction is stirred for 2 hrs and monitored by HPLC. The reaction is then quenched by adding it to a mixture of ice and 1M HCl (200 mL). The aqueous mixture is extracted with DCM (3×100 mL) and the organic layers combined and washed with 1M HCl (2×200 mL) and H₂O (3×100 mL). The organic phase is dried (MgSO₄) to provide a solution of the α,β-unsaturated ketone (3). The α,β-unsaturated ketone (3) may be isolated by rotary evaporation or it may be used in solution without further purification. If the intention is to use the α,β-unsaturated ketone (3) in solution the volume is reduced to 100 mL by rotary evaporation and stored for later use.

Example 3
General Procedure—Conjugate Addition of Amine to α,β-Unsaturated Ketones of Formula (3) to Produce Compounds of Formula (4)

To the amine W—NH₂(7.4 mmol) in DCM (10 mL) is added a solution of the α,β-unsaturated ketone (3) (5.7 mmol) in DCM (50 mL). The solution is stirred at room temperature for 15 mins, or until analysis indicates that all of (3) has been consumed. The solution of compound (4) is immediately used without purification for the subsequent reaction.

Example 4
General Procedure—Acylation of Aminoketone (4)

The amine acid P²—NHCH(U)—CO₂H (15 mmol) and DIC (15 mmol) is added to a solution of DCM containing 10 mmol of the conjugate addition adduct 4. The reaction is stirred at room temperature overnight. The DCM is removed by rotary evaporation and the residue is then subjected to column chromatography on silica gel using petroleum spirit:EtOAc to give 5.

As an alternative, the DIC may be replaced with HATU (15 mmol) and DIPEA (15 mmol). The reaction is stirred at room temperature overnight. The DCM is removed by rotary evaporation and the residue is taken up in EtOAc (100 mL). The organic layer is washed with saturated sodium bicarbonate solution (2×100 mL), saturated ammonium chloride solution (2×100 mL) and brine (2×100 mL). The organic phase is dried and the solvent removed under reduced pressure. The residue is subjected to column chromatography on silica gel using petroleum ether:EtOAc to give 5.

Example 5
General Procedure—P²Deprotection and Cyclization

The procedure adopted for the removal of the P2 protecting group will vary depending upon the exact nature of the protecting group. As will be appreciated by a skilled addressee a large number of possible protecting groups may be used and a skilled worker in the art will readily be able to determine an appropriate procedure for the removal of any particular protecting group from procedures known in the art. Nevertheless in order to assist the reader general procedures for the removal of the more common protecting groups are provided.

P²=Fmoc: To compound 5 (2 mmol) in DCM (3 mL) is added diethylamine (20 mmol). The reaction is stirred at room temperature for 1 hr. The DCM and diethylamine is then removed by rotary evaporation. DCM (5 mL) and sodium triacetoxyborohydride (3 mmol) are then added, and the reaction stirred overnight at room temperature. The organic phase is washed with saturated sodium bicarbonate solution (25 mL), dried (MgSO₄) and the DCM removed to give the cyclised product A. This may be purified by flash chromatography on silica gel or used without purification.

P²=Boc: To compound 5 (2 mmol) in DCM (3 mL) is added TFA (3 mL) and the reaction stirred at room temperature for 2 hrs. The DCM and TFA are then removed by rotary evaporation. DCM (5 mL) and sodium triacetoxyborohydride (3 mmol) is then added, and the reaction stirred overnight at room temperature. The organic phase is washed with saturated sodium bicarbonate solution (25 mL), dried (MgSO₄) and the DCM removed to give the cyclised product A. This may be purified by flash chromatography on silica gel or used without purification.

P²=Cbz: A mixture of crude 5 (1 mmol) and 5% Pd/C (200 mg) in 2-propanol (15 mL) is shaken at room temperature under hydrogen (30 psi) for 24 hrs. The mixture is then filtered through a pad of Celite and the filtrate concentrated under reduced pressure to give a crude product. Purification by flash chromatography on silica gel (100% EtOAc) may be used to give A.

Example 6
General Procedure—P¹Deprotection and Derivatization with R¹X

The procedure adopted for the removal of the P1 protecting group will vary depending upon the exact nature of the protecting group. As will be appreciated by a skilled addressee a large number of possible protecting groups may be used and a skilled worker in the art will readily be able to determine an appropriate procedure for the removal of any particular protecting group from procedures known in the art. Nevertheless in order to assist the reader general procedures for the removal of the more common protecting groups are provided.

Deprotection, P¹=Cbz:

To the cyclised product A (1 mmol) in methanol (5 mL) is added catalytic Pd/C. The reaction is stirred under a hydrogen atmosphere overnight. The reaction mixture is filtered through Celite and the methanol removed by rotary evaporation to give the free amine. The amine may be used in the next reaction without purification.

Deprotection, P¹=Boc:

To the cyclised product A (1 mmol) in DCM (1 mL) is added TFA (1 mL) and the reaction stirred at room temperature for 2 hrs. The solvent is removed by rotary evaporation to give the amine TFA salt, which may be used in the next reaction without purification.

Deprotection, P¹=Alloc:

To the cyclised product A (1 mmol) in DCM (6 mL) is added 1,3-dimethylbarbituric acid (0.2 mmol) and palladium tetrakis triphenylphosphine (10 mg). The reaction is evacuated and stirred at room temperature for 1 hr. The DCM is removed under reduced pressure to give the crude free amine, which may be used in the next reaction without purification.

Derivatisation with R¹X when X═C(═O):

To the free amine (1 mmol) in DCM (5 mL) is added DIPEA (1 mmoL), BOP reagent (1.5 mmol) and acid component R¹CO₂H (1.5 mmol). The reaction is stirred at room temperature for 2 hrs. Rotary evaporation and preparative HPLC gives the purified adduct.

Example 7
General Procedure—U Modification via P³Deprotection and Dialkylation with Dibromide

The procedure adopted for modification of U via deprotection and derivatization will vary depending on the exact nature of the U group. As will be appreciated by a skilled addressee a large number of modifications are possible, and a skilled worker in the art will readily be able to determine an appropriate procedure for the conversion into a desired R group. Nevertheless in order to assist the reader, one general modification procedure commonly employed for a number of the following examples is provided.

P³=Boc:

To the protected amine (1 mmol) in DCM (5 mL) is added TFA (5 mL) and the reaction stirred at room temperature for 2 hrs. DCM (20 mL) is added and the solution is washed with saturated sodium bicarbonate solution (20 mL), dried (MgSO₄) and evaporated to give the crude amine. To the crude amine is added DMF (0.5 mL), potassium carbonate (50 mg) and 1,5-dibromopentane (5 mmol). The reaction mixture is stirred at room temperature for 1.5 hrs, after which DCM (20 mL) is added, the organic layer washed with saturated sodium bicarbonate solution (20 mL) and H₂O (20 mL), dried (MgSO₄) and evaporated. The residue may be purified by preparative HPLC to give the piperidinyl product. The purified product is isolated as the TFA salt, but is readily converted into the free base via neutralisation with aqueous NaHCO₃and extraction into an organic solvent, or further converted into the HCl salt by acidification with 1 N HCl.

Example 8
Synthesis of Compound 8 N-(2-(methoxy(methyl)amino)-2-oxoethyl)-2-naphthamide

To a mixture of 2-naphthoic acid (5.8 g, 33.7 mmol), 2-amino-N-methoxy-N-methylacetamide (Gly Weinreb amide; prepared from Boc-Gly Weinreb amide 15 as in Example 43) (3.8 g, 32.1 mmol) and DIPEA (12.0 mL, 68.9 mmol) in DCM (70 mL) was added BOP (14.9 g, 33.7 mmol) in one portion at room temperature. The resulting mixture was stirred for 1 hr then saturated NaHCO₃aqueous solution was added. The organic layer was washed with brine (5×60 mL) and 1 N HCl (2×30 mL), dried over MgSO₄, filtered and concentrated under reduced pressure to give the crude product, which was used in the next reaction without further purification.

Example 9
Synthesis of Compound 9 N-(2-(methoxy(methyl)amino)-2-oxoethyl)-2-naphthamide

To a solution of 8 (3.5 g, 12.85 mmol) in dry THF (10 mL) was added a solution of vinylmagnesium bromide in THF (1 M, 31 mL) slowly at 0° C. After addition, the resulting mixture was stirred at room temperature for 1 hr then was poured into an icy 1 N HCl solution (50 mL). The aqueous layer was extracted with DCM (3×80 mL) and the combined organic layers were dried over MgSO₄, filtered and concentrated under reduced pressure to give the crude product. MS(ESI) 240 (M+1); HPLC t_R5.46 min.

Example 10
Synthesis of Compound 10 N-(4-(3,5-dichlorobenzylamino)-2-oxobutyl)-2-naphthamide

To a solution of 3,5-dichlorobenzylamine (12 mg, 0.068 mmol) in DCM (0.2 mL) was added a solution of 9 (13 mg, 0.054 mmol) in DCM (0.5 mL) at room temperature. The resulting mixture was stirred until all of the 9 had been consumed (within one hr) and then was used straight in the next reaction. MS(ESI) 415 (M+1); HPLC t_R6.00 min.

Example 11
Synthesis of Compound 11 (S)—N-(4-(5-(3-Pbf-guanidino)-2-(Fmoc-amino)-N-(3,5-dichlorobenzyl)pentanamido)-2-oxobutyl)-2-naphthamide

To a solution of freshly prepared aminoketone 10 in DCM (2 mL) was added Fmoc-L-Arg(Pbf)-OH (53 mg, 0.082 mmol) followed by DIC (12.5 μl, 0.082 mmol) at room temperature. The resulting mixture was stirred for 2 hrs then the solvent was removed under reduced pressure. The residue was filtered through a short plug of silica gel eluting with DCM followed by EtOAc to give the desired product 11 as a white solid. It was used in the next step without further purification. MS(ESI) 1045 (M+1); HPLC t_R9.99 min.

Example 12
Synthesis of Compound 12 (S)—N-(4-(5-(3-Pbf-guanidino)-2-amino-N-(3,5-dichlorobenzyl)pentanamido)-2-oxobutyl)-2-naphthamide

Diethylamine (0.5 mL) was added to Fmoc-protected 11 (56 mg, 0.054 mmol) at room temperature and the resulting mixture was stirred for 30 min. The excess amount of the diethylamine was removed under reduced pressure to give the desired free amine 12. It was used in the next step without further purification. MS(ESI) 823 (M+1); HPLC t_R7.49 min.

Example 13
Synthesis of Compound 13 N-(((3S,5S)-3-(3-(3-Pbf-guanidino)propyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide

The amino ketone 12 (44 mg, 0.053 mmol) in DCM (2 mL) was cyclized by addition of NaBH(OAc)₃(40mg, 0.18 mmol) in one portion at room temperature. The resulting mixture was stirred for 3 hrs, followed by addition of saturated NaHCO3 aqueous solution (3 mL). The aqueous layer was extracted with DCM (3×3 mL) and the combined organic layers were dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was filtered through a short plug of silica gel eluting with DCM followed by EtOAc then EtOAc/IPA (9:1) to give the desired product 13 as a white solid. It was used in the next step without further purification. MS(ESI) 807 (M+1); HPLC t_R7.75 min.

Example 14
Synthesis of Compound 14 N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide

A solution of TFA/DCM (2:1) (1 mL) with 5% H₂O was added to 13 at room temperature and the resulting mixture was stirred for 4 hrs. The solvents were removed under reduced pressure and the residue was purified by prep HPLC (100% H₂O to MeCN/H₂O 9:1, gradient) to give 14 (7.6 mg) as a white solid (TFA salt). The overall yield (from 9) was ca. 18%. MS(ESI) 556.2 (M+1); HPLC t_R5.74 min.

Example 15
Synthesis of Compound 15 tert-butyl 2-(methoxy(methyl)amino)-2-oxoethylcarbamate (Boc-Gly Weinreb amide)

To a stirred mixture of Boc-Gly-OH (20 g, 114.1 mmol), DIPEA (19.8 mL, 114.1 mmol) and BOP (50.5 g, 114.1 mmol) in DCM (20 mL) was added a pre-mixed solution of N,O-dimethylhydroxylamine hydrochloride (11.2 g, 114.1 mmol) and DIPEA (19.8 mL, 114.1 mmol) in DCM (20 mL) at room temperature. The resulting mixture was stirred for 16 h then washed with 1N HCl (3×120 mL), H₂O (3×120 mL), saturated NaHCO₃aqueous solution (3×120 mL) and brine (40 mL), dried over MgSO₄, filtered and concentrated under reduced pressure to give 15 as a white solid (20 g, 80%), which was used in the next step without further purification.

MS(ESI) 219 (M+1); HPLC t_R4.12 min.

Example 16
Synthesis of Compound 16 tert-butyl 2-oxobut-3-enylcarbamate

At 0° C. a solution of vinylmagnesium bromide in THF (184 mL, 1 M) was added in one portion to Weinreb amide 15 (20 g, 91.6 mmol) under nitrogen with stirring. The resulting mixture was allowed to stir for 2 h, and poured into a 1 N HCl/ice mixture (400 mL). The aqueous mixture was extracted with DCM (5×100 mL), the combined DCM extract was washed with 1N HCl (2×100 mL), saturated NaHCO₃aqueous solution (100 mL) and brine (100 mL), then dried over MgSO₄. Solvent was removed under reduced pressure gave the ketone 16 (12.9 g, 76%) as a pale yellow oil, which was used in the next step without further purification. MS(ESI) 186 (M+1); HPLC t_R4.19 min.

Example 17
Synthesis of Compound 17 tert-butyl 4-(2,2-diphenylethylamino)-2-oxobutylcarbamate

To a stirred solution of 2,2-diphenylethylamine (0.33 g, 1.66 mmol) in DCM (10 mL) was added α,β-unsaturated ketone 16 (0.31 g, 1.66 mmol) at room temperature. Stirring continued for 2 h; the crude reaction mixture of 17 was used in the next step without purification. MS(ESI) 383 (M+1); HPLC t_R5.98 min

Example 18
Synthesis of Compound 18 (S)-tert-butyl 3-methyl-4,8-dioxo-10-phenyl-2,9-dioxa-3,7-diazadecane-6-carboxylate

To a suspension of Cbz-L-Asp-OtBu-DCHA salt (10.1 g, 20.0 mmol), N,O-dimethylhydroxylamine-HCl (5.9 g, 60.5 mmol) and DIPEA (12.0 mL, 68.9 mmol) in DCM (150 mL) was added BOP (10.6 g, 24.0 mmol) in one portion at room temperature. The resulting suspension was stirred for 3 hrs then H₂O (100 mL) was added. The organic layer was washed with 1 N HCl (2×100 mL), saturated NaHCO₃aqueous solution (2×100 mL) and brine (3×100 mL) and then dried over MgSO₄, filtered and concentrated under reduced pressure to give the crude product. Purification by flash chromatography on silica gel (PET ether/EtOAc 1:2) gave 18 (6.4 g, 87%) as a colorless oil. MS(ESI) 367 (M+1); HPLC t_R6.87 min.

Example 19
Synthesis of Compound 19 (S)-3-methyl-4,8-dioxo-10-phenyl-2,9-dioxa-3,7-diazadecane-6-carboxylic acid

Compound 18 (300 mg, 0.82 mmol) was dissolved in a TFA/DCM (1:1) solution (2 mL) and the resulting mixture was stirred at room temperature for 2 hrs. The solvents were removed under reduced pressure and the residue was re-dissolved in DCM (10 mL). This solution was washed with 1 N HCl (1×10 mL) and the organic layer was dried over MgSO₄, filtered and concentrated under reduced pressure to give the crude product 19 (235 mg, 92%), which was used in the next reaction without further purification. MS(ESI) 311 (M+1); HPLC t_R4.96 min.

Example 20
Synthesis of Compound 20 (S)-benzyl 8-(2,2-diphenylethyl)-3,16,16-trimethyl-4,7,11,14-tetraoxo-2,15-dioxa-3,8,13-triazaheptadecan-6-ylcarbamate

Compound 20 was prepared from Compound 17 and 19 following the procedure of Example 5. MS(ESI) 675 (M+1); HPLC t_R8.31 min.

Example 21
Synthesis of Compound 21 tert-butyl ((3S,5S)-1-(2,2-diphenylethyl)-3-(2-(methoxy(methyl)amino)-2-oxoethyl)-2-oxo-1,4-diazepan-5-yl)methylcarbamate

A mixture of crude 20 (350 mg) and 5% Pd/C (200 mg) in 2-propanol (15 mL) was shaken at room temperature under hydrogen (30 psi) for 24 hrs. The mixture was then filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to give the crude product. Purification by flash chromatography on silica gel (100% of EtOAc) gave 21 (175 mg, 65% over 3 steps) as a white solid. MS(ESI) 525 (M+1); HPLC t_R6.24 min.

Example 22
Synthesis of Compound 22 2-((2S,7S)-7-(aminomethyl)-4-(2,2-diphenylethyl)-3-oxo-1,4-diazepan-2-yl)-N-methoxy-N-methylacetamide

Compound 21 (175 mg, 0.333 mmol) was dissolved in a TFA/DCM (1:1) solution (1 mL) and the resulting mixture was stirred at room temperature for 2 hrs. The solvents were removed under reduced pressure and the residue was re-dissolved in EtOAc (20 mL). Saturated NaHCO₃aqueous solution (10 mL) and brine (10 mL) were added to the above solution and the aqueous layer was extracted with EtOAc (9×20 mL). The combined organic layers were dried over MgSO₄, filtered and concentrated under reduced pressure to give the crude product 22 (120 mg, 85%) as a yellow solid, which was used in the next reaction without further purification. MS(ESI) 425 (M+1); HPLC t_R5.20 min.

Example 23
Synthesis of Compound 23 N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(2-(methoxy(methyl)amino)-2-oxoethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide

To a solution of 22 (50 mg, 0.118 mmol) and 6-fluoro-2-naphthoic acid (27 mg, 0.142 mmol) in DCM (4 mL) was added DIC (22 μl, 0.142 mmol) at room temperature. The resulting mixture was stirred for 2 hrs then the solvent was removed under reduced pressure to give the crude product. Purification by flash chromatography on silica gel (eluting with Petroleum ether:EtOAc (1:1) then EtOAc) gave 23 (29 mg, 41%) as a white solid. MS(ESI) 597 (M+1); HPLC t_R6.75 min.

Example 24
Synthesis of Compound 24 N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-oxoethyl)-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide

To a solution of 23 (29 mg, 0.049 mmol) in dry THF (1 mL) was added LiAlH(OtBu)₃(38 mg, 0.145 mmol) in one portion at room temperature and the resulting suspension was stirred overnight. This suspension was then slowly poured into a cold (0° C.) 0.4 M KHSO₄aqueous solution (2 mL, 0.8 mmol) and the resulting mixture was diluted with EtOAc (3 mL). The aqueous layer was extracted with EtOAc (3×3 mL) and the combined organic layers were washed with 1 N HCl (3×6 mL), saturated NaHCO₃aqueous solution (1×6 mL), and brine (1×6 mL). The organic solution was then dried over MgSO₄, filtered and concentrated under reduced pressure to give the crude product 24 (24 mg, 91%), which was used in the next reaction without further purification. MS(ESI) 538 (M+1); HPLC t_R6.41 min.

Example 25
Synthesis of Compound 25 N-(((3S,5S)-3-(2-(diethylamino)ethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide

To a solution of 24 (24 mg, 0.044 mmol) in DCM (2 mL) was added diethylamine (55 μl, 0.532 mmol) at room temperature. After stirring for 5 mins, NaBH(OAc)₃(20 mg, 0.090 mmol) was added to the above solution in one portion and the resulting suspension was stirred for another 10 mins. Saturated NaHCO₃aqueous solution (4 mL) was added to the suspension and the aqueous layer was extracted with DCM (3×4 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO₄, filtered and concentrated under reduced pressure to give the crude product. This crude product was purified by prep HPLC (100% H₂O to MeCN/H₂O 9:1, gradient) to give the 25 as a white solid (TFA salt). MS(ESI) 595.3 (M+1); HPLC t_R6.22 min.

Example 26
Synthesis of Compound 26 benzyl 2-(methoxy(methyl)amino)-2-oxoethylcarbamate

To Cbz-glycine (10 g, 47.8 mmol, Aldrich) in DCM (100 mL) was added BOP reagent (21.5 g, 48.6 mmol) and DIPEA (6.5 mL, 46.0 mmol). After stirring at room temperature for 10 mins, N,O-dimethylhydroxylamine hydrochloride (4.9 g, 50.2 mmol) and DIPEA (6.5 mL, 46.0 mmol) were added. The reaction was stirred at room temperature overnight. The DCM was removed by rotary evaporation and the residue taken up in EtOAc (100 mL). The organic phase was washed with H₂O (3×100 mL), saturated sodium bicarbonate solution (3×100 mL), H₂O (3×100 mL), 1M HCl (3×100 mL), brine (3×100 mL). The organic phase was dried (MgSO₄) and the EtOAc removed to give the Weinreb amide 26 as a white solid (7.78 g, 64%).

Example 27
Synthesis of Compound 27 benzyl 2-oxobut-3-enylcarbamate

To the Weinreb amide 26 (3.89 g, 15.42 mmol) in DCM (10 mL) at 0° C. was added vinyl magnesium bromide (45 mmol) in THF (45 mL). The reaction was stirred for 2 hrs and monitored by HPLC. The reaction was added to a mixture of ice and 1M HCl (200 mL). The aqueous mixture was extracted with DCM (3×100 mL) and washed with 1M HCl (2×200 mL) and H₂O (3×100 mL). The organic phase was dried (MgSO₄) and the volume reduced to 100 mL by rotary evaporation. The α,β-unsaturated ketone 27 was stored and used in solution without purification.

Example 28
Synthesis of Compound 28 (S)-9-fluorenylmethyl 10-(2,2-diphenylethyl)-2,2-dimethyl-18-phenyl-4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-triazaoctadecan-8-ylcarbamate

To 2,2-diphenylethylamine (0.95 g, 7.4 mmol) in DCM (10 mL) was added the α,β-unsaturated ketone 27 (5.7 mmol) in DCM (75 mL). After stirring at room temperature for 15 mins, Fmoc-L-2,4-diaminobutyric acid(Boc)-OH (2.4 g, 8.55 mmol) and DIC (0.87 mL, 5.6 mmol) were added. The reaction was stirred at room temperature overnight. The DCM was removed by rotary evaporation and the residue was subjected to column chromatography on silica gel using petroleum spirit:EtOAc (1:1 to 0:1) to give 28 (1.5 g, 31%)

Alternatively, to 2,2-diphenylethylamine (0.97 g, 7.4 mmol) in DCM (20 mL) was added the α,β-unsaturated ketone 27 (5.95 mmol) in DCM (40 mL). After stirring at room temperature for 15 mins, Fmoc-L-2,4-diaminobutyric acid(Boc)-OH (2.4 g, 8.55 mmol), DIPEA (2.5 mL) and HATU (2.3 g, 6.0 mmol) were added. The reaction was stirred at room temperature overnight. The DCM was removed by rotary evaporation and the residue was taken up in EtOAc (100 mL). The organic layer was washed with saturated sodium bicarbonate solution (2×100 mL), saturated ammonium chloride solution (2×100 mL) and brine (2×100 mL). The organic phase was dried and the solvent removed under reduced pressure. The residue was subjected to column chromatography on silica gel using petroleum spirit:EtOAc (3:1 to 1:1 to 0:1) to give 28 (0.86 g, 17%).

Example 29
Synthesis of Compound 29 (3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)-5-(benzyloxycarbonylaminomethyl)-1-(2,2-diphenylethyl)-1,4-diazepan-2-one

To Compound 28 (1.5 g, 1.8 mmol) in DCM (3 mL) was added diethylamine (1.5 mL, 14.5 mmol). The reaction was stirred at room temperature for 1 hr. The DCM and diethylamine was removed by rotary evaporation. DCM (5 mL), sodium triacetoxyborohydride (0.4 g, 1.9 mmol) was added, and the reaction was stirred overnight at room temperature. The organic phase was washed with saturated sodium bicarbonate solution (25 mL), dried (MgSO₄) and the DCM removed to give the cyclised product 29, which was used in the next step without purification.

Example 30
Synthesis of Compound 30 (3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)-5-aminomethyl-1-(2,2-diphenylethyl)-1,4-diazepan-2-one

To the cyclised product 29 in methanol (5 mL) was added catalytic Pd/C. The reaction was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered through Celite and the methanol removed by rotary evaporation to give the amine 30 (0.7 g, 83% from 28).

Example 31
Synthesis of Compound 31 N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide

To the amine 30 (0.08 g, 0.17 mmol) in DCM (1 mL) was added DIPEA (0.25 mL), BOP reagent (0.08 g, 0.18 mmol) and 6-fluoro-2-naphthoic acid (0.06 g, 0.32 mmol). The reaction was stirred at room temperature for 2 hrs. TFA (1 mL) was added and the reaction stirred at room temperature for 2 hrs. Rotary evaporation and preparative HPLC gave 31 (0.05 g, 54%). MS(ESI) 539.3 (M+1); HPLC t_Rmin 5.92

Example 32
Synthesis of Compound 32 6-chloro-2-naphthoic acid

A suspension of 6-bromo-2-naphthoic acid (3.0 g, 11.47 mmol), CuCl (11.7 g, 114.64 mmol) and CuI (2.19 g, 11.50 mmol) in degassed DMF (45 mL) was heated to reflux under argon in dark for 4 hrs. After cooling to room temperature, the solution was decanted into H₂O (200 mL) and the resulting mixture was extracted with EtOAc (2×500 mL). The combined organic layers were then washed with H₂O (4×500 mL) followed by brine (1×500 mL), dried over MgSO₄, filtered and concentrated under reduced pressure to dryness. The residue was trituated with CH₃CN and the solid obtained was then re-crystallized from EtOAc to give the pure product 32 (2.2 g, 93%) as a off-white solid. HPLC t_R6.47 min.

Example 33
Synthesis of Compound 33 (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide

To the amine (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-aminoethyl)-1,4-diazepan-5-yl)methyl)acrylamide (21 mg, 0.05 mmol) in DMF (0.25 mL) was added K₂CO₃(5 mg) and 1,5-dibromopropane (0.066 mL, 0.5 mmol). The reaction mixture was left at room temperature for 4 hrs. The solvent was removed under high vacuum, and the residue purified by preparative HPLC to give 8 mg (˜30%) of 33 as the TFA salt. MS(ESI) 599.4 (M+1); HPLC t_Rmin 6.31

Example 34
Synthesis of Compound 34 (S)-9-fluorenylmethyl 10-(2-phenylbutyl)-2,2-dimethyl-18-phenyl-4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-triazaoctadecan-8ylcarbamate

To 2-phenylbutylamine hydrochloride (0.26 g, 1.4 mmol) in DCM (10 mL) and DIPEA (0.25 mL, 1.8 mmol) was added the α,β-unsaturated ketone 27 (1.06 mmol) in DCM (20 mL). After stirring at room temperature for 15 mins, Fmoc-diaminobutyric acid(Boc)-OH (0.7 g, 1.56 mmol) and DIC (0.25 mL, 1.61 mmol) were added. The reaction was stirred at room temperature overnight. The DCM was removed by rotary evaporation and the residue was subjected to column chromatography on silica gel using petroleum spirit:EtOAc (1:1 to 0:1), providing Compound 34 as a mixture of diastereomers (0.17 g, 21%).

Example 35
Synthesis of Compound 35 (3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)-5-(benzyloxycarbonylaminomethyl)-1-(2-phenylbutyl)-1,4-diazepan-2-one

To Compound 34 (0.17 g, 0.2 mmol) in DCM (3 mL) was added diethylamine (1.5 mL). The reaction was stirred at room temperature for 1 hr. The DCM and diethylamine was removed by rotary evaporation. DCM (5 mL) and sodium triacetoxyborohydride (0.1 g, 0.47 mmol) were added and the reaction was stirred overnight at room temperature. The organic phase was washed with saturated sodium bicarbonate solution (25 mL), dried (MgSO₄) and the DCM removed to give the cyclised product 35 as a mixture of diastereomers (0.11 g, 100%).

Example 36
Synthesis of Compound 36 (3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)-5-(aminomethyl)-1-(2-phenylbutyl)-1,4-diazepan-2-one

To the cyclised product 35 (0.11 g) in methanol (5 mL) was added catalytic Pd/C. The reaction was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered through Celite and the methanol removed by rotary evaporation to give the amine 36 as a mixture of diastereomers (0.11 g, 100%).

Example 37
Synthesis of Compound 37 (3S,5S)-3-(2-aminoethyl)-5-(N-2-naphthamidomethyl)-1-(2-phenylbutyl)-1,4-diazepan-2-one

To the amine 36 (0.02 mg, 0.05 mmol) in DCM (1 mL) was added DIPEA (0.1 mL, 0.7 mmol), BOP reagent (0.02 mg, 0.045 mmol) and 2-naphthoic acid (0.015 mg, 0.09 mmol). The reaction was stirred at room temperature for 2 hrs. TFA (1 mL) was added and the reaction stirred at room temperature for 2 hrs. Rotary evaporation and preparative HPLC gave 37 as a mixture of diastereomers (13.4 mg, 57%). MS(ESI) (M+1); HPLC t_R5.59 min

Example 38
Synthesis of Compounds 38-39 N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide and N-(((3S,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide

Prepared from Compound 37 by alkylation as in Example 33. Preparative HPLC purification separated the two diastereomers. The correct configuration was assigned by resynthesis of the compounds using (S)-2-phenylbutylamine 43 or (R)-2-phenylbutylamine. 38: MS(ESI) 541.3 (M+1); HPLC t_R5.78 min; 39: MS(ESI) 541.3 (M+1); HPLC t_R5.67 min

Example 39
Synthesis of Compound 40 (S)-2-phenylbutanol

To a suspension of sodium borohydride (2.36 g, 62.4 mmol) in THF (50 mL) was added a solution of (S)-2-phenylbutyric acid (4.27 g, 26.0 mmol) in THF (40 mL) slowly at 0° C. The mixture was stirred until the evolution of gas ceased. A solution of iodine (6.60 g, 26.0 mmol) in THF (40 mL) was then added slowly at 0° C. After addition, the resulting mixture was allowed to warm to room temperature and stirred for 1 hr. The reaction solution was then slowly poured into a 1 N HCl solution (280 mL) and the resulting mixture was diluted with EtOAc (250 mL). The aqueous layer was extracted with EtOAc (150 mL×3) and the combined organic layers were then washed with saturated NaHCO₃(aq), 0.5 M Na₂S₂O₃(aq) and brine. This organic solution was dried over MgSO₄, filtered and concentrated under reduced pressure to give the crude product. Purification by flash chromatography on silica gel (Petroleum ether:EtOAc 4:1) gave the desired product 40 as a colorless oil in quantitative yield. HPLC t_R5.24 min.

Example 40
Synthesis of Compound 41 (S)-1-mesyloxy2-phenylbutane

To a mixture of 40 (3.9 g, 26.0 mmol) and triethylamine (5.5 mL, 39.5 mmol) in DCM (90 mL) was added a solution of methanesulfonyl chloride (4.47 g, 39.0 mmol) in DCM (30 mL) slowly at 0° C. After addition, the resulting mixture was allowed to warm to room temperature and stirred for 2 hrs. 1 N HCl (70 mL) was then added to the above mixture and the aqueous layer was extracted with DCM (1×70 mL). The combined organic layers were washed with brine (150 mL), dried over MgSO₄, filtered and concentrated under reduced pressure to give the crude product 41 as a colorless oil. This crude product was used in the next step without further purification. HPLC t_R6.48 min.

Example 41
Synthesis of Compound 42 (S)-1-azido-2-phenylbutane

A suspension of 41 (5.93 g, 26.0 mmol) and sodium azide (5.7 g, 78.0 mmol) in DMF (60 mL) was heated at 85° C. for 3 hrs. After cooling to room temperature, the mixture was diluted with H₂O (200 mL) and extracted with EtOAc (250 mL). The organic layer was then washed with H₂O (4×150 mL) followed by brine (150 mL), dried over MgSO₄, filtered and concentrated under reduced pressure to give the crude product. Purification by flash chromatography on silica gel (100% petroleum ether as the eluent) gave the pure product 42 (4.03 g, 88%) as a colorless oil. HPLC t_R7.67 min.

Example 42
Synthesis of Compound 43 (S)-2-phenylbutylamine

A mixture of 42 (4.0 g, 22.8 mmol) and Lindlar's catalyst (1.5 g) in EtOAc (50 mL) was shaken at room temperature under H₂(40 psi) over-night. The mixture was then filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to give the crude product 43 (3.4 g, 100%) as a light yellowish oil. This crude product was used for the conjugate addition reactions without further purification. MS (ESI) 150 (M+1); HPLC t_R1.84 min.

Example 43
Synthesis of Compound 44 allyl 2-(methoxy(methyl)amino)-2-oxoethylcarbamate

To Alloc-glycine (1.45 g, 9.1 mmol) in DCM (20 mL) was added BOP reagent (3.3 g, 7.46 mmol) and DIPEA (1.5 mL, 10.7 mmol). After stirring at room temperature for 10 mins, N,O-dimethylhydroxylamine hydrochloride (0.8 g, 8.2 mmol) and DIPEA (1.5 mL, 10.7 mmol) were added. The reaction was stirred at room temperature overnight. The DCM was removed by rotary evaporation and the residue taken up in EtOAc (100 mL). The organic phase was washed with H₂O (3×100 mL), saturated sodium bicarbonate solution (3×50 mL), H₂O (3×50 mL), 1 M HCl (3×50 mL), brine (3×50 mL). The organic phase was dried (MgSO₄) and the EtOAc removed to give the Weinreb amide 44 as a white solid (0.43 g, 23%).

Alternatively, tert-butyl 2-(methoxy(methyl)amino)-2-oxoethylcarbamate 16 (Boc-Gly Weinreb amide, 1.4 g, 6.4 mmol) in DCM (5 mL) and TFA (3 mL) were stirred at room temperature 1 hr. The solvent was removed under reduced pressure, followed by addition of DCM (20 mL) and then DIPEA until basic. The solution was cooled to 0° C. and allyl chloroformate added (1.4 mL, 13.2 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was neutralised with 1M HCl and extracted with EtOAc. The EtOAc was removed by rotary evaporation and the residue was subjected to column chromatography on silica gel using petroleum spirit:EtOAc (1:1 to 0:1), providing 44 (0.86 g, 66%).

Example 44
Synthesis of Compound 45 allyl 2-oxobut-3-enylcarbamate

To the Weinreb amide 44 (0.43 g, 2.1 mmol) in DCM (5 mL) at 0° C. was added vinyl magnesium bromide (10 mmol) in THF (10 mL). The reaction was stirred for 2 hrs and monitored by HPLC. The reaction was added to a mixture of ice and 1M HCl (100 mL). The aqueous mixture was extracted with DCM (3×50 mL) and washed with 1 M HCl (2×100 mL) and H₂O (3×50 mL). The organic phase was dried (MgSO₄) and the volume reduced to 50 mL by rotary evaporation. The α,β-unsaturated ketone 45 was stored and used in solution without further purification.

Example 45
Synthesis of Compound 46 (S)-9-fluorenylmethyl 10-(3,5-dichlorobenzyl)-2,2-dimethyl-4,9,13,1 6-tetraoxo-3,17-dioxa-5,10,15-triazaiscos-19-en-8-ylcarbamate

To 3,5-dichlorobenzylamine (0.49 g, 2.8 mmol) in DCM (5 mL) was added the α,β-unsaturated ketone 45 (2.12 mmol) in DCM (10 mL). After stirring at room temperature for 15 mins, Fmoc-diaminobutyric acid(Boc)-OH (1.35 g, 3.1 mmol) and DIC (0.5 mL, 3.2 mmol) was added. The reaction was stirred at room temperature overnight. The DCM was removed by rotary evaporation and the residue was subjected to column chromatography on silica gel using petroleum spirit:EtOAc (1:1 to 0:1), providing compound 46 (0.48 g, 22%).

Example 46
Synthesis of Compound 47 (3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)-5-(allyloxycarbonylaminomethyl)-1-(3,5-dichlorobenzyll)-1,4-diazepan-2-one

To Compound 46 (0.48 g, 0.63 mmol) in DCM (3 mL) was added diethylamine (1.5 mL). The reaction was stirred at room temperature for 1 hr. The DCM and diethylamine was removed by rotary evaporation. DCM (5 mL), sodium triacetoxyborohydride (0.2 g, 0.94 mmol) was added, and the reaction was stirred overnight at room temperature. The organic phase was washed with saturated sodium bicarbonate solution (25 mL), dried (MgSO₄) and the DCM removed to give the cyclised product 47 (0.24 g, 72%).

Example 47
Synthesis of Compound 48 (3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)-5-aminomethyl-1-(3,5-dichlorobenzyl)-1,4-diazepan-2-one

To the cyclised product 47 (0.24 g, 0.45 mmol) in DCM (3 mL) was added 1,3-dimethylbarbituric acid (13 mg, 0.08 mmol) and palladium tetrakis triphenylphosphine (5 mg). The reaction was evacuated and stirred and room temperature for 1 hr. The DCM was removed under reduced pressure to give the crude product 48 (0.15 g. 75%) which was used in the next reaction without purification.

Example 48
Synthesis of Compound 49 (3S,5S)-3-(2-aminoethyl)-5-(2-naphthoylaminomethyl)-1-(3,5-dichlorobenzyl)-1,4-diazepan-2-one

To the amine 48 (0.05 mg, 0.11 mmol) in DCM (1 mL) was added DIPEA (0.1 mL, 0.7 mmol), BOP reagent (0.05 mg, 0.11 mmol) and 2-naphthoic acid (0.04 mg, 0.23 mmol). The reaction was stirred at room temperature for 2 hrs. TFA (1 mL) was added and the reaction stirred at room temperature for 2 hrs. Rotary evaporation and preparative HPLC gave 49 (48 mg, 90%). MS(ESI) 499.3 (M+1); HPLC t_R5.77 min

Example 49
Synthesis of Compound 50 N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthalene-2-sulfonamide

Prepared from allyl 2-oxobut-3-enylcarbamate 45, Boc-L-Arg(Fmoc)₂-OH and 2,2-diphenylethylamine according the the procedures of Examples 46-48, with the following modification: the Boc group was removed with TFA during the deprotection/cyclization procedure of Example 47, rather than using diethylamine for Fmoc removal. Following Alloc deprotection by the procedure of Example 48, the free amine was dissolved in DCM to which was added naphthalene-2-sulfonyl chloride (10 mg) and DIPEA (20 μL) and the reaction stirred for 2 h at room temperature. Diethylamine (1 mL) was added and stirred overnight to remove the Fmoc protection, and the reaction evaporated to dryness. Preparative HPLC gave title compound 50 (13 mg). MS(ESI) 613.5 (M+1); HPLC t_R5.89 min.

Example 50
Synthesis of Compound 51 (S)-9-fluorenylmethyl 10-(2-ethylbutyl)-2,2-dimethyl-18-phenyl-4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-triazaoctadecan-8-ylcarbamate

To 2-ethylbutylamine (0.15 g, 1.48 mmol) in DCM (10 mL) was added the α,β-unsaturated ketone 27 (1.47 mmol) in DCM (30 mL). After stirring at room temperature for 15 mins, Fmoc-diaminobutyric acid(Boc)-OH (0.95 g, 2.16 mmol) and DIC (0.34 mL, 2.19 mmol) were added. The reaction was stirred at room temperature overnight. The DCM was removed by rotary evaporation and the residue was subjected to column chromatography on silica gel using petroleum spirit:EtOAc (1:1 to 0:1), providing Compound 51 (0.5 g, 46%).

Example 51
Synthesis of Compound 52 (3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)-5-(benzyloxycarbonylaminomethyl)-1-(2-ethylbutyl)-1,4-diazepan-2-one

To Compound 51 (0.5 g, 0.67 mmol) in DCM (3 mL) was added diethylamine mL). The reaction was stirred at room temperature for 1 hr. The DCM and diethylamine were removed by rotary evaporation. DCM (5 mL) and sodium triacetoxyborohydride (0.2 g, 0.94 mmol) were added and the reaction was stirred overnight at room temperature. The organic phase was washed with saturated sodium bicarbonate solution (25 mL), dried (MgSO₄) and the DCM removed to give the crude cyclised product 52 (0.4 g).

Example 52
Synthesis of Compound 53 (3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)-5-(aminomethyl)-1-(2-ethylbutyl)-1,4-diazepan-2-one

To the cyclised product 52 (0.4 g) in methanol (5 mL) was added catalytic Pd/C. The reaction was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered through Celite and the methanol removed by rotary evaporation to give the amine 53 (0.17 g, 68% from 51).

Example 53
Synthesis of Compound 54 N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide

To the amine 53 (0.030 g, 0.08 mmol) in DCM (1 mL) was added DIPEA (0.1 mL, 0.7 mmol), BOP reagent (0.03 g, 0.07 mmol) and 2-naphthoic acid (0.025 g, 0.14 mmol). The reaction was stirred at room temperature for 2 hrs. TFA (1 mL) was added and the reaction stirred at room temperature for 2 hrs. Rotary evaporation and preparative HPLC gave Compound 54 (23 mg, 68%). MS(ESI) 425.7 (M+1); HPLC t_R5.27

Example 54
Synthesis of Compound 55 (3S,5S)-3-[2-(piperdin-1-yl)ethyl]-5-(benzyloxycarbonylaminomethyl)-1-(2-ethylbutyl)-1,4-diazepan-2-one

To Compound 54 (0.25 g, 0.5 mmol) in DCM (3 mL) was added TFA (1.5 mL), with the solution stirred at room temperature for 1 hr. DCM (20 mL) was added and the solution was washed with saturated sodium bicarbonate solution (20 mL), dried over MgSO₄and evaporated to give the crude amine (0.16 g). To this was added DMF (0.25 mL), potassium carbonate (10 mg) and 1,5-dibromopentane (0.35 mL, 2.5 mmol). The reaction mixture was stirred at room temperature for 1.5 hrs, after which DCM (20 mL) was added, the organic layer washed with saturated sodium bicarbonate solution (20 mL) and H₂O (20 mL), dried (MgSO₄) and evaporated to give crude 55, which was used in the next reaction without purification.

Example 55
Synthesis of Compound 56 (3S,5S)-3-[2-(piperidin-1-yl)ethyl]-5-aminomethyl-1-(2-ethylbutyl)-1,4-diazepan-2-one

To the cyclised product 55 (0.4 g) in methanol (5 mL) was added catalytic Pd/C. The reaction was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered through Celite and the methanol removed by rotary evaporation to give the amine 56 (0.12 g).

Example 56
Synthesis of Boc-L-Glu(piperidine)-OH 57 (S)-2-(tert-butoxycarbonylamino)-5-oxo-5-(piperidin-1-yl)pentanoic acid

HATU (2.5 g) and DIPEA (1.5 mL) was added to Boc-L-Glu(OH)-OBn (2.0 g) in DCM (50 mL), stirred for 10 min, then piperidine (0.7 mL) was added and the reaction stirred overnight at room temperature. The reaction was washed with sodium bibicarbonate solution (2×), saturated NH₄Cl (2×), brine (2×), dried over MgSO₄, filtered, and evaporated to give 2.9 g of Boc-L-Glu(piperidine)-OBn. The benzyl ester (0.6 g) was dissolved in EtOH (15 mL) with catalytic Pd/C and hydrogenated for 1 h, filtered over Celite, and the EtOH evaporated by rotary evaporation to give 0.51 g of 57.

Example 57
Synthesis of Compound 58 (3S,5S)-3-(2-tert-butoxycarbonylaminopropyl)-5-[benzyloxycarbonyl(methylamino)methyl]-1-(2,2 diphenylethyl)-1,4-diazepan-2-one

Prepared from Cbz-Sar, 2,2-diphenylethylamine and Fmoc-L-Orn(Boc) according to the procedures of Examples 27-30.

Example 58
Synthesis of Compound 59 (3S,5S)-3-(2-tert-butoxycarbonylaminopropyl)-5-(methylamino)methyl-1-(2,2-diphenylethyl)-1,4 diazepan-2-one

The cyclised product 58 (1.9 g) was dissolved in methanol (10 mL) with catalytic Pd/C and hydrogenated under a hydrogen atmosphere (40 psi) overnight. The reaction mixture was filtered through Celite and the methanol removed by rotary evaporation to give the amine 59 (1.86 g, 97%).

Example 59
Synthesis of Compound 60 N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-bromo-N-methyl-2-naphthamide

The amine 59 was coupled with 6-bromo-2-naphthoic acid then deprotected with TFA according to Example 31. Rotary evaporation and preparative HPLC gave 60 (7.8 mg). MS(ESI) 629.4 (M+1); HPLC t_R6.27 min.

Example 60
Synthesis of Compound 61 (3S,5S)-3-(tert-butoxycarbonylaminopropyl)-5-(6-bromo-2-naphthamidomethyl)-1-(2,2-diphenylethyl)-1,4-diazepan-2-one

Prepared from 2,2-diphenylethylamine, Fmoc-L-Orn(Boc) and 6-bromo-2-naphthoic acid according to the procedures of Examples 28-31, without the TFA deprotection step of Example 31.

Example 61
Synthesis of Compound 62 N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-4-methyl-2-oxo-1,4-diazepan-5-yl)methyl)-6-bromo-2-naphthamide

Compound 61 (20.8 mg) was dissolved in DMF (1 mL) and treated with methyl iodide (6 μL) at room temperature for 1 week. Additional methyl iodide (0.5 mL) and K₂CO₃were added and the reaction left at room temperature for an additional 2 days. TFA (2 mL) was added and the reaction stirred at room temperature for 2 h. Rotary evaporation followed by evaporation under high vacuum then preparative HPLC gave 62 (8.5 mg). MS(ESI) 629.3 (M+1); HPLC t_R6.22 min.

Example 62
Synthesis of Compound 63 N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide

Obtained from 9, 2,2-diphenylethylamine and Fmoc-L-Orn(Boc) according to Examples 10-12. The Boc group was removed under standard conditions to give the free amine. MS(ESI) 535 (M+1); HPLC t_R5.78 min

Example 63
Synthesis of Compound 64 N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide

The amine 63 (0.79 g, 1.48 mmol), 1,5-dibromopentane (0.2 mL, 1.48 mmol) and K₂CO₃(0.79 g) in DMF (11 mL) was stirred at room temperature for 4 h. The resulting mixture was diluted with ethylacetate (30 mL), washed with H₂O (5×30 mL), brine (10 mL) and dried over MgSO₄. Purification by preparative HPLC yielded 64 (0.23 g, 25%) MS(ESI) 603.3 (M+1); HPLC t_R6.04 min

Example 64
Synthesis of Compound 65 N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-(isopropylamino)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide

To a stirred mixture of the amine 63 (11 mg, 0.02 mmol), acetone (2 mL) and MgSO₄(50 mg) in DCM (5 mL) was added sodium triacetoxyborohydride (8.5 mg, 0.04 mmol) at room temperature. Stirring continued for 2 h, the mixture was concentrated, re-dissolved in EtOAc (5 mL), washed with saturated aqueous NaHCO₃solution (10 mL) and brine (10 mL), dried over MgSO₄and concentrated under reduced pressure. Purification by preparative HPLC yielded 65 (9.5 mg, 80%). MS(ESI) 577.2 (M+1); HPLC t_R5.97 min.

Example 65
Synthesis of Compound 66 tert-butyl (methylamino)(methylthio)methylenecarbamate

DIAD (2.7 mL, 13.8 mmol) was added to a stirred mixture of thiopseudourea (2.0 g, 6.9 mmol), PPh₃(3.6g, 13.8 mmol), and MeOH (0.55 mL, 13.8 mmol) in dry THF (5 mL) at 0° C. under nitrogen. Stirring continued at 0° C. for 3 h then at room temperature for 16 h. The solvent was removed under reduced pressure and the resulting residue was re-dissolved in EtOAc, washed with saturated aqueous NaHCO3 solution (20 mL) and brine (20 mL), and dried over MgSO₄. Purification by silica gel chromatography using 20% EtOAc in petroleum ether as eluent gave 66 (1.63 g, 78%) as a colourless oil. MS(ESI) 305 (M+1); HPLC t_R7.97 min.

Example 66
Synthesis of Compound 67 N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-(3-methylguanidino)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide

A mixture of Compound 63 (10 mg, 0.019 mmol), guanylating agent 66 (56.9 mg, 0.19 mmol) and DIPEA (6.6 μL, 0.038 mmol) in DCM (5 mL) was stirred at room temperature for 16 h. TFA (5 mL) was added, and the resulting mixture was stirred at room temperature for 30 min. Solvent was removed under reduced pressure, and the crude product was purified by preparative HPLC to give 67 (0.53 mg, 4.7%) as a white solid. MS(ESI) 591.3 (M+1); HPLC t_R5.94 min

Example 67
Synthesis of Compound 68 (S)-9-fluorenylmethyl 1-phenyl-10-(2,2-diphenylethyl)-18,18-dimethyl-4,9,13,16-tetraoxo-2,17-dioxa-4,10,15-triazanonadecan-8-ylcarbamate

To a stirred mixture of Fmoc-L-Orn(Cbz)-OH (1.78 g, 3.65 mmol), DIPEA (0.64 mL, 3.65 mmol) and HATU (1.39 g, 3.65 mmol) in DCM (10 mL) was added a solution of amine 17 at room temperature. Stirring continued for 3 h, the reaction mixture was washed with saturated NaHCO₃aqueous solution (20 mL) and brine (20 mL), and dried over MgSO₄. The solvent was removed under reduced pressure, with the crude 68 used in the next step without further purification. MS(ESI) 853 (M+1); HPLC t_R9.90 min.

Example 68
Synthesis of Compound 69 (S)-(9H-fluoren-9-yl)methyl 7-((4-(tert-butoxycarbonylamino)-3-oxobutyl)(2,2-diphenylethyl)carbamoyl)-3-methyl-1,3-diazepane-1-carboxylate

A mixture of 68 (136 mg, 0.159 mmol) and Pd/C (20 mg) in ethanol (5 mL) was shaken under H₂at 30 psi for 16 h, then filtered, concentrated under reduced pressure to give the crude amine (90 mg, 78%). The amine (90 mg, 0.125 mmol) was treated with excess formaldehyde solution in H₂O (37 mmol) in MeOH (5 mL) followed by sodium triacetoxyborohydride (23.5 mg, 0.375 mmol). After 1 h, the reaction mixture was washed with saturated NaHCO₃aqueous solution (10 mL) and brine (10 mL), dried over MgSO₄, filtered and concentrated. The crude material was used in the next step without further purification. MS(ESI) 745 (M+1); HPLC; HPLC t_R7.83 min.

Example 69
Synthesis of Compound 70 (S)-(9H-fluoren-9-yl)methyl 7-((4-(2-naphthamido)-3-oxobutyl)(2,2-diphenylethyl)-carbamoyl)-3-methyl-1,3-diazepane-1-carboxylate

Compound 69 (8 mg, 0.011 mmol) was treated with 1:1 v/v trifluoacetic acid/DCM mixture (2 mL) for 30 min at room temperature. The mixture was concentrated under reduced pressure, re-dissolved in DCM (5 mL), washed with saturated NaHCO₃aqueous solution (5 mL) and brine (5 mL), dried over MgSO₄and filtered. The filtrate was then treated with a mixture of 2-naphthoic acid (1.8 mg, 0.011 mmol), DIPEA (5.7 μL, 0.033 mmol) and BOP (4.8 mg, 0.011 mmol) in DCM (1 mL) with stirring at room temperature. After 3 h, the reaction mixture was washed with saturated NaHCO₃aqueous solution (10 mL) and brine (10 mL), dried over MgSO₄, filtered and concentrated. The crude material was used in the next step without further purification. MS(ESI) 799 (M+1); HPLC t_R7.90 min.

Example 70
Synthesis of Compound 71 N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-(methylamino)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide

To a stirred solution of 70 (0.011 mmol) in DCM (5 mL) was added diethylamine (5 mL) at room temperature. The reaction was stirred for 1 h, then concentrated under reduced pressure. The residue was re-dissolved in DCM (5 mL) followed by addition sodium triacetoxyborohydride (5 mg, 0.08 mmol) at room temperature. Stirring continued for 1 h, with the resulting mixture washed with saturated NaHCO₃aqueous solution (10 mL) and brine (10 mL), dried over MgSO₄, filtered and concentrated. Purification by preparative HPLC yielded 71 (0.21 mg) as a white solid. MS(ESI) 549.3 (M+1); HPLC t_R5.93 min

Example 71
Synthesis of Compound 72 (S)-2-(allyloxycarbonylamino)-3-(naphthalen-2-yl)propanoic acid

To a stirred mixture of L-3-(2-naphthyl)alanine hydrochloride (5.0 g, 19.8 mmol), Na₂CO₃(7.3 g, 69.3 mmol) and 1,4-dioxane (30 mL) in H₂O (50 mL) was added allylchloroformate (2.1 mL, 19.8 mmol) at 0° C. The resulting mixture was stirred for 16 h then concentrated under reduced pressure. The residue was diluted with ethylacetate (50 mL), and at 0° C. acidified to pH 2. The aqueous phase was extracted with ethylacetate (3×20 mL), the combined organic phase was washed with H₂O (50 mL) and brine (20 mL), dried over MgSO₄, filtered and concentrated under reduced pressure to give 72 as a colourless oil (5.8 g, 97%), which was used in the next step without further purification. HPLC t_R6.60 min.

Example 72
Synthesis of Compound 73 (S)-allyl 1-(methoxy(methyl)amino)-3-(naphthalen-2-yl)-1-oxopropan-2-ylcarbamate

To a stirred mixture of the acid 72 (5.84 g, 19.5 mmol), DIPEA (3.7 mL, 2.09 mmol) and BOP (8.63 g, 19.5 mmol) in DCM (10 mL) was added a pre-mixed solution of N,O-dimethylhydroxylamine hydrochloride (1.9 g, 19.5 mmol) and DIPEA (7.3 mL, 41.6 mmol) in DCM (10 mL) at room temperature. Stirring continued for 16 h the reaction mixture was washed with 1N HCl (3×60 mL), H₂O (3×60 mL), saturated NaHCO₃aqueous solution (3×60 mL) and brine (60 mL), dried over MgSO₄. Purification by silica gel chromatography using 20% ethylacetate in petroleum ether as eluent gave 73 (4.83 g, 71%) as a colourless oil. MS(ESI) 343 (M+1); HPLC t_R7.07 min.

Example 73
Synthesis of Compound 74 (S)-allyl 1-(naphthalen-2-yl)-3-oxopent-4-en-2-ylcarbamate

At 0° C. a solution of vinylmagnesium bromide in THF (11.5 mL, 1 M) was added in one portion to Weinreb amide 73 (1.58 g, 4.62 mmol) under nitrogen with stirring. The resulting mixture was allowed to stir for 2 h, and poured into a 1N HCl/ice mixture (50 mL). The aqueous mixture was extracted with DCM (3×20 mL), the combined DCM extract was washed with 1N HCl (50 mL), saturated NaHCO₃aqueous solution (50 mL) and brine (20 mL), dried over MgSO₄. Solvent was removed under reduced pressure producing the product 74 (1.14 g, 80%), which was used in the next step without further purification. MS(ESI) 310 (M+1); HPLC t_R7.51 min.

Example 74
Synthesis of Compound 75 (S)-allyl 5-(2,2-diphenylethylamino)-1-(naphthalen-2-yl)-3-oxopentan-2-ylcarbamate

To a stirred solution of 2,2-diphenylethylamine (0.45 g, 2.3 mmol) in DCM (55 mL) was added the vinyl ketone 74 (0.71 g, 2.3 mmol) in one portion. Stirring continued for 2 h, with the reaction mixture used in the next step without purification. MS(ESI) 507 (M+1); HPLC t_R7.22 min.

Example 75
Synthesis of Compound 76 (S)-allyl 5-(N-(Boc-L-Arg(Cbz)₂) 2,2-diphenylethylamino)-1-(naphthalen-2-yl)-3-oxopentan-2-ylcarbamate

To a stirred solution of the amine adduct 75 (2.3 mmol) was added a mixture of Boc-Arg(Cbz)₂-OH (1.25 g, 2.3 mmol), DIPEA (0.8 mL, 4.6 mmol) and HATU (0.87 g, 2.3 mmol) in DCM (15 mL) at room temperature. Stirring continued for 16 h, after which the reaction mixture was washed with saturated NaHCO₃aqueous solution (3×20 mL) and brine (10 mL) then dried over MgSO₄. Purification by silica gel chromatography using 20% ethylacetate in petroleum ether as eluent gave 76 as a colourless oil (708 mg, 30% over 3 steps). MS(ESI) 1031 (M+1); HPLC t_R10.80 min.

Example 76
Synthesis of Compound 77 allyl (S)-1-((3S,5RS)-1-(2,2-diphenylethyl)-3-(bis Cbz 3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethylcarbamate

To a stirred solution of acyclic intermediate 76 (0.48 g, 0.47 mmol) in DCM (5 mL) was added TFA (5 mL) at room temperature. Stirring continued for 30 min, after which the mixture was diluted with DCM (20 mL) then washed with saturated NaHCO3 aqueous solution (3×20 mL) and brine (10 mL), and dried over MgSO₄. To the resulting solution was added sodium triacetoxyborohydride (0.2 g, 0.94 mmol) with stirring at room temperature, after 30 min the mixture was washed with saturated NaHCO₃aqueous solution (3×20 mL) and brine (10 mL), then dried over MgSO₄. The crude 77, a mixture of diastereomers at the diazepan-2-one C5, was used in the next step without further purification. MS(ESI) 915 (M+1)

Example 77
Synthesis of Compound 78 bis (Cbz) 1-(3-((2S,7RS)-7-((S)-1-amino-2-(naphthalen-2-yl)ethyl)-4-(2,2-diphenylethyl)-3-oxo-1,4-diazepan-2-yl)propyl)guanidine

A mixture of compound 77 (36 mg, 0.039 mmol), 1,3-dimethylbarbituric acid (7.4 mg, 0.047 mmol) and Pd(PPh₃)₄in DCM (5 mL) was stirred at room temperature under vacuum for 4 h. The resulting mixture was used in the next step without further purification. MS(ESI) 832 (M+1)

Example 78
Synthesis of Compounds 79 and 80 N—((S)-1-((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethyl)acetamide and N—((S)-1-((3S,5R)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethyl)acetamide

A solution of the amine 78 (0.09 mmol) in DCM (5 mL) was treated with acetic anhydride (8.6 μL, 0.09 mmol) with stirring at room temperature. After 3 h the mixture was concentrated, re-dissolved in EtOAc, washed with saturated NaHCO₃aqueous solution (10 mL) and brine (10 mL), dried over MgSO₄, then concentrated under reduced pressure. The residue was dissolved in MeOH (10 mL), Pd/C (5 mg) was added, and the solution shaken under H₂at 20 psi for 16 h. The reaction was filtered, concentrated and purified by preparative HPLC to give the preferred diastereomer 79 (3 mg) and the less preferred diastereomer 80 (6 mg) as white solids.

79: MS(ESI) 606.4 (M+1); HPLC t_R6.033 min

80: MS(ESI) 606.3 (M+1); HPLC t_R6.046 min

Example 79
Synthesis of Compounds 81 and 82 (S)-2-acetamido-N—((S)-1-((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethyl)-3-(1H-imidazol-5-yl)propanamide and (S)-2-acetamido-N—((S)-1-((3S,5R)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethyl)-3-(1H-imidazol-5-yl)propanamide

To a stirred mixture of Ac-L-His-OH (33.6 mg, 0.156 mmol), DIPEA (112.5 μL, 0.312 mmol) and BOP (68.8 mg, 0.156 mmol) in DMF (1 mL) was added the amine 78 (0.039 mmol) at room temperature. Stirring continued for 16 h, then the reaction mixture was diluted with DCM/H₂O mixture (10 mL, 1:1 v/v), and the aqueous phase was extracted with DCM (3×5 mL). The combined DCM extracts were washed with saturated NaHCO₃aqueous solution (3×20 mL) and brine (10 mL), dried over MgSO₄, and concentrated under reduced pressure. The residue was re-dissolved in MeOH (5 mL), and Pd/C (20 mg) was added. The resulting mixture was shaken under H₂at 30 psi for 16 h, then was filtered, concentrated and purified by preparative HPLC to give the preferred diastereomer 81 (1.9 mg) and the less preferred diastereomer 82 (0.9 mg) as white solids.

81: MS(ESI) 743.4 (M+1); HPLC t_R5.489 min

82: MS(ESI) 743.4 (M+1); HPLC t_R5.555 min

Example 80
Synthesis of Compounds 83 and 84 propyl (S)-1-((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethylcarbamate and propyl (S)-1-((3S,5R)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethylcarbamate

A mixture of 77 (36 mg, 0.039 mmol) and Pd/C (5 mg) in MeOH (5 mL) was shaken under H₂at 20 psi for 16 h, then was filtered, concentrated and purified by preparative HPLC to give the preferred diastereomer 83 (0.07 mg) and the less preferred diastereomer 84 (2.7 mg) as white solids.

83: MS(ESI) 650.3 (M+1); HPLC t_R6.52 min

84: MS(ESI) 650.2 (M+1); HPLC t_R6.64 min

Example 81
Synthesis of Compounds 85-87 1-(3-((2S,7S)-7-(N—R1 (R)-1-amino-2-(naphthalen-2-yl)ethyl)-4-(2,2-diphenylethyl)-3-oxo-1,4-diazepan-2-yl)propyl)guanidine

Compounds 85-87 were prepared in the same fashion as the preferred diastereomers Compounds 79, 81 and 83 using the procedures described in Examples 72-81 with D-(2-naphthyl)alanine hydrochloride as the starting material.

Compound
R₁group
MS (M + 1)
t_R(min)

85
Ac
606.2
6.01

86
Ac-His
743.5
5.41

87
Propyloxycarbonyl
650.4
6.42

Examples 82-90
Synthesis via Scheme 2: Preparation of all Four Diastereomers of N-((1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide 88

Example 82
Synthesis of Compound 89 2,2-dimethyl-10-(2,2-diphenylethyl)-4,7,11-trioxo-3,12-dioxa-5,10-diazapentadec-14-ene

2,2-diphenylethylamine (3g) was added to Boc-vinylketone 16 (2.8 g) as in Example 17. To the crude adduct 17 was added Alloc-Cl (1.6 mL) and the reaction stirred until TLC indicated consumption of the secondary amine. THE solvent was evaporated and the residue purified by column chromatography (SiO2 gel, pet. ether/EtOAc) to give 3.2 g (57%) of 89.

Example 83
Synthesis of Compound 90 (S)-allyl 2-amino-5-(benzyloxycarbonylamino)pentanoate L-H-Orn(Cbz)-Oallyl

H-L-Orn(Cbz)-OH (6.66 g, 25 mmol), allyl alcohol (17.56 mL, 25 mmol) and p-TsOH (5.7 g, 30 mmol) were dissolved in benzene (200 mL) and refluxed under Dean-Stark conditions for 5 h. The majority of the solvent was then distilled off, with the remainder removed under vacuum. The resulting solid was recrystallized from DCM, filtered and dried to give 11.19 g (94%) of the tosylate salt. To obtain the free amine the solid was dissolved in DCM, washed with sat. NaHCO₃, the aqueous layer washed with DCM (3×), and the organic layers dried over MgSO₄and evaporated to dryness.

Example 84
Synthesis of Compound 91 (R)-allyl 2-amino-5-(benzyloxycarbonylamino)pentanoate D-H-Orn(Cbz)-Oallyl

H-D-Orn(Cbz)-OH (6.66 g, 25 mmol) was converted into 10.93 g (91%) of the tosylate salt of 91 as in Example 83, then converted into the free amine.

Example 85
Synthesis of Compound 92 (2R)-allyl 5-(benzyloxycarbonylamino)-2-(10-(2,2-diphenylethyl)-2,2-dimethyl-4,11-dioxo-3,12-dioxa-5,10-diazapentadec-14-en-7-ylamino)pentanoate

The protected aminoketone 89 (746 mg, 1.6 mmol), D-Orn(Cbz)-Oallyl 91 (538 mg, 1.76 mmol) and NaBH(OAc)₃(678 mg, 3.2 mmol) in a minimum volume of DCM were stirred for 24 h. A drop of AcOH was added just before workup, at which point saturated NaHCO₃was added, extracted with DCM (3×), and the organic extracts combined and washed with saturated NaHCO₃and H₂O, dried over MgSO₄, and evaporated to dryness. The product was purified by column chromatography (SiO₂gel, pet. ether/EtOAc) to give 890 mg (74%) of 92 as a mixture of diastereoisomers.

Example 86
Synthesis of Compound 93 (2S)-allyl 5-(benzyloxycarbonylamino)-2-(10-(2,2-diphenylethyl)-2,2-dimethyl-4,11-dioxo-3,12-dioxa-5,10-diazapentadec-14-en-7-ylamino)pentanoate

L-Orn(Cbz)-Oallyl 90 (592 mg, 1.93 mmol) was converted into a mixture of the set of diastereomers 93 (925 mg, 76%) following the procedures of Example 86.

Example 87
Synthesis of Compounds 94 and 95 (3R,5S)-5-(N-Boc aminomethyl)-3-(N-Cbz 3-aminopropyl)-1-(2,2-diphenylethyl)-1,4-diazepan-2-one and (3R,5R)-5-(N-Boc aminomethyl)-3-(N-Cbz 3-aminopropyl)-1-(2,2-diphenylethyl)-1,4-diazepan-2-one

The Alloc/allyl protected derivative 92 (840 mg, 1.11 mmol) was dissolved in a minimum of DCM. 1,3-Dimethylbarbituric acid (346 mg, 2.22 mmol) and catalytic Pd(PPh₃)₄were added, and the reaction degassed under vacuum, sealed and stirred overnight. The reaction was diluted to 50 mL with DCM, DIPEA (430 mg, 3.33 mmol) and BOP (540 mg, 1.22 mmol) were added, and the reaction stirred for 30 min. The DCM was removed under vacuum and the residue taken up in EtOAc, washed (saturated NaHCO₃, H₂O, saturated NaCl), dried (MgSO₄) and evaporated to dryness (TLC: EtOAc, 2 spots, Rf 0.33 and 0.57). The two diastereomeric products were separated by column chromatography (SiO₂gel, pet. ether/EtOAc) to give 362 mg of the earlier eluting (3R,5S) isomer 94, and 342 mg of the later eluting (3R,5R) isomer 95.

Example 88
Synthesis of Compounds 96 and 97 (3S,5R)-5-(N-Boc aminomethyl)-3-(N-Cbz 3-aminopropyl)-1-(2,2-diphenylethyl)-1,4-diazepan-2-one and (3S,5S)-5-(N-Boc aminomethyl)-3-(N-Cbz 3-aminopropyl)-1-(2,2-diphenylethyl)-1,4-diazepan-2-one

The (3S,5R) (312 mg) and (3S,5S) (331 mg) isomers were obtained from the L-Orn-derived acyclic material 93 (870 mg) following the procedure of Example 87.

Example 89
Synthesis of Compounds 98-101 5-(N-Boc aminomethyl)-3-(N,N′-Cbz₂3-guanidinopropyl)-1-(2,2-diphenylethyl)-1,4-diazepan-2-one

The Orn Cbz group of 94 was removed by hydrogenation (H₂, 30 psi) over catalytic Pd/C in methanol overnight. The solution was filtered through Celite and evaporated to give a solid. A solution of the resulting amine (187 mg, 0.39 mmol) in DCM was mixed with a solution of the guanylating reagent CbzNHC(=NCbz)NHTf (196 mg, 0.43 mmol) in DCM. TEA (43 mg, 0.43 mmol) was added, and the reaction stirred overnight. The solution was diluted with DCM, washed (KHSO₄, sat. NaHCO₃, brine), dried (MgSO₄) and evaporated to dryness, then purified by flash chromatography over SiO₂using hexanes/EtOAc as eluent, to give (3R,5S) 98 (182 mg, 59%). The other isomers 95-97 were converted in a similar manner to give:

99 (3R,5R): 171 mg (68%) from 148 mg of amine

100 (3S,5S): 80 mg (65%) from 72 mg of amine

101 (3S,5R):142 mg (58%) from 144 mg of amine

Example 90
Synthesis of Compounds 102-105

102 N-(((3R,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide

103 N-(((3R,5R)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide

104 N-(((3S,5R)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide

105 N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide

The Boc derivative 99 (180 mg) in DCM (1 mL) was treated with TFA (1 mL) for 20 mL. The solvent was removed by evaporation, a solution of NaHCO₃was added, and extracted 3× with DCM. The dichoromethane solution was dried over MgSO₄, filtered and evaporated to dryness. A portion (56 mg, 0.086 mmol) of the crude deprotected amine in DCM was stirred with 2-naphthoic acid (16 mg), DIPEA (60 uL) and BOP (42 mg) for 30 min. MeOH was added and the reaction stirred overnight. The reaction was filtered, then purified by flash chromatography over SiO₂using petroleum ether/EtOAc as eluent, to give the (3R,5R) isomer (43 mg, 94%). The other isomers were converted in a similar manner to give: (3R,5S): 41 mg (85%) from 60 mg 98, (3S,5R): 27 mg (70%) from 40 mg 101, and (3S,5S): 13 mg (74%) from 20 mg 100 Each compound was dissolved in dioxane:MeOH and hydrogenated over catalytic Pd/C under 30 psi H₂overnight. The solution was filtered through Celite and evaporated to give a solid. 102 (3R,5S): 27 mg (96%) from 41 mg, 103 (3R,5R): 25 mg (85%) from 43 mg, 104 (3S,5R): 11 mg (quantitative) from 13 mg, and 105 (3S,5S): 3 mg (73%) from 6 mg.

Compound
stereochemistry
MS (M + 1)
t_R(min)

102
(3R,5S)
577.4
5.775

103
(3R,5R)
577.5
5.750

104
(3S,5R)
577.5
5.783

105
(3S,5S)
577.3
5.787

Example 91
Synthesis of Compounds 425,565, 580-585

425 6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide

565 6-chloro-N-(((3S,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide

580 6-chloro-N-(((3R,5R)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide

581 6-chloro-N-(((3S,5R)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide

582 6-chloro-N-(((3R,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide

583 6-chloro-N-(((3S,5R)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide

584 6-chloro-N-(((3R,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide

585 6-chloro-N-(((3R,5R)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide

Compounds 425, 565, and 580-585 were prepared following similar procedures as used to prepare Compounds 102-104 (Scheme 2 route). In addition, compounds 425, 565, 580 and 585 were prepared according to the Scheme 1 route; a detailed procedure for the preparation of Compound 425 is contained in Examples 92-99.

Compound
stereochemistry
MS (M + 1)
t_R(min)

425
(3S,5S,2′S)
575.3
6.269

565
(3S,5S,2′R)
574.8
6.265

580
(3R,5R,2′R)
575.4
6.404

581
(3S,5R,2′S)
575.2
6.262

582
(3R,5S,2′S)
575.2
6.110

583
(3S,5R,2′R)
575.1
6.211

584
(3R,5S,2′R)
575.2
6.253

585
(3R,5R,2′S)
575.4
6.274

Example 92
Synthesis of Compound 586 (S)—N-(2-oxo-4-(2-phenylbutylamino)butyl)-3-phenylpropanamide

To a solution of (S)-phenylbutylamine (8.5 g, 57.07 mmol) in DCM (100 ml) was added a solution of α,β-unsaturated ketone 27 (12.5 g, 57.1 mmol) in DCM (100 ml) at room temperature in one portion. The resulting mixture was stirred until all of the α,β-unsaturated ketone had been consumed (within one hour), then the conjugate addition adduct 586 was used straight in the next reaction.

HPLC t_R5.71 min

MS(ESI) 369.3 (M+1)

Example 93
Synthesis of Compound 587 (S)-9-fluorenylmethyl 10-[(S)-2-phenylbutyl]-2,2-dimethyl-18-phenyl-4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-triazaoctadecan-8-ylcarbamate

To the freshly prepared amine 586 in DCM (200 mL) was added Fmoc-L-Dab(Boc)OH (32.7 g, 74.2 mmol) followed by DIPC (11.5 g, 74.2 mmol) at room temperature. The resulting mixture was stirred for 2 hours, the by-product diisopropylurea was removed by filtration through a pad of Celite®, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography using 30-70% EtOAc/Pet. Spirit as eluent to give 587 (19.9 g, 44% yield over two steps).

TLC rf 0.23 (50% EtOAc/Pet. Spirit)

HPLC t_R10.03 min

MS(ESI) 791.2 (M+1)

Example 94
Synthesis of Compound 588 (S)-10-[(S)-2-phenylbutyl]-2,2-dimethyl-8-amino-1 8-phenyl-4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-triazaoctadecane

Diethylamine (30 mL) was added to a solution of the acylated amine 587 (19.9 g, 25.19 mmol) in DCM (30 mL) at room temperature and the resulting mixture was stirred for 30 min. The solvent and diethylamine were removed under reduced pressure to give the desired product 588. It was used in the next step without further purification.

HPLC t_R6.85 min

MS(ESI) 569.3 (M+1)

Example 95
Synthesis of Compound 589 (3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)-5-(benzyloxycarbonylaminomethyl)-1-[(S)-2-phenylbutyl]-1,4-diazepan-2-one

To a solution of crude Fmoc deprotected material 588 in DCM (50 ml) was added AcOH (15 mL) followed by NaBH(OAc)₃(5.34 g, 25.2 mmol) in one portion at room temperature. The resulting mixture was stirred for 30 min, then washed with saturated NaHCO₃(aq) solution (80 mL×3), brine (80 mL) and dried over MgSO₄. Filtration and concentration of the organic phase under reduced pressure gave the crude product, which was purified by silica gel column chromatography using 50-100% EtOAc/Pet. Spirit followed by 20% MeCN/EtOAc to give the product 589 (12.3 g, 88% over two steps).

TLC rf 0.19 (70% EtOAc/Pet. Spirit)

HPLC t_R7.06 min

MS(ESI) 553.3 (M+1)

Example 96
Synthesis of Compound 590 tert-butyl 2-{(2S,7S)-7-aminomethyl-3-oxo-4-[(S)-2-phenylbutyl]-1,4-diazepan-2-yl}ethylcarbamate

A mixture of Cbz-protected product 589 (12.3 g, 22.3 mmol) and 5% Pd/C (2 g) in MeOH (100 mL) was shaken at room temperature under hydrogen at atmospheric pressure for one hour. The mixture was then filtered through a pad of Celite®, and the filtrate was concentrated under reduced pressure to give the crude amine 590. The crude material was used in the next step without further purification.

HPLC t_R5.77 min

MS(ESI) 419.3 (M+1)

Example 97
Synthesis of Compound 591 tert-butyl 2-((2S,7S)-7-((6-chloro-2-naphthamido)methyl)-3-oxo-4-((S)-2-phenylbutyl)-1,4-diazepan-2-yl)ethylcarbamate

To a solution of the free amine 590 and 6-chloro-2-naphthoic acid (4.58 g, 22.3 mmol) in DCM (125 ml) was added diisopropylethylamine (7.74 mL, 44.5 mmol) and BOP (9.84 g, 22.3 mmol) at room temperature. The resulting mixture was stirred for 16 hours then DCM was removed under reduced pressure. The residue was taken up in EtOAc (80 mL), then washed with saturated NaHCO₃(aq) (100 mL×5), brine (100 mL) and dried over MgSO₄. Filtration and concentration of the organic phase gave the crude material, which was purified by silica gel column chromatography using 80-100% EtOAc/Pet. Spirit as eluent to give the product 591 (10.7 g, 79%).

TLC rf 0.31 (80% EtOAc/Pet. Spirit)

HPLC t_R7.66 min

MS(ESI) 607.2 (M+1)

Example 98
Synthesis of Compound 465 N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide

To the Boc protected material 591 (10.7 g, 17.6 mmol) in DCM (26 mL) was added TFA (26 ml) in one portion, the resulting mixture was stirred at room temperature for one hour. DCM was removed under reduced pressure and the residue was taken up in EtOAc (30 mL), washed with saturated NaHCO₃(aq) (30 mL×3), brine (30 mL) and dried over MgSO₄. Filtration and concentration of the organic phase under reduced pressure gave the crude amine 465, which was used in the next step without further purification.

HPLC t_R5.98 min

MS(ESI) 507.0 (M+1)

Example 99
Synthesis of Compound 425 6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide

To a mixture of crude amine 465 in CH₃CN (800 mL) was added 1,5-dibromopentane (23.9 mL, 175.7 mmol) followed by K₂CO₃(48.6 g, 351.4 mmol). The resulting mixture was stirred at room temperature for 44 hours, monitored by HPLC for conversion of sm (6.0 min) to product (6.4 min), avoiding extended reaction times leading to overalkylation to generate a bromopentyl-alkylated byproduct (7.1 min). During isolation, excessive heating/concentration of the crude solution must be avoided before removal of excess dibromopropane, to avoid overalkylation of the piperidine ring. The K₂CO₃was removed by filtration through a pad of Celite®, and the filtrate was washed with Pet. Spirit (800 mL×2). The MeCN phase was concentrated under reduced pressure to 400 mL, and was washed with Pet. Spirit (400 mL×2). The MeCN was further concentrated under reduced pressure to 200 mL, and was washed with Pet. Spirit (200 mL×2). Evaporation of the final Pet. Spirit washing showed no more 1,5-dibromopentane was extracted, so the MeCN phase was concentrated under reduced pressure.

Aminopropyl-functionalized TLC rf 0.05-0.47 (80% EtOAc/Pet. Spirit)

Analytical HPLC t_R6.41 min

MS(ESI) 575.2 (M+1).

The crude product was purified by a combination of flash column chromatography over aminopropyl-functionalized silica gel, and/or by recrystallization from acetonitrile.

Flash column: To a column packed with amino propyl-functionalized silica gel (154 g) in 20% ethyl acetate/petroleum spirit was loaded the crude free base oil (7.2 g). The column was eluted with 20% ethyl acetate/petroleum spirit (150 mL), followed by 50% ethyl acetate/petroleum spirit (150 mL), 80% ethyl acetate/petroleum spirit (150 mL×2), 100% ethyl acetate (150 mL) and finally 100% acetonitrile (150 mL). Fractions containing 425 were combined and evaporated to dryness to yield a white crystalline solid.

Crystallization: The white crystalline solid (2.87 g) obtained by column purification was dissolved in boiling acetonitrile (50 mL) 85° C. Activated carbon (Darco® G-60, −100 mesh, Sigma-Aldrich) (200 mg) was added to remove colour impurity. A further portion of acetonitrile (50 mL) was added, and the resulting mixture was heated to boiling for 5 min. The charcoal was filtered off while the solution was hot, with the filter paper and the charcoal rinsed with hot acetonitrile (25 mL). The clear acetonitrile solution was reduced down to 50 mL and left to stand to cool to room temperature for 16 h. The white crystals were filtered off and dried by suction to give 2.22 g (99.0% pure by HPLC analysis). An additional 117.2 mg (93.3% purity) was recovered by additional crystallization from the filtrate.

Conversion to bisHCl Salt: The free base (2.4229 g, 42.1 mmol) was suspended in a 1:1 mixture of acetonitrile and milliQ H₂O (10 mL). A solution of 1 M HCl (aq.) was added until all the solids dissolved (approximately 5 mL). An additional quantity of milliQ H₂O was then added (20 mL) and the resulting solution frozen and lyopholised overnight, resulting in a white powder (2.61 g, 95.6% yield).

HPLC t_R6.27 min

MS(ESI) 575.1 (M+1).

¹H NMR (600 MHz, CDCl₃): δ 0.75 (t, 3H, J=7.2 Hz), 1.40 (m, 1H), 1.56 (m, 1H), 1.65 (m, 1H), 1.76˜1.90 (m, 4H), 1.90˜2.06 (m, 2H), 2.13 (m, 1H), 2.30 (br, 1H), 2.57 (m, 1H), 2.64˜2.86 (m, 4H), 2.90˜3.10 (m, 2H), 3.25 (dd, 1H, J=15.2, 10.4 Hz), 3.53 (m, 2H), 3.70˜3.85 (m, 3H), 4.00 (m, 2H), 4.10 (dd, 1H, J=13.6, 5.6 Hz), 4.45 (m, 1H), 7.10 (d, 2H, J=7.2 Hz), 7.18 (t, 1H, J=7.2 Hz), 7.26 (t, 1H, J=7.2 Hz), 7.37 (dd, 1H, J=9.0, 1.8 Hz), 7.71 (d, 1H, J=8.4 Hz), 7.75 (s, 1H), 7.86 (d, 1H, J=9.0 Hz), 8.09 (d, 1H, J=9.0 Hz), 8.64 (s, 1H), 8.68 (m, 1H), 9.85 (br, 1H).

¹³C NMR (100 MHz, CDCl₃): δ 11.78, 21.86, 23.08 (2), 24.59, 26.14, 28.09, 42.01, 46.24, 47.22, 53.14, 53.53, 54.03, 56.74, 57.79, 61.96, 125.35, 126.24, 126.89, 127.20, 127.33, 127.85, 128.51, 128.72, 130.69, 130.76, 130.91, 133.48, 135.28, 142.29, 167.18, 167.74

Example 100
Synthesis of Compound 579 6-chloro-N-(([5,6,6-²H₃](3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)[²H₂]methyl)-2-naphthamide

Compound 579 was synthesized according to the procedures in Examples 92-99, except that the Fmoc deprotection/reductive amination steps of Examples 94 and 95 were replaced by the following procedures in order to introduce the deuterium atoms.

To a solution of (S)-9-fluorenylmethyl 10-[(S)-2-phenylbutyl]-2,2-dimethyl-18-phenyl-4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-triazaoctadecan-8-ylcarbamate 587 (370.5 mg, 0.47 mmol) in dry THF (7.5 ml) was added dry triethylamine (7.5 mL, 54 mmol) in one portion at room temperature followed by D₂O (99.96 atom % deuterium, 3.0 ml, 168 mmol). This mixture was stirred under nitrogen at room temperature for 16 h, with the reaction mixture used in the next step without isolation.

MS(ESI) 573.0 (M+1).

t_R6.95 min.

To the crude deuterium exchange reaction mixture was added NaBD₃CN (152 mg, 2.31 mmol) in one portion, with the reaction stirred at room temperature for 24 h. A further portion of NaBD₃CN (182.4 mg, 3.28 mmol) was added and stirring continued at room temperature for 24 h. The reaction was quenched by the addition of saturated NaHCO₃(aq) and the aqueous mixture extracted with EtOAc (3×10 mL×3). The combined organic extracts were washed with brine (15 mL), dried over MgSO₄and concentrated in vacuo. Flash chromatography (60% EtOAc/Pet. Spirit) yielded the product (175.8 mg, 67%).

TLC R_f0.32 (70% EtOAc/Pet. Spirit)

Analytical HPLC t_R7.06 min; MS(ESI) m/z 558.0 (M+1), 559.0, 557.0, 560.0.

Example 101
Syntheses of Compounds 106-520

Compounds 106-520, with substituents as identified in Table 1, were prepared as in the previous examples according to the routes identified in Schemes 1-5, as summarized in Table 2, with experimental properties summarized in Table 4.

TABLE 1

Identity of Compounds

Cpd.
R¹X
R²
R³
Y
R
W

14
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
3,5-dichlorobenzyl

25
6-fluoro-2-naphthoyl
H
H
CH₂
(CH₂)₂N(CH₂CH₃)₂
2,2-diphenylethyl

31
6-fluoro-2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
2,2-diphenylethyl

33
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2,2-diphenylethyl

37
2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
2-phenylbutyl

38
2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-phenylbutyl

39
2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(R)-2-phenylbutyl

49
2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
3,5-dichlorobenzyl

50
2-naphthylsulfonyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

54
2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
2-ethylbutyl

60
6-bromo-2-naphthoyl
Me
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

62
6-bromo-2-naphthoyl
H
Me
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

63
2-naphthoyl
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

64
2-naphthoyl
H
H
CH₂
(CH₂)₃(1-piperidinyl)
2,2-diphenylethyl

65
2-naphthoyl
H
H
CH₂
(CH₂)₃NHCH(CH₃)₂
2,2-diphenylethyl

67
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NHMe
2,2-diphenylethyl

71
2-naphthoyl
H
H
CH₂
(CH₂)₂CH₂NHMe
2,2-diphenylethyl

79
acetyl
H
H
(S)—CHCH₂-
(CH₂)₃NHO(═NH)NH₂
2,2-diphenylethyl

(2-naphthyl)

81
Ac-L-His
H
H
(S)—CHCH₂-
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

(2-naphthyl)

83
propyloxycarbonyl
H
H
(S)—CHCH₂-
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

(2-naphthyl)

85
acetyl
H
H
(R)—CHCH₂-
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

(2-naphthyl)

86
Ac-L-His
H
H
(R)—CHCH₂-
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

(2-naphthyl)

87
propyloxycarbonyl
H
H
(R)—CHCH₂-
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

2-naphthyl)

105
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

106
4-biphenylcarbonyl
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

107
indole-2-carbonyl
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

108
4-biphenylcarbonyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

109
indole-2-carbonyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

110
2-naphthylacetyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

111
1,2,3,4-tetrahydro-2-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

naphthoyl

112
quinolin-3-carbonyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

113
quinoxaline-2-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

carbonyl

114
isoquinoline-3-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

carbonyl

115
benzoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

116
quinaldoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

117
2-naphthoyl
H
H
CH₂
(CH₂)₄NH₂
1-naphthylmethyl

118
2-naphthylacetyl
H
H
CH₂
(CH₂)₄NH₂
1-naphthylmethyl

119
1-naphthoyl
H
H
CH₂
(CH₂)₄NH₂
1-naphthylmethyl

120
indole-3-acetyl
H
H
CH₂
(CH₂)₄NH₂
1-naphthylmethyl

121
4-biphenylacetyl
H
H
CH₂
(CH₂)₄NH₂
2-naphthylmethyl

122
2-naphthoyl
H
H
CH₂
(CH₂)₄NH₂
2-naphthylmethyl

123
2-naphthylacetyl
H
H
CH₂
(CH₂)₄NH₂
2-naphthylmethyl

124
1-naphthoyl
H
H
CH₂
(CH₂)₄NH₂
2-naphthylmethyl

125
1-naphthylacetyl
H
H
CH₂
(CH₂)₄NH₂
2-naphthylmethyl

126
2-naphthoyl
H
H
CH₂
(CH₂)₄NH₂
2,2-diphenylethyl

127
S-Tic
H
H
CH₂
(CH₂)₄NH₂
2,2-diphenylethyl

128
R-Tic
H
H
CH₂
(CH₂)₄NH₂
2,2-diphenylethyl

129
2-benzofurananoyl
H
H
CH₂
(CH₂)₄NH₂
2,2-diphenylethyl

130
R-Tic
H
H
CH₂
(CH₂)₃NHC(═NH)NHMe
2,2-diphenylethyl

131
S-Tic
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

132
2-benzofuranoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

133
indane-2-carbonyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

134
R-Tic
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

135
benzothiophene-2-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

carbonyl

136
2,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

137
2,5-dichlorobenzoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

138
benzoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

139
cyclohexanoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

140
3-phenoxybenzoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

141
4-phenoxybenzoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

142
indole-2-carbonyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

143
3-phenyl-propanoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

144
3,4-dimethylbenzoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

145
4-tert-butylbenzoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

146
2,4-dimethoxybenzoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

147
cyclohexylacetyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

148
piperonyloyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

149
benzimidazole-5-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

carbonyl

150
benzotriazole-5-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

carbonyl

151
cyclopentanoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

152
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

153
trans-cinnamoyl
H
H
CH₂
(CH₂)3 NHC(═NH)NH₂
2,2-diphenylethyl

154
3,5-dichlorobenzoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

155
2,4-dichloro-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

phenylacetyl

156
1-methoxy-2-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

naphthoyl

157
3,4-dichloro-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

phenylacetyl

158
6-methoxy-2-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

naphthoyl

159
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

160
2,4-dichloro-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

cinnamoyl

161
adamantane-1-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

carbonyl

162
phenoxyacetyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

163
3-methoxy-2-napthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

164
4-bromobenzoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

165
S-benzodioxan-2-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

carbonyl

166
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

167
3-(2-thienyl)acryloyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

168
R-benzodioxan-2-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

carbonyl

169
4-hydroxycinnamoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

170
2-methoxycinnamoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

171
4-methylcinnamoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

172
2-trifluoromethyl-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

cinnamoyl

173
3-fluorocinnamoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

174
alpha-methyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

cinnamoyl

175
trans-2-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

phenylcyclopropane-

1-carbonyl

176
2,4-dichloro-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

phenoxyacetyl

177
3-chlorocinnamoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

178
1,3-benzothiazole-6-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

carbonyl

179
5-phenyl-2-furoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

180
3-methoxycinnamoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

181
6-bromo-2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

182
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
phenethyl

183
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
3,4-dichlorophenethyl

184
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,4-dichlorophenethyl

185
benzothiophene-5-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

carbonyl

186
3-methyl-2-phenyl-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

pyrazole-4-carbonyl

187
4-methoxycinnamoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

188
6-fluoro-2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

189
2-chlorocinnamoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

190
2-hydroxycinnamoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

191
3-methylcinnamoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

192
3-trifluoromethyl-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

cinnamoyl

193
3-hydroxycinnamoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

194
2-fluorocinnamoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

195
2-methylcinnamoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

196
alpha-fluorocinnamoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

197
2-naphthoyl
H
H
CH₂
4-piperidinyl
2,2-diphenylethyl

198
2-naphthoyl
H
H
CH₂
CH₂(4-piperidinyl)
2,2-diphenylethyl

199
4-fluorocinnamoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

200
4-trifluoromethyl-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

cinnamoyl

201
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylpropyl

202
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
cyclohexanemethyl

203
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
1-adamantane-methyl

204
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
(S)-1,1-diphenyl-2-

propyl

205
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
(R)-1,1-diphenyl-2-

propyl

206
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
cyclohexyl

207
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
(R)-1,1-diphenyl-1-

fluoro-2-propyl

208
2,6-difluorocinnamoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

209
2-chloro-6-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

fluorocinnamoyl

210
4-bromocinnamoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

211
4-ethoxycinnamoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

212
6-bromonaphthoyl
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

213
trans-cinnamoyl
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

214
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

215
1,4-dimethoxy-2-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

naphthoyl

216
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)N(Me)₂
2,2-diphenylethyl

217
6-hydroxy-2-
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

naphthoyl

218
6-amino-2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

219
4-Me cinnamoyl
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

220
4-fluoro cinnamoyl
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

221
6-fluoro-2-napthoyl
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

222
2-ethylhexanoyl
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

223
3,4-dimethylbenzoyl
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

224
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

225
2-ethylhexanoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-diphenylethyl

226
2-naphthoyl
H
H
CH₂
(CH₂)₃NH(cyclohexyl)
2,2-diphenylethyl

227
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2-naphthyl

228
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
(9-fluorenyl)methyl

229
2-naphthoyl
H
H
CH₂
CH₂(3-pyridinyl)
2,2-diphenylethyl

230
2-naphthoyl
H
H
CH₂
CH₂(4-pyridinyl)
2,2-diphenylethyl

231
4-fluorocinnamoyl
H
H
CH₂
(CH₂)₃NH(cyclohexyl)
2,2-diphenylethyl

232
2-naphthoyl
H
H
CH₂
(CH₂)₄NHCH(CH₃)₂
2,2-diphenylethyl

233
2,4-difluorocinnamoyl
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

234
4-cyanocinnamoyl
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

235
3-(2-naphthyl)acryloyl
H
H
CH₂
(CH₂)₃NH₂
2 2,2-diphenylethyl

236
4-fluoro-
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

phenoxyacetyl

237
5-(4-chlorophenyl)-2-
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

furoyl

238
4-(pyrrol-1-yl)-benzoyl
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

239
2-oxo-1-phenyl-
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

pyrrolidine-3-carbonyl

240
5-(4-chlorophenyl)-
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

isoxazole-3-carbonyl

241
5-(2-furyl)-isoxazole-
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

3-carbonyl

242
2-phenyl-4-thiazole
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

carbonyl

243
4-(3,5-dimethyl1H--
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

pyrazol-1-yl) benzoyl

244
3-methyl-2-phenyl
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

pyrazole-4-carbonyl

245
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
cyclohexaneethyl

246
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2-norbornaneethyl

247
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-bis(4-

methoxyphenyl)ethyl

248
2-naphthoyl
H
H
CH₂
(CH₂)₄NHCH₂Ph
2,2-diphenylethyl

249
2-naphthoyl
H
H
CH₂
(CH₂)₄NH(cyclopentyl
2,2-diphenylethyl

250
2-naphthoyl
H
H
CH₂
(CH₂)₄NH(cyclobuty)l
2,2-diphenylethyl

251
2-naphthoyl
H
H
CH₂
CH₂)₄NH(cyclobuty)l₂
2,2-diphenylethyl

252
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
benzyl

253
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2,2-bis(4-

fluorophenyl)ethyl

254
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2-naphthalenemethyl

255
3-(5-methyl-2-
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

thienyl)-acryloyl

256
5-phenyl-pyrazole-3-
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

carbonyl

257
4-fluorocinnamoyl
Me
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

258
4-fluorocinnamoyl
H
Me
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

259
4-(3-methyl-5-oxo-2-
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

pyrazolin-1-yl)benzoyl

260
4-bromocinnamoyl
H
H
CH₂
(CH₂)₃NH₂
2,2-diphenylethyl

261
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₃(1-pyrrolidinyl)
2,2-diphenylethyl

262
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₃(1-piperidinyl)
2,2-diphenylethyl

263
2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
2,2-diphenylethyl

264
2-naphthoyl
H
H
CH₂
(CH₂)₃(1-pyrrolidinyl)
2,2-diphenylethyl

265
2-naphthoyl
H
H
CH₂
(CH₂)₃(1-azetidinyl)
2,2-diphenylethyl

266
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
1-naphthalenemethyl

267
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2-(2-naphthyl)ethyl

268
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(NH)NH₂
(S)—CH₂CH(Ph)NHCOMe

269
trans-cinnamoyl
H
H
CH₂
(CH₂)₃(1-piperidinyl)
2,2-diphenylethyl

270
3,4-dimethylbenzoyl
H
H
CH₂
(CH₂)₃(1-piperidinyl)
2,2-diphenylethyl

271
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₃(1-piperidinyl)
2,2-diphenylethyl

272
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
(S)—CH₂CH(Ph)-

NHCOcBu

273
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
(S)—CH₂CH(Ph)-

NHCOcHex

274
2-naphthoyl
H
H
CH₂
CH₂NH₂
2,2-diphenylethyl

275
4-chlorocinnamoyl
H
H
CH₂
CH₂NH₂
2,2-diphenylethyl

276
4-fluorocinnamoyl
H
H
CH₂
(CH₂)₂NH₂
2,2-diphenylethyl

277
4-methylcinnamoyl
H
H
CH₂
(CH₂)₂NH₂
2,2-diphenylethyl

278
2-naphthoyl
H
H
CH₂
CH₂(1-piperidinyl)
2,2-diphenylethyl

279
4-chlorocinnamoyl
H
H
CH₂
CH₂(1-piperidinyl)
2,2-diphenylethyl

280
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂NH₂
2,2-diphenylethyl

281
3,4-dimethylbenzoyl
H
H
CH₂
(CH₂)₂NH₂
2,2-diphenylethyl

282
trans-cinnamoyl
H
H
CH₂
(CH₂)₂NH₂
2,2-diphenylethyl

283
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₂NH₂
2,2-diphenylethyl

284
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2,2-diphenylethyl

285
3,4-dimethylbenzoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2,2-diphenylethyl

286
trans-cinnamoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2,2-diphenylethyl

287
4-fluorocinnamoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2,2-diphenylethyl

288
4-methylcinnamoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2,2-diphenylethyl

289
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
3,5-dimethylbenzyl

290
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
(S)—CH₂CH(Ph)NHCOPh

291
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
(R)—CH₂CH(Ph)NHCOPh

292
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
CH₂CH(Ph)OMe

293
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
CH₂CH(Ph)OnPr

294
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
CH₂CH(Ph)OBn

295
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
CH₂CH(Ph)Oallyl

296
2-naphthoyl
H
H
CH₂
(CH₂)₃CH₃
2,2-diphenylethyl

297
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₃CH₃
2,2-diphenylethyl

298
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₂CONH₂
2,2-diphenylethyl

299
2-naphthoyl
H
H
CH₂
(CH₂)₂CONH₂
2,2-diphenylethyl

300
4-methylcinnamoyl
H
H
CH₂
(CH₂)₃NHCOCH3
2,2-diphenylethyl

301
4-methylcinnamoyl
H
H
CH₂
(CH₂)₃
2,2-diphenylethyl

NHCO(cyclohexyl)

302
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
CH₂CH(Ph)OPh

303
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
CH₂CH(Ph)CO₂Et

304
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
2-ethylbutyl

305
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
3,5-dimethyl-

cyclohexylmethyl

306
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₂NHCO(cyclohexyl)
2,2-diphenylethyl

307
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₂NHCOCH₂(cyclohexyl)
2,2-diphenylethyl

308
benzoyl
H
H
(CH₂)₂
(CH₂)₂NH₂
2,2-diphenylethyl

309
3,4-dichlorobenzoyl
H
H
(CH₂)₂
(CH₂)₂NH₂
2,2-diphenylethyl

310
2-naphthoyl
H
H
(CH₂)₂
(CH₂)₂NH₂
2,2-diphenylethyl

311
benzoyl
H
H
(CH₂)₂
(CH₂)₂(1-
2,2-diphenylethyl

piperidinyl)

312
3,4-dichlorobenzoyl
H
H
(CH₂)₂
(CH₂)₂(1-
2,2-diphenylethyl

piperidinyl)

313
2-naphthoyl
H
H
(CH₂)₂
(CH₂)₂(1-
2,2-diphenylethyl

piperidinyl)

314
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
CH₂CH(Ph)CONMe₂

315
2-naphthoyl
H
H
CH₂
CH₂cyclohexyl
2,2-diphenylethyl

316
4-chlorocinnamoyl
H
H
CH₂
CH₂cyclohexyl
2,2-diphenylethyl

317
2-naphthoyl
H
H
CH₂
(CH₂)₂CO(1-
2,2-diphenylethyl

piperidinyl)

318
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₂CO(1-
2,2-diphenylethyl

piperidinyl)

319
2-naphthoyl
H
H
CH₂
CH₂CH₂Ph
2,2-diphenylethyl

320
4-chlorocinnamoyl
H
H
CH₂
CH₂CH₂Ph
2,2-diphenylethyl

321
2-naphthoyl
H
H
CH₂
(CH₂)₂cyclohexyl
2,2-diphenylethyl

322
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₂cyclohexyl
2,2-diphenylethyl

323
2-naphthoyl
H
H
CH₂
CH₂Ph
2,2-diphenylethyl

324
4-chlorocinnamoyl
H
H
CH₂
CH₂Ph
2,2-diphenylethyl

325
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂NH₂
3,5-dichlorobenzyl

326
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₂NH₂
3,5-dichlorobenzyl

327
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
3-chloro-5-

fluorobenzyl

328
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
3,5-difluorobenzyl

329
2-naphthoyl
H
H
CH₂
(CH₂)₃NH₂
3-chloro-5-

fluorobenzyl

330
2-naphthoyl
H
H
CH₂
(CH₂)₃NH₂
3,5-difluorobenzyl

331
2-naphthoyl
H
H
CH₂
(CH₂)₃NH₂
2,5-dichlorobenzyl

332
2-naphthoyl
H
H
CH₂
(CH₂)₃NH₂
2,6-dichlorobenzyl

333
2-naphthoyl
H
H
CH₂
(CH₂)₃NH₂
3,5-dimethoxybenzyl

334
2-naphthoyl
H
H
CH₂
(CH₂)₃NH₂
2-chlorobenzyl

335
2-naphthoyl
H
H
CH₂
(CH₂)₃NH₂
2,3-dichlorobenzyl

336
2-naphthoyl
H
H
CH₂
(CH₂)₃NH₂
2,4-dichlorobenzyl

337
2-naphthoyl
H
H
CH₂
(CH₂)₃NH₂
3,4-dichlorobenzyl

338
2-naphthoyl
H
H
CH₂
(CH₂)₃NH₂
3-fluoro-5-

methylbenzyl

339
2-naphthoyl
H
H
CH₂
(CH₂)₃NH₂
3-fluoro-5-

(trifluoromethyl)-

benzyl

340
2-naphthoyl
H
H
CH₂
(CH₂)₃NH₂
4-chlorobenzyl

341
2-naphthoyl
H
H
CH₂
(CH₂)₃NH₂
2-phenylbutyl

342
2-naphthoyl
H
H
CH₂
(CH₂)₃NH₂
1-(1-phenyl-

cyclohexyl)-methyl

343
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl))
3,5-dichlorobenzyl

344
2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
3,5-dichlorobenzyl

345
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
3,5-dichlorobenzyl

346
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂NH₂
2-ethylbutyl

347
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₂NH₂
2-ethylbutyl

348
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2-ethylbutyl

349
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2-ethylbutyl

350
2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2-ethylbutyl

351
4-chloro-3-fluoro-
H
H
CH₂
(CH₂)₂NH₂
2-ethylbutyl

benzoyl

352
4-chloro-3-methyl-
H
H
CH₂
(CH₂)₂NH₂
2-ethylbutyl

benzoyl

353
3-chloro-4-fluoro-
H
H
CH₂
(CH₂)₂NH₂
2-ethylbutyl

benzoyl

354
3-chloro-4-methyl-
H
H
CH₂
(CH₂)₂NH₂
2-ethylbutyl

benzoyl

355
4-chlorocinnamoyl
H
H
CH₂
CH₂(1-piperidinyl)
2-ethylbutyl

356
2-naphthoyl
H
H
(CH₂)₂
CH₂CH₂(1-
2,2-diphenylethyl

pyrrolidinyl)

357
2-naphthoyl
H
H
CH₂
(CH₂)₃NH₂
3,5-

bis(trifluoromethyl)-

benzyl

358
2-naphthoyl
H
H
CH₂
(CH₂)₃NH₂
3-chlorobenzyl

359
2-naphthoyl
H
H
CH₂
(CH₂)₃(1-piperidinyl)
2-phenylbutyl

360
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
CH₂CH(Ph)CON[—(CH₂)₅—]

361
2-naphthoyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
CH₂CH(Ph)CONHPh

362
3,4-dichlorobenzoyl
H
H
(CH₂)₂
(CH₂)₂NHOH(CH₃)₂
2,2-diphenylethyl

363
3,4-dichlorobenzoyl
H
H
(CH₂)₂
(CH₂)₂N(CH(CH₃)₂)₂
2,2-diphenylethyl

364
3,4-dichlorobenzoyl
H
H
CH₂
CH₂NH₂
3,5-dichlorobenzyl

365
2-naphthoyl
H
H
CH₂
CH₂NH₂
3,5-dichlorobenzyl

366
4-chlorocinnamoyl
H
H
CH₂
CH₂NH₂
3,5-dichlorobenzyl

367
3,4-dichlorobenzoyl
H
H
CH₂
CH₂(1-piperidinyl)
3,5-dichlorobenzyl

368
4-chlorocinnamoyl
H
H
CH₂
CH₂(1-piperidinyl)
3,5-dichlorobenzyl

369
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂NH₂
2-phenylbutyl(

370
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₂NH₂
2-phenylbutyl

371
3,4-dichlorobenzoyl
H
H
CH₂
CH₂(1-pyrrolidinyl)
3,5-dichlorobenzyl

372
2-naphthoyl
H
H
CH₂
CH₂(1-pyrrolidinyl)
3,5-dichlorobenzyl

373
2-naphthoyl
H
H
CH₂
(CH₂)₃NH₂
(S)-β-methylphenethyl

374
2-naphthoyl
H
H
CH₂
(CH₂)₂CH₂NH₂
(R)-β-methylphenethyl

375
2-naphthoyl
H
H
CH₂
(CH₂)₂N(CH₃)₂
2,2-diphenylethyl

376
6-fluoro-2--napthoyl
H
H
CH₂
(CH₂)₃(1-piperidinyl)
2,2-diphenylethyl

377
2-naphthoyl
H
H
CH₂
(CH₂)₃NH₂
3,5-diethynylbenzyl

378
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₂N(CH₂CH₃)₂
2,2-diphenylethyl

379
2-naphthoyl
H
H
CH₂
(CH₂)₂N(CH₂CH₃)₂
2,2-diphenylethyl

380
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(R)-2-phenylbutyl

381
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(R)-2-phenylbutyl

382
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-phenylbutyl

383
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
2,2-diphenylethyl

384
2-naphthoyl
H
H
CH₂
(CH₂)₂(1-pyrrolidinyl)
2,2-diphenylethyl

385
2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2,2-diphenylethyl

386
6-fluoro-2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
2-ethylbutyl

387
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
2-ethylbutyl

388
6-bromo-2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
2-ethylbutyl

389
6-fluoro-2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2-ethylbutyl

390
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2-ethylbutyl

391
6-bromo-2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2-ethylbutyl

392
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂NH₂
3,5-dimethyl-

cyclohexyl

393
2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
3,5-dimethyl-

cyclohexyl

394
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₂NH₂
3,5-dimethyl-

cyclohexyl

395
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2,2-diphenylethyl

396
6-fluoro-2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2,2-diphenylethyl

397
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₂(1-pyrrolidinyl)
2,2-diphenylethyl

398
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₂NHCH(CH₃)₂
2,2-diphenylethyl

399
2-naphthoyl
H
H
CH₂
(CH₂)₂NHCH(CH₃)₂r
2,2-diphenylethyl

400
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂NHCH(CH₃)₂
2,2-diphenylethyl

401
2-naphthoyl
H
H
CH₂
(CH₂)₃NH₂
2,6-dimethyl-

cyclohexylmethyl

402
2-naphthoyl
H
H
CH₂
(CH₂)₃NH₂
(S)-2-phenylbutyl

403
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
3,5-dimethyl-

cyclohexylmethyl

404
3,4-dichlorobenzoyl
H
H
CH₂
CH₂CH₂NHOH(CH₃)₂
3,5-dimethyl-

cyclohexylmethyl

405
2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
3-methyl-2-

phenylbutyl

406
2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
(S)-2-phenylbutyl

407
2-naphthoyl
H
H
CH₂
(CH₂)₃NH₂
(R)-2-phenylbutyl

408
4-chlorocinnamoyl
H
H
CH₂
CH₂(imidazol-3-yl)
2,2-diphenylethyl

409
3-(4-chlorophenyl)-
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2,2-diphenylethyl

propanoyl

410
3-(4-chlorophenyl)-
H
H
CH₂
(CH₂)₂NH₂
2,2-diphenylethyl

propanoyl

411
4-chlorocinnamoyl
H
H
CH₂
CH₂NHCO(2-pyridyl)
2,2-diphenylethyl

412
4-chlorocinnamoyl
H
H
CH₂
CH₂(2-pyridinyl)
2,2-diphenylethyl

413
2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(R)-3-methyl-2-

phenylbutyl

414
2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-3-methyl-2-

phenylbutyl

415
4-isopropylcinnamoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2,2-diphenylethyl

416
4-isopropylcinnamoyl
H
H
CH₂
(CH₂)₂NH₂
2,2-diphenylethyl

417
2,4-
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2,2-diphenylethyl

dimethylcinnamoyl

418
2,4-
H
H
CH₂
(CH₂)₂NH₂
2,2-diphenylethyl

dimethylcinnamoyl

419
2,4-difluorocinnamoyl
H
H
CH₂
(CH₂)₂1-piperidinyl)
2,2-diphenylethyl

420
2,4-difluorocinnamoyl
H
H
CH₂
(CH₂)₂NH₂
2,2-diphenylethyl

421
4-chlorocinnamoyl
H
H
CH₂
CH₂NHCO(cyclohexyl)
2,2-diphenylethyl

422
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₂(4-morpholinyl)
2,2-diphenylethyl

423
4-chlorocinnamoyl
H
H
CH₂
CH₂CH₂N[-C(Me)═CHCH═C(Me)-]
2,2-diphenylethyl

424
4-chlorocinnamoyl
H
H
CH₂
CH₂CH₂(2,5-dimethyl-
2,2-diphenylethyl

2-pyrrolidin-1-yl)

425
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-phenylbutyl

426
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₂(1-pyrrolidinyl)
(S)-2-phenylbutyl

427
4-chlorocinnamoyl
H
H
CH₂
(CH₂)₂NHCH(CH₃)₂
(S)-2-phenylbutyl

428
6-chloro-2-naphthoyl
H
H
CH₂
CH₂CH₂(1-
(S)-2-phenylbutyl

pyrrolidinyl)

429
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-phenylbutyl

430
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂1-pyrrolidinyl)
(S)-2-phenylbutyl

431
Obz
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2,2-diphenylethyl

432
4-bromocinnamoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2,2-diphenylethyl

433
5-(4-chlorophenyl)-
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2,2-diphenylethyl

isoxazole-3-carbonyl

434
4-chlorocinnamoyl
H
H
CH₂
CH₂CONH(2-pyridyl)
2,2-diphenylethyl

435
4-chlorocinnamoyl
H
H
CH₂
CH₂CO(1-piperidinyl)
2,2-diphenylethyl

436
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂CO(1-
(S)-2-phenylbutyl

piperidinyl)

437
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂CO(1-
(S)-2-phenylbutyl

piperidinyl)

438
6-chloro-2-naphthoyl
H
H
CH₂
CH₂(1-piperidinyl)
(S)-2-phenylbutyl

439
3,4-dichlorobenzoyl
H
H
CH₂
CH₂(1-piperidinyl)
(S)-2-phenylbutyl

440
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₃(1-piperidinyl)
(S)-2-phenylbutyl

441
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₃(1-piperidinyl)
(S)-2-phenylbutyl

442
4-chlorocinnamoyl
H
H
C(Me)_\2
CH₂CH₂NH₂
2,2-diphenylethyl

443
4-chlorocinnamoyl
H
H
C(Me)v
(CH₂)₂(1-
2,2-diphenylethyl

piperidinyl

444
2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
(R)-2-(4-chloro-

phenyl)propyl

445
2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
2-(4-chloro-

phenyl)propyl

446
2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(R)-2-(4-chloro-

phenyl)propyl

447
2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-(4-chloro-

phenyl)propyl

448
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂N(phenyl)CH₃
(S)-2-phenylbutyl

449
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂N(CH₂CH₃)₂
(S)-2-phenylbutyl

450
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(4-morpholinyl)
(S)-2-phenylbutyl

451
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂NH(phenyl)
(S)-2-phenylbutyl

452
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂NH(benzyl)
(S)-2-phenylbutyl

453
4-chlorocinnamoyl
H
H
CH₂
CH₂(2-NH₂-Ph)
2,2-diphenylethyl

454
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂NHC(CH₃)₃
(S)-2-phenylbutyl

455
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(4-CH₃-
(S)-2-phenylbutyl

piperazin-1-yl)

456
2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(R)-2-phenylpentyl

457
2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-phenylpentyl

458
p-trifluoromethyl-
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2,2-diphenylethyl

benzoyl

459
p-trifluoromethyl-
H
H
CH₂
(CH₂)₂NH₂
2,2-diphenylethyl

benzoyl

460
m-trifluoromethyl-
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2,2-diphenylethyl

benzoyl

461
m-trifluoromethyl-
H
H
CH₂
(CH₂)₂NH₂
2,2-diphenylethyl

benzoyl

462
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂NHCH(CH₃)₂
3,5-dichlorobenzyl

463
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂NHCH(CH₃)₂
3,5-dichlorobenzyl

464
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂NHCH(CH₃)₂
(S)-2-phenylbutyl

465
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
(S)-2-phenylbutyl

466
2-naphthoyl
H
H
CH₂
CH₂(2-NH₂-Ph)
2,2-diphenylethyl

467
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂N(benzyl)CH₃
(S)-2-phenylbutyl

468
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(piperazin-1-yl)
(S)-2-phenylbutyl

469
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂N(n-pentyl)CH₃
(S)-2-phenylbutyl

470
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂N[(CH(CH₃)₂]₂
(S)-2-phenylbutyl

471
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(4-CH₃-
(S)-2-phenylbutyl

piperidin-1-yl)

472
6-chloro-2-naphthoyl
H
H
CH₂
4-piperidinyl
(S)-2-phenylbutyl

473
6-chloro-2-naphthoyl
H
H
CH₂
1-isopentyl-4-
(S)-2-phenylbutyl

piperidinyl

474
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₃CH₃
(S)-2-phenylbutyl

475
6-chloro-2-naphthoyl
H
H
CH₂
CH₂CH₂iPr
(S)-2-phenylbutyl

476
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(3,5-Me₂-
(S)-2-phenylbutyl

piperidin-1-yl)

477
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(4-OH-
(S)-2-phenylbutyl

piperidin-1-yl)

478
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(4-CO₂H-
(S)-2-phenylbutyl

piperidin-1-yl)

479
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂NH[—(CH₂)₆—]
(S)-2-phenylbutyl

480
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂[(S)-2-Me-
(S)-2-phenylbutyl

piperidin-1-yl]

481
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂N(tBu)CH₃
(S)-2-phenylbutyl

482
2-naphthoyl
H
H
CH₂
CH₂(2-(piperidin-1-
2,2-diphenylethyl

yl)phenyl)

483
2-naphthoyl
H
H
CH₂
(CH₂)₂CON(Me)nBu
(S)-2-phenylbutyl

484
2-naphthoyl
H
H
CH₂
(CH₂)₂CONHcHex
(S)-2-phenylbutyl

485
6-chloro-2-naphthoyl
H
H
CH₂
1-ethyl-piperidin-4-yl
(S)-2-phenylbutyl

486
3,4-dichlorobenzyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2,2-diphenylethyl

487
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂NHC(═NH)NH₂
(S)-2-phenylbutyl

488
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂NHC(═NH)NHMe
(S)-2-phenylbutyl

489
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂NH₂
(R)-2-isopropylbutyl

490
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂NH₂
(S)-2-isopropylbutyl

491
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(R)-2-isopropylbutyl

492
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-isopropylbutyl

493
6-chloro-2-naphthoyl
H
H
CH₂
S—CH₂C(Me₂)NH₂
(S)-2-phenylbutyl

494
6-chloro-2-naphthoyl
H
H
CH₂
R—CH₂C(Me₂)NH₂
(S)-2-phenylbutyl

495
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂NH₂
(S)-2-phenylbutyl

496
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂NHCH(CH₃)_\2
(S)-2-phenylbutyl

497
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
3,5-dichlorobenzyl

498
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
3,5-dichlorobenzyl

499
6-chloro-2-naphthoyl
H
H
CH₂
S—CH₂C(Me₂)(1-
(S)-2-phenylbutyl

piperidinyl)

500
6-chloro-2-naphthoyl
H
H
CH₂
R—CH₂C(Me₂)(1-
(S)-2-phenylbutyl

piperidinyl)

501
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
(R)-2-isopropylbutyl

502
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
(S)-2-isopropylbutyl

503
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(R)-2-isopropylbutyl

504
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-isopropylbutyl

505
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂cHex
(S)-2-phenylbutyl

506
6-chloro-2-naphthoyl
H
H
CH₂
nHex
(S)-2-phenylbutyl

507
6-carboxy-2-
H
H
CH₂
CH₂)₂(1-piperidinyl)
2,2-diphenylethyl

naphthoyl

508
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂NHC(═NH)NH—CH(CH₃)₂
(S)-2-phenylbutyl

509
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₄OH
(S)-2-phenylbutyl

510
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂OMe
(S)-2-phenylbutyl

511
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂OBn
(S)-2-phenylbutyl

512
6-chloro-2-naphthoyl
H
H
CH₂
iBu
(S)-2-phenylbutyl

513
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂NH₂
2-ethyl-3-methyl-but-

3-enyl

514
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2-ethyl-3-methyl-but-

3-enyl

515
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
2-ethyl-3-methyl-but-

3-enyl

516
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(R)-2-ethyl-3-methyl-

but-3-enyl

517
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-ethyl-3-methyl-

but-3-enyl

518
4-biphenylcarboxylyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
cyclohexanemethyl

519
indole-3-acetyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
cyclohexanemethyl

520
3-quinolinecarboxylyl
H
H
CH₂
(CH₂)₃NHC(═NH)NH₂
cyclohexanemethyl

521
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(4,4-difluoro-1-
(S)-2-phenylbutyl

piperidinyl)

522
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂OH
(S)-2-phenylbutyl

523
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(3,3-difluoro-1-
(S)-2-phenylbutyl

piperidinyl)

524
3,4-dichlorobenzyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-phenylbutyl

525
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2-cyclopropylbutyl

526
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
2-cyclopropylbutyl

527
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2-cyclopropylbutyl

528
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂N[—CO(CH₂)₂CO—]
(S)-2-phenylbutyl

529
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₃NHCONH₂
(S)-2-phenylbutyl

530
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂NHCH(Me)CF₃
(S)-2-phenylbutyl

531
3,4-dichlorobenzoyl
H
H
CH₂
CH₂CH₂N[—COC(Me)₂CH₂CO—]
(S)-2-phenylbutyl

532
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂N[—(CH₂)₆—]
(S)-2-phenylbutyl

533
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂NHCONHiPr
(S)-2-phenylbutyl

534
4-biphenyl carboxylic
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-phenylbutyl

535
2-phenylthiazole-4-
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-phenylbutyl

carbonyl

536
4-chloro-biphenyl-2-
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-phenylbutyl

carbonyl

537
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂N(Ac)iPr
(S)-2-phenylbutyl

538
6-chloro-2-naphthoyl
H
H
CH₂
CH₂NHiPr
(S)-2-phenylbutyl

539
6-chloro-2-naphthoyl
H
H
CH₂
CH₂NC(═NH)NH₂
(S)-2-phenylbutyl

540
2,4-
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-phenylbutyl

dichlorophenylacetyl

541
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂NH₂
2,4-dichlorobenzyl

542
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2,4-dichlorobenzyl

543
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂NHSO₂Me
2,4-dichlorobenzyl

544
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂NHSO₂(4-Me-Ph)
2,4-dichlorobenzyl

545
3,4-dichlorobenzoyl
H
H
CH₂
(S)—(CH₂)₂NHCO—CH(iPr)NH₂
2,4-dichlorobenzyl

546
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
2,4-dichlorobenzyl

547
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2,4-dichlorobenzyl

548
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
2-(3-thienyl)butyl

549
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(R)-2-(3-thienyl)butyl

550
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-(3-thienyl)butyl

551
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂NH₂
2-ethyl-2-methylbutyl

552
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2-ethyl-2-methylbutyl

553
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂(4-morpholinyl)
2,2-diphenylethyl

554
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂(4-morpholinyl)
(S)-2-phenylbutyl

555
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂(4-morpholinyl)
3,5-dichlorobenzyl

556
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(4-morpholinyl)
3,5-dichlorobenzyl

557
(4-chloro-
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-phenylbutyl

benzyl)NHCO

558
3,4-dichlorobenzyl +
Ac
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-phenylbutyl

MeCO

559
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂NH₂
2-ethyl-2-methylbutyl

560
3,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2-ethyl-2-methylbutyl

561
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
2,3,5-trichlorobenzyl

562
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂NHSO₂iPr
(S)-2-phenylbutyl

563
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂NHCO₂nBu
(S)-2-phenylbutyl

564
6-chloro-2-naphthoyl
H
H
CH₂
1-iPr-4-piperidinyl
(S)-2-phenylbutyl

565
6-chloro-2-naphthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(R)-2-phenylbutyl

566
5-(4-chlorophenyl)-
H
H
CH₂
(CH₂)₂(1-piperidinyl)
3,5-dichlorobenzyl

isoxazole-3-carbonyl

567
2,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
3,5-dichlorobenzyl

568
6-methoxy-2-
H
H
CH₂
(CH₂)₂(1-piperidinyl)
3,5-dichlorobenzyl

naphthoyl

569
6-chloro-2-naphthoyl
H
H

¹³CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-phenylbutyl

570
1-methoxy-2-napthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
3,5-dichlorobenzyl

571
4-(trifluoro-
H
H
CH₂
(CH₂)₂(1-piperidinyl)
3,5-dichlorobenzyl

methoxy)cinnamoyl

572
5-(4-chlorophenyl)-
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-phenylbutyl

isoxazole-3-carbonyl

573
2,4-dichlorobenzoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-phenylbutyl

574
4,5-dichlorophthaloyl
R1
H
CH₂
(CH₂)₂(1-piperidinyl)
3,5-dichlorobenzyl

575
3-fluoro-4-(trifluoro-
H
H
CH₂
(CH₂)₂(1-piperidinyl)
3,5-dichlorobenzyl

methoxy)cinnamoyl

576
6-methoxy-2-
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-phenylbutyl

naphthoyl

577
1-methoxy-2-napthoyl
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-phenylbutyl

578
3-fluoro-4-(trifluoro-
H
H
CH₂
(CH₂)₂(1-piperidinyl)
(S)-2-phenylbutyl

methoxy)cinnamoyl

579
6-chloro-2-naphthoyl
H
H
CD₂
(CH₂)₂(1-piperidinyl)
(S)-2-phenylbutyl

TABLE 2

Synthesis of Compounds

Conversion

Scheme 1:

of A to

Cpd.
Route to A
VN(R²)—Y—CO₂H
P²NH—CH(U)—CO₂H
Product
U modification

14
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

25
Scheme 1
Boc-Gly-OH
Cbz-L-Asp[(NMe)OMe-OH
Scheme 4
reduction to

aldehyde then

reductive

amination

31
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

33
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

37
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

38
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

38
Scheme 1
2-naphthoic-
Fmoc-L-Dab(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

then dialkylation

with alkyl

dibromide

39
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

49
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

50
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

54
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

60
Scheme 1
Cbz-Sar
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

62
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 3
P1 deprotect, R1

acylate, ring

methylate, P3

deprotect

63
Scheme 2
Boc-Gly-OH
H-L-Orn(Cbz)-Oallyl
Scheme 4
P3 deprotection

63
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

64
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

then dialkylation

with alkyl

dibromide

65
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection,

Gly-OH

reductive

alkylation

67
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection,

Gly-OH

guanylation

79
Scheme 1
Alloc-β-(2-
Boc-L-Arg-(Cbz)₂-OH
Scheme 4
P3 deprotection

naphthyl)-L-Ala

81
Scheme 1
Alloc-β-(2-
Boc-L-Arg-(Cbz)₂-OH
Scheme 4
P3 deprotection

naphthyl)-L-Ala

83
Scheme 1
Alloc-β-(2-
Boc-L-Arg-(Cbz)₂-OH
Scheme 4
P3 deprotection

naphthyl)-L-Ala

85
Scheme 1
Alloc-β-(2-
Boc-L-Arg-(Cbz)₂-OH
Scheme 4
P3 deprotection

naphthyl)-L-Ala

86
Scheme 1
Alloc-β-(2-
Boc-L-Arg-(Cbz)₂-OH
Scheme 4
P3 deprotection

naphthyl)-L-Ala

87
Scheme 1
Alloc-β-(2-
Boc-L-Arg-(Cbz)₂-OH
Scheme 4
P3 deprotection

naphthyl)-L-Ala

105
Scheme 2
Boc-Gly-OH
H-L-Orn(Cbz)-Oallyl
Scheme 5
P3 deprotection,

guanidinylation,

deprotection

105
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

105
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

105
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

106
Scheme 2
Boc-Gly-OH
H-L-Orn(Cbz)-Oallyl
Scheme 4
P3 deprotection

106
Scheme 2
Boc-Gly-OH
H-L-Orn(Cbz)-Oallyl
Scheme 4
P3 deprotection

107
Scheme 2
Boc-Gly-OH
H-L-Orn(Cbz)-Oallyl
Scheme 4
P3 deprotection

108
Scheme 2
Boc-Gly-OH
H-L-Orn(Cbz)-Oallyl
Scheme 5
P3 deprotection,

guanidinylation,

deprotection

109
Scheme 2
Boc-Gly-OH
H-L-Orn(Cbz)-Oallyl
Scheme 5
P3 deprotection,

guanidinylation,

deprotection

110
Scheme 2
Boc-Gly-OH
H-L-Orn(Cbz)-Oallyl
Scheme 5
P3 deprotection,

guanidinylation,

deprotection

111
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

112
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

113
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

114
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

115
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

116
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

117
Scheme 2
Boc-Gly-OH
Boc-L-Lys(Cbz)-OH
Scheme 4
P3 deprotection

118
Scheme 2
Boc-Gly-OH
Boc-L-Lys(Cbz)-OH
Scheme 4
P3 deprotection

119
Scheme 2
Boc-Gly-OH
Boc-L-Lys(Cbz)-OH
Scheme 4
P3 deprotection

120
Scheme 2
Boc-Gly-OH
Boc-L-Lys(Cbz)-OH
Scheme 4
P3 deprotection

121
Scheme 2
Boc-Gly-OH
Boc-L-Lys(Cbz)-OH
Scheme 4
P3 deprotection

122
Scheme 2
Boc-Gly-OH
Boc-L-Lys(Cbz)-OH
Scheme 4
P3 deprotection

123
Scheme 2
Boc-Gly-OH
Boc-L-Lys(Cbz)-OH
Scheme 4
P3 deprotection

124
Scheme 2
Boc-Gly-OH
Boc-L-Lys(Cbz)-OH
Scheme 4
P3 deprotection

125
Scheme 2
Boc-Gly-OH
Boc-L-Lys(Cbz)-OH
Scheme 4
P3 deprotection

126
Scheme 2
Boc-Gly-OH
Boc-L-Lys(Cbz)-OH
Scheme 4
P3 deprotection

127
Scheme 2
Boc-Gly-OH
Boc-L-Lys(Cbz)-OH
Scheme 4
P3 deprotection

128
Scheme 2
Boc-Gly-OH
Boc-L-Lys(Cbz)-OH
Scheme 4
P3 deprotection

129
Scheme 2
Boc-Gly-OH
Boc-L-Lys(Cbz)-OH
Scheme 4
P3 deprotection

130
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

131
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

132
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

133
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

134
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

135
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

136
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

137
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

138
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

139
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

140
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

141
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

142
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

143
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

144
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

145
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

146
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

147
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

148
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

149
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

150
Scheme 2
Boc-Gly-OH
H-L-Arg(Cbz)₂-Oallyl
Scheme 4
P3 deprotection

151
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

152
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

153
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

154
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

155
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

156
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

157
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

158
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

159
Scheme 1
Alloc-Gly-OH
Boc-L-Canavanine
Scheme 4
P3 deprotection

(Fmoc)-OH

160
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

161
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

162
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

163
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

164
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

165
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

166
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

167
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

168
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

169
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

170
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

171
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

172
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

173
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

174
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

175
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

176
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

177
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

178
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

179
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

180
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

181
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

182
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

183
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

184
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

185
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

186
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

187
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

188
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

189
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

190
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

191
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

192
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

193
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

194
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

195
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

196
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

197
Scheme 1
2-naphthoic-
Fmoc-β-(1-Boc-4-
Scheme 3
P3 deprotection

Gly-OH
piperidinyl)-DL-Gly-OH

198
Scheme 1
2-naphthoic-
Fmoc-β-(1-Boc-4-
Scheme 3
P3 deprotection

Gly-OH
piperidinyl)-DL-Ala-OH

199
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

200
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

201
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

202
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

203
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

204
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

205
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

206
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

207
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

208
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

209
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

210
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

211
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

212
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

213
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

214
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

215
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

216
Scheme 1
2-naphthoic-
Fmoc-L-Arg(NMe)₂Pbf-OH
Scheme 3
P3 deprotection

Gly-OH

217
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

218
Scheme 1
Alloc-Gly-OH
Boc-L-Arg(Fmoc)₂-OH
Scheme 4
P3 deprotection

219
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

220
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

221
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

222
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

223
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn (Boc)-OH
Scheme 4
P3 deprotection

224
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

225
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection,

guanidinylation

226
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection,

Gly-OH

reductive

alkylation

227
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

228
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

229
Scheme 1
2-naphthoic-
Fmoc-L-3-PyridylAla-OH
Scheme 3
none

Gly-OH

230
Scheme 1
2-naphthoic-
Fmoc-L-4-PyridylAla-OH
Scheme 3
none

Gly-OH

231
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection,

reductive

alkylation

232
Scheme 1
2-naphthoic-
Fmoc-L-Lys(i-Pr)Fmoc-
Scheme 3
P3 deprotection

Gly-OH
OH

233
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

234
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

235
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

236
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

237
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

238
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

239
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

240
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

241
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

242
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

243
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

244
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

245
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

246
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

247
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

248
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection,

Gly-OH

reductive

alkylation

249
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection,

Gly-OH

reductive

alkylation

250
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection,

Gly-OH

reductive

alkylation

251
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection,

Gly-OH

reductive

alkylation

252
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

253
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

254
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

255
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

256
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

257
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

258
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P1 deprotect, R1

acylate, ring

methylate, P3

deprotect

259
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

260
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

261
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

262
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

262
Scheme 1
Boc-Gly-OH
Fmoc-L-Orn(Cbz)-OH
Scheme 5
P3 deprotection,

dialkylation

263
Scheme 1
2-naphthoic-
Fmoc-L-Dab(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

263
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

264
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

then dialkylation

with alkyl

dibromide

265
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

then dialkylation

with alkyl

dibromide

266
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

267
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

268
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

269
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

270
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

271
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

272
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

273
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

274
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dap(Boc)-OH
Scheme 4
P3 deprotection

275
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dap(Boc)-OH
Scheme 4
P3 deprotection

276
Scheme 1
Cbz-Gly-OH
Boc-L-Dab(Fmoc)-OH
Scheme 4
P3 deprotection

276
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

277
Scheme 1
Cbz-Gly-OH
Boc-L-Dab(Fmoc)-OH
Scheme 4
P3 deprotection

277
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

278
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dap(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

279
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dap(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

279
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dap(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

280
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

281
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

282
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

283
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

284
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

285
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

286
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

287
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

288
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

289
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

290
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

291
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

292
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

293
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

294
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

295
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

296
Scheme 1
Cbz-Gly-OH
Boc-L-Nle-OH
Scheme 4
none

297
Scheme 1
Cbz-Gly-OH
Boc-L-Nle-OH
Scheme 4
none

298
Scheme 1
Cbz-Gly-OH
Boc-L-Gln-OH
Scheme 4
none

299
Scheme 1
Cbz-Gly-OH
Boc-L-Gln-OH
Scheme 4
none

300
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

then acylation

301
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

then acylation

302
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

303
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

304
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

305
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

306
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then acylation

307
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then acylation

308
Scheme 1
Cbz-β-Ala
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

309
Scheme 1
Cbz-β-Ala
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

310
Scheme 1
Cbz-β-Ala
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

311
Scheme 1
Cbz-β-Ala
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

312
Scheme 1
Cbz-β-Ala
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

313
Scheme 1
Cbz-β-Ala
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

314
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
R5 deprotection

Gly-OH

and amidation

then P3

deprotection

315
Scheme 1
Cbz-Gly-OH
Boc-L-Cha-OH
Scheme 4
none

316
Scheme 1
Cbz-Gly-OH
Boc-L-Cha-OH
Scheme 4
none

317
Scheme 1
Cbz-Gly-OH
Boc-L-Glu(1-piperidinyl)-
Scheme 4
none

OH

318
Scheme 1
Cbz-Gly-OH
Boc-L-Glu(1-piperidinyl)-
Scheme 4
none

OH

319
Scheme 1
Cbz-Gly-OH
Boc-L-Hfe-OH
Scheme 4
none

320
Scheme 1
Cbz-Gly-OH
Boc-L-Hfe-OH
Scheme 4
none

321
Scheme 1
Cbz-Gly-OH
Boc-L-hCha-OH
Scheme 4
none

322
Scheme 1
Cbz-Gly-OH
Boc-L-hCha-OH
Scheme 4
none

323
Scheme 1
Cbz-Gly-OH
Boc-L-Phe-OH
Scheme 4
none

324
Scheme 1
Cbz-Gly-OH
Boc-L-Phe-OH
Scheme 4
none

325
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

326
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

327
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

328
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
P3 deprotection

Gly-OH

329
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

330
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

331
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

332
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

333
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

334
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

335
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

336
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

337
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

338
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

339
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

340
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

341
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

342
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

343
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

344
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

345
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

346
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

347
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

348
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

348
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

349
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

350
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

351
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

352
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

353
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

354
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

355
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dap(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

356
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dap(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

357
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

358
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

359
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

then dialkylation

with alkyl

dibromide

360
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
R5 deprotection

Gly-OH

and amidation

then P3

deprotection

361
Scheme 1
2-naphthoic-
Fmoc-L-Arg(Pbf)-OH
Scheme 3
R5 deprotection

Gly-OH

and amidation

then P3

deprotection

362
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dap(Boc)-OH
Scheme 4
P3 deprotection,

alkylation

363
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dap(Boc)-OH
Scheme 4
P3 deprotection,

dialkylation

364
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dap(Boc)-OH
Scheme 4
P3 deprotection

365
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dap(Boc)-OH
Scheme 4
P3 deprotection

366
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

367
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dap(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

367
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dap(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

368
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dap(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

369
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

370
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

371
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dap(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

372
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dap(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

373
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

374
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

375
Scheme 1
2-naphthoic-
Cbz-L-Asp[N(Me)OMe]-
Scheme 3
P3 conversion to

Gly-OH
OH

aldehyde then

reductive

amination

376
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

377
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

378
Scheme 1
Boc-Gly-OH
Cbz-L-Asp[N(Me)OMe]-
Scheme 4
P3 conversion to

OH

aldehyde then

reductive

amination

379
Scheme 1
Boc-Gly-OH
Cbz-L-Asp[N(Me)OMe]-
Scheme 4
P3 conversion to

OH

aldehyde then

reductive

amination

380
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

381
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

382
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

383
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

384
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

385
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

386
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

387
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

388
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

389
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

390
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

391
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

392
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

393
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

394
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

395
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

396
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

397
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

398
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection,

alkylation

399
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection,

alkylation

400
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection,

alkylation

401
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

402
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

403
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

404
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection,

alkylation

405
Scheme 1
2-naphthoic-
Fmoc-L-Dab(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

406
Scheme 1
2-naphthoic-
Fmoc-L-Dab(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

407
Scheme 1
2-naphthoic-
Fmoc-L-Orn(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

408
Scheme 1
Cbz-Gly-OH
Fmoc-L-His(Boc)-OH
Scheme 4
P3 deprotection

409
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

410
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

411
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dap(Boc)-OH
Scheme 4
P3 deprotection,

acylation

412
Scheme 2
Cbz-Gly-OH
H-β-(2-pyridyl)-L-Ala-
Scheme 4
none

Oallyl

413
Scheme 1
2-naphthoic-
Fmoc-L-Dab(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

then dialkylation

with alkyl

dibromide

414
Scheme 1
2-naphthoic-
Fmoc-L-Dab(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

then dialkylation

with alkyl

dibromide

415
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

416
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

417
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

418
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

419
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

420
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

421
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dap(Boc)-OH
Scheme 4
P3 deprotection,

acylation

422
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

423
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection,

condensation

424
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection,

condensation,

reduction

425
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

426
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

427
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

428
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

429
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

430
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

431
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 3
P3 deprotection

then dialkylation

with alkyl

dibromide

432
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

433
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

434
Scheme 1
Cbz-Gly-OH
Fmoc-L-Asp(OtBu)-OH
Scheme 4
P3 deprotection,

amidation

435
Scheme 1
Cbz-Gly-OH
Fmoc-L-Asp(OtBu)-OH
Scheme 4
P3 deprotection,

amidation

436
Scheme 1
Cbz-Gly-OH
Boc-L-Gln(piperidyl)-OH
Scheme 4
none

437
Scheme 1
Cbz-Gly-OH
Boc-L-Gln(piperidyl)-OH
Scheme 4
none

438
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dap(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

439
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dap(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

440
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

441
Scheme 1
Cbz-Gly-OH
Fmoc-L-Orn(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

442
Scheme 1
Boc-Aib
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

443
Scheme 1
Boc-Aib
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

444
Scheme 1
2-naphthoic-
Fmoc-L-Dab(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

445
Scheme 1
2-naphthoic-
Fmoc-L-Dab(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

446
Scheme 1
2-naphthoic-
Fmoc-L-Dab(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

then dialkylation

with alkyl

dibromide

447
Scheme 1
2-naphthoic-
Fmoc-L-Dab(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

then dialkylation

with alkyl

dibromide

448
Scheme 1
Cbz-Gly-OH
Fmoc-L-Asp[N(Me)OMe]-
Scheme 4
P3 conversion to

OH

aldehyde then

reductive

amination

449
Scheme 1
Cbz-Gly-OH
Fmoc-L-Asp[N(Me)OMe]-
Scheme 4
P3 conversion to

OH

aldehyde then

reductive

amination

450
Scheme 1
Cbz-Gly-OH
Fmoc-L-Asp[N(Me)OMe]-
Scheme 4
P3 conversion to

OH

aldehyde then

reductive

amination

451
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 conversion to

aldehyde then

reductive

amination

452
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 conversion to

aldehyde then

reductive

amination

453
Scheme 1
Fmoc-Gly-OH
Boc-L-(2-NO2)-Phe-OH
Scheme 5
nitro

hydrogenation

454
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 conversion to

aldehyde then

reductive

amination

455
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 conversion to

aldehyde then

reductive

amination

456
Scheme 1
2-naphthoic-
Fmoc-L-Dab(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

then dialkylation

with alkyl

dibromide

457
Scheme 1
2-naphthoic-
Fmoc-L-Dab(Boc)-OH
Scheme 3
P3 deprotection

Gly-OH

then dialkylation

with alkyl

dibromide

458
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

459
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
none

460
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

461
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
none

462
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection,

reductive

alkylation

463
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection,

reductive

alkylation

464
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection,

reductive

alkylation

465
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 3
P3 deprotection

466
Scheme 1
Fmoc-Gly-OH
Boc-L-(2-NO2)-Phe-OH
Scheme 4
nitro

hydrogenation

467
Scheme 1
Cbz-Gly-OH
Fmoc-L-Asp[N(Me)OMe]-
Scheme 4
P3 conversion to

OH

aldehyde then

reductive

amination

468
Scheme 1
Cbz-Gly-OH
Fmoc-L-Asp[N(Me)OMe]-
Scheme 4
P3 conversion to

OH

aldehyde then

reductive

amination

469
Scheme 1
Cbz-Gly-OH
Fmoc-L-Asp[N(Me)OMe]-
Scheme 4
P3 conversion to

OH

aldehyde then

reductive

amination

470
Scheme 1
Cbz-Gly-OH
Fmoc-L-Asp[N(Me)OMe]-
Scheme 4
P3 conversion to

OH

aldehyde then

reductive

amination

471
Scheme 1
Cbz-Gly-OH
Fmoc-L-Asp[N(Me)OMe]-
Scheme 4
P3 conversion to

OH

aldehyde then

reductive

amination

472
Scheme 1
Cbz-Gly-OH
N-Fmoc-1(1-Boc-
Scheme 4
P3 deprotection

piperidin-4yl)-D,L-Gly-OH

473
Scheme 1
Cbz-Gly-OH
N-Fmoc-1(1-Boc-
Scheme 4
P3 deprotection,

piperidin-4yl)-D,L-Gly-OH

reductive

alkylation

474
Scheme 1
Cbz-Gly-OH
Boc-L-Nle-OH
Scheme 4
none

475
Scheme 1
Cbz-Gly-OH
Fmoc-L-HoLeu-OH
Scheme 4
none

476
Scheme 1
Cbz-Gly-OH
Fmoc-L-Asp[N(Me)OMe]-
Scheme 4
P3 conversion to

OH

aldehyde then

reductive

amination

477
Scheme 1
Cbz-Gly-OH
Fmoc-L-Asp[N(Me)OMe]-
Scheme 4
P3 conversion to

OH

aldehyde then

reductive

amination

478
Scheme 1
Cbz-Gly-OH
Fmoc-L-Asp[N(Me)OMe]-
Scheme 4
P3 conversion to

OH

aldehyde then

reductive

amination

479
Scheme 1
Cbz-Gly-OH
Fmoc-L-Asp[N(Me)OMe]-
Scheme 4
P3 conversion to

OH

aldehyde then

reductive

amination

480
Scheme 1
Cbz-Gly-OH
Fmoc-L-Asp[N(Me)OMe]-
Scheme 4
P3 conversion to

OH

aldehyde then

reductive

amination

481
Scheme 1
Cbz-Gly-OH
Fmoc-L-Asp[N(Me)OMe]-
Scheme 4
P3 conversion to

OH

aldehyde then

reductive

amination

482
Scheme 1
Fmoc-Gly-OH
Boc-L-(2-NO₂)-Phe-OH
Scheme 5
nitro

hydrogenation

then dialkylation

with alkyl

dibromide

483
Scheme 1
2-naphthoic-
Boc-L-Gln(Me,nBu)-OH
Scheme 4
none

Gly-OH

484
Scheme 1
2-naphthoic-
Boc-L-Gln(chex)-OH
Scheme 4
none

Gly-OH

485
Scheme 1
Cbz-Gly-OH
N-Fmoc-1-(1-Boc-
Scheme 4
P3 deprotection,

piperidin-4-yl)-D,L-Gly-OH

reductive

alkylation

486
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection,

alkylation

487
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection,

alkylation

488
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection,

alkylation

489
Scheme 1
Boc-Gly-OH
Cbz-DL-γ-nitro-Leu-OH
Scheme 4
P3 reduction to

amine

490
Scheme 1
Boc-Gly-OH
Cbz-DL-γ-nitro-Leu-OH
Scheme 4
P3 reduction to

amine

491
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

492
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

493
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection,

dialkylation with

alkyl dibromide

494
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection,

dialkylation with

alkyl dibromide

495
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

496
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then reductive

alkylation

497
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

498
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

499
Scheme 1
Boc-Gly-OH
Cbz-DL-γ-nitro-Leu-OH
Scheme 4
P3 reduction to

amine then

dialkylation with

alkyl dibromide

500
Scheme 1
Boc-Gly-OH
Cbz-DL-γ-nitro-Leu-OH
Scheme 4
P3 reduction to

amine then

dialkylation with

alkyl dibromide

501
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

502
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

503
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection,

dialkylation with

alkyl dibromide

504
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection,

dialkylation with

alkyl dibromide

505
Scheme 1
Cbz-Gly-OH
Fmoc-L-HoCha-OH
Scheme 4
none

506
Scheme 1
Cbz-Gly-OH
Fmoc-L-2-aminooctanoic
Scheme 4
none

acid

507
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection,

alkylation

508
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection,

alkylation

509
Scheme 1
Cbz-Gly-OH
Boc-L-5-HO-Nle-OH
Scheme 4
none

510
Scheme 1
Cbz-Gly-OH
Fmoc-L-HoSer(Me)-OH
Scheme 4
none

511
Scheme 1
Alloc-Gly-OH
Boc-L-HoSer(Bzl)-OH
Scheme 4
none

512
Scheme 1
Cbz-Gly-OH
Boc-L-Leu-OH
Scheme 4
none

513
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

514
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection,

dialkylation with

alkyl dibromide

515
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

516
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection,

dialkylation with

alkyl dibromide

517
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection,

dialkylation with

alkyl dibromide

518
Scheme 2
Boc-Gly-OH
Boc-L-Arg(Cbz)₂-OH
Scheme 4
P3 deprotection

519
Scheme 2
Boc-Gly-OH
Boc-L-Arg(Cbz)₂-OH
Scheme 4
P3 deprotection

520
Scheme 2
Boc-Gly-OH
Boc-L-Arg(Cbz)₂-OH
Scheme 4
P3 deprotection

521
Scheme 1
Boc-Gly-OH
Cbz-L-Asp[N(Me)OMe]
Scheme 4
P3 conversion to

aldehyde then

reductive

amination

522
Scheme 1
Boc-Gly-OH
Cbz-L-Asp[N(Me)OMe]
Scheme 4
P3 conversion to

aldehyde then

reduction

523
Scheme 1
Boc-Gly-OH
Cbz-L-Asp[N(Me)OMe]
Scheme 4
P3 conversion to

aldehyde then

reductive

amination

524
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5;
P3 deprotection

reductive
then dialkylation

alkylation for
with alkyl

R1X
dibromide

525
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

526
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

527
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

528
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)
Scheme 4
P3 deprotection,

diacylation with

anhydride

529
Scheme 1
Cbz-Gly-OH
Boc-L-citrulline-OH
Scheme 4
none

530
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)
Scheme 4
P3 deprotection,

reductive

alkylation

531
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)
Scheme 4
P3 deprotection,

diacylation with

anhydride

532
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

533
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)
Scheme 4
P3 deprotection,

then acylation

with isocyanate

534
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

535
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

536
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

537
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then reductive

alkylation then

acetylation

538
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dap(Boc)-OH
Scheme 4
P3 deprotection

then reductive

alkylation

539
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dap(Boc)-OH
Scheme 4
P3 deprotection

then guanylation

540
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection,

guanidinylation,

deprotection

541
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

542
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

543
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then sulfonylation

544
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then sulfonylation

545
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection,

acylation,

deprotection

546
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

547
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

548
Scheme 1
N-(6-Cl-2-
Fmoc-L-Dab(Boc)-OH
Scheme 3
P3 deprotection

napthoic)-Gly-

OH

549
Scheme 1
N-(6-Cl-2-
Fmoc-L-Dab(Boc)-OH
Scheme 3
P3 deprotection

napthoic)-Gly-

then dialkylation

OH

with alkyl

dibromide

550
Scheme 1
N-(6-Cl-2-
Fmoc-L-Dab(Boc)-OH
Scheme 3
P3 deprotection

napthoic)-Gly-

then dialkylation

OH

with alkyl

dibromide

551
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

552
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

553
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

554
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

555
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

556
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

557
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5,
P3 deprotection

use
then dialkylation

isocyanate
with alkyl

for R1X
dibromide

558
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5;
P3 deprotection

reductive
then dialkylation

alkylation
with alkyl

then
dibromide

acetylation

for R1X and

R2

559
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

560
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

561
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

562
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then sulfonylation

563
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then acylation

with

chloroformate

564
Scheme 1
Cbz-Gly-OH
Fmoc-DL-2-(1-Boc-4-
Scheme 4
P3 deprotection

piperidyl)-Gly-OH

then reductive

alkylation with

ketone

565
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

566
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

567
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

568
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

569
Scheme 1
Cbz-[¹⁵N,1,2-
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

¹³C₂]Gly-OH

then reductive

alkylation then

acetylation

570
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

571
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

572
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

573
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

574
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

575
Scheme 1
Alloc-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

576
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

577
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

578
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 5
P3 deprotection

then dialkylation

with alkyl

dibromide

579
Scheme 1
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

with D₂O

then reductive

exchange

alkylation then

during Fmoc

acetylation

deprotection

and

NaBD₃CN

reduction

580
Scheme 1
Cbz-Gly-OH
Fmoc-D-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

581
Scheme 2
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

582
Scheme 2
Cbz-Gly-OH
Fmoc-D-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

583
Scheme 2
Cbz-Gly-OH
Fmoc-L-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

584
Scheme 2
Cbz-Gly-OH
Fmoc-D-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

585
Scheme 1
Cbz-Gly-OH
Fmoc-D-Dab(Boc)-OH
Scheme 4
P3 deprotection

then dialkylation

with alkyl

dibromide

Example 102
Human MC5R Radioligand Binding Assay

Assessments of compound binding to human MC5R (hMC5R) ) by displacement of an ¹²⁵I-labeled NDP-MSH receptor ligand peptide were performed essentially as described in the data sheets produced by Perkin Elmer to accompany their frozen hMC5R membranes (Perkin Elmer catalog number RBXMC5M400UA).

NDP-MSH: Radiolabeled in House and Purified by HPLC:

Na¹²⁵I (0.5 mCi, 17.4 Ci/mg) was added to 50 μL sodium phosphate (50 mM, pH 7.4) in an eppendorf tube precoated with IODOGEN. After incubation for 10 mins the phosphate buffer containing the iodine was added to NDP-MSH (10 ul at 1 mg/mL) in a separate eppendorf tube. This was incubated for a further 10 mins. The iodinated NDP-MSH was purified by HPLC on a Zorbax SB 300 column using solvent A: 0.05% TFA and solvent B: 90% acetonitrile 0.045% TFA with a linear gradient, 0-67% B over 60 mins. The ¹²⁵I NDP-MSH eluted at 52 mins after the unlabeled starting material (48 min) and was counted and stored in the freezer. It was used within 48 hrs, as radioactive decay and ligand decomposition resulted in greatly reduced specific binding observed after 72 hrs.

Reagents:

Incubation buffer: 25 mM HEPES-KOH (pH 7.0), 1.5 mM CaCl₂, 1 mM MgSO₄, 0.1 M NaCl, 1 mM 1,10-phenanthroline, and 1 Complete™ protease inhibitor tablet/100 mL (Roche, catalog number 1873580)

Perkin Elmer frozen hMC5 membranes: catalog number RBXMC5M400UA, 0.4 mL/vial; 400 microassays/vial, 0.78 mg/mL protein concentration

Vials of frozen membranes were thawed rapidly immediately before use, diluted with binding buffer and vortexed. Resuspended membranes were kept on ice until they were added to the wells of the plate.

Binding Protocol for 400 Microassays per Vial:

Assays were performed in 96 well polypropylene plates. Membranes (0.78 μg 40 μL of a 1:40 dilution in incubation buffer) were added to [¹²⁵I] NDP-MSH (0.84 nM; 2200 Ci/mmol) and test compounds in a total volume of 140 μL. This was incubated for 1 hr at 37° C. Non-specific binding was determined with 3 mM NDP-MSH. Plates were filtered using a Tomtec cell harvester with GF/A filters (Wallac) (presoaked in 0.6% polyethylenimine) and washed three times with 1.0 mL ice-cold wash buffer (the above incubation buffer without 1,10-phenanthroline and Complete™ protease inhibitor tablet). The filters were dried in a 37° C. oven, placed in a sample bag and 5 mL Betaplatescint (Wallac) was added. Prepared filters were counted in cassettes in a Microbeta Trilux (Wallac) for 1 min. Non-specific binding just under 5%. Data analysis was performed using GraphPad Prism 4, employing competition binding with a single site model and a fixed Hill coefficient. The following equation was used: Y=Bottom+(Top-Bottom)/1/10̂(X−log EC₅₀), where X=log(concentration) and Y=binding to fit the data.

Example 103
Identification of Preferred Diastereomer for Binding to MC5R

The four diastereomers of one set of substituents were tested for binding in the hMC5R assay as in Examples 102, as listed in Table 3.

TABLE 3

Activity of Four Diastereomers

human MC5R

Cpd.
stereochemistry
IC₅₀(nM)

102
(3R,5S)
3500

103
(3R,5R)
500

104
(3S,5R)
1500

105
(3S,5S)
56

As can be seen the 3S, 5S isomer is almost ten times more active than the next most active isomer and significantly more active than the other two possible isomers. This unexpectedly high level of differential activity and hence specificity of the (S,S) diastereoisomer was unexpected and is not predictable from a knowledge of the hMC5R or its previously known ligands.

Example 104
Activity of Selected Compounds: hMC5R Binding

Representative compounds of the present invention were tested for binding in the hMC5R assay as in Example 102, as listed in Table 4. The compounds were tested as their trifluoroacetate or hydrochloride salts, or as their free base.

TABLE 4

Properties of Compounds

MC5R radioligand

Cpd.
MS (M + 1)
t_R(min)
IC₅₀

14
556.2
5.74
xxx

25
595.3
6.22
xxx

31
539.3
5.92
xx

33
599.4
6.31
xxxx

37
473.4
5.59
xxx

38
541.3
5.78
xxx

39
541.3
5.67
xxx

49
499.3
5.77
xx

50
613.5
5.89
x

54
425.7
5.27
xx

60
629.4
6.27
x

62
629.3
6.22
xx

63
535.3
5.76
xx

64
603.3
6.04
xxx

65
577.2
5.97
xxx

67
591.3
5.94
xxxx

71
549.3
5.93
xx

79
606.4
6.033
x

81
743.4
5.489
xx

83
650.3
6.524
xx

85
606.2
6.008
x

86
743.5
5.410
xx

87
650.4
6.424
x

102
577.4
5.775
x

103
577.5
5.750
xx

104
577.5
5.783
x

105
577.3
5.79
xxx

106
561.4
6.05
xx

107
524.3
5.63
xx

108
603.3
6.11
xxx

109
566.2
5.65
xx

110
591.2
5.82
xx

111
581.3
5.95
xxx

112
578.3
5.26
xxx

113
579.3
5.52
xx

114
578.3
5.72
xx

115
527.3
5.41
xx

116
578.3
5.78
xx

117
509.2
5.51
xx

118
523.3
5.56
x

119
523.2
5.51
x

120
512.3
5.10
x

121
549.4
5.96
xx

122
509.2
5.56
xx

123
523.4
5.63
x

124
509.2
5.41
x

125
523.3
5.68
x

126
549.3
5.79
xx

127
554.2
5.87
x

128
554.2
5.87
xx

129
539.1
5.58
x

130
596.5
5.87
x

131
582.4
5.88
x

132
567.4
5.62
x

133
567.4
5.62
x

134
582.4
5.88
xx

135
583.4
5.86
xx

136
595.4
5.31
xxx

137
595.4
5.87
xx

138
527.2
5.33
xx

139
533.3
5.54
x

140
620.2
6.16
xxx

141
620.2
6.21
xx

142
566.3
5.70
xxx

143
555.2
5.55
xx

144
555.2
5.74
xxx

145
583.4
6.21
xx

146
587.2
4.90
x

147
547.4
5.78
xx

148
571.2
5.34
xx

149
567.1
4.48
x

150
568.1
4.87
x

151
519.5
5.23
x

152
595.4
5.92
xxx

153
553.5
5.58
xxx

154
595.4
5.95
xx

155
609.4
5.88
xx

156
607.5
5.96
xxx

157
609.4
—
x

158
607.4
5.88
xxx

159
579.3
5.83
xx

160
621.3
6.22
xxx

161
585.6
6.00
x

162
557.4
5.50
x

163
607.5
5.94
xx

164
607.2
5.69
xx

165
585.4
5.64
xx

166
557.3
6.06
xxx

167
559.5
5.47
xxx

168
585.5
5.58
xx

169
569.5
5.17
xx

170
583.6
5.70
xx

171
567.6
5.79
xxx

172
621.4
6.01
xx

173
571.5
5.65
xxx

174
567.5
5.50
xx

175
567.5
5.37
xx

176
625.5
5.81
xxx

177
587.4
5.65
xxx

178
584.5
4.84
xx

179
593.4
5.60
xx

180
583.6
5.41
xx

181
655.2
5.97
xxxx

182
501.4
5.20
xx

183
570.2
5.64
x

184
570.2
5.66
xx

185
583.5
5.43
xxx

186
607.3
5.28
xxx

187
583.4
5.37
xxx

188
595.6
5.64
xxx

189
587.4
5.78
xx

190
569.5
5.23
xx

191
567.7
5.92
xxx

192
621.4
6.19
xx

193
569.6
5.23
xx

194
571.5
5.69
xxx

195
567.5
5.98
xxx

196
571.5
6.00
xx

197
561.3
5.84
xx

198
575.4
5.98
xx

199
571.1
5.69
xxx

200
621.3
6.19
xxx

201
591.2
6.02
xx

202
493.3
5.41
xx

203
545.2
5.91
xx

204
591.3
5.88
xxx

205
591.3
5.90
xx

206
479.4
5.09
xx

207
609.4
6.13
xx

208
589.3
5.69
xxx

209
605.3
5.85
xxx

210
631.4
6.09
xxxx

211
597.4
5.89
xxx

212
615.3
6.20
xxx

213
511.3
5.63
xx

214
545.4
5.92
xxx

215
637.6
6.15
xx

216
605.5
5.94
xxx

217
553.3
5.88
xxx

218
592.4
4.99
x

219
525.3
5.79
xxx

220
529.5
5.59
xxx

221
553.5
5.87
xxx

222
507.2
5.64
x

223
513.5
5.68
xx

224
553.3
5.89
xxx

225
549.7
5.87
xx

226
617.4
6.21
xxx

227
523.3
5.49
x

228
575.5
5.72
x

229
569.2
5.87
xx

230
569.2
5.83
x

231
611.2
6.20
xxxx

232
591.4
6.03
xxx

233
547.5
5.70
xxx

234
536.5
5.47
xx

235
561.7
6.11
xx

236
533.5
5.53
xx

237
585.5
6.23
xxx

238
550.5
5.81
xxx

239
568.5
5.45
x

240
586.5
6.18
xxx

241
542.5
5.57
xx

242
568.4
5.91
xx

243
579.7
5.60
xx

244
565.5
5.42
x

245
506.4
5.73
xx

246
519.3
5.78
xx

247
637.5
5.84
x

248
624.3
6.28
xxx

249
603.2
6.14
xxx

250
589.4
6.04
xxx

251
543.3
6.30
xxx

252
487.2
5.13
x

253
613.5
6.06
xxx

254
537.4
5.66
x

255
531.6
5.65
xx

256
551.5
5.47
xx

257
543.5
5.77
x

258
543.5
5.66
xx

259
581.5
5.10
xx

260
591.4
5.94
xxx

261
599.4
5.99
xxx

262
613.5
6.08
xxx

263
521.4
5.85
xx

264
589.3
5.81
xxx

265
575.5
5.79
xxx

266
537.2
5.61
x

267
551.4
5.70
x

268
558.4
4.86
x

269
579.6
5.73
xxx

270
581.4
5.84
xxx

271
621.2
6.07
xxx

272
598.6
5.27
xx

273
626.7
5.64
x

274
507.3
6.35
xx

275
517.4
6.51
xxx

276
515.3
5.18
xxx

277
511.4
5.81
xxx

278
575.3
6.71
xxx

279
585.4
6.83
xxxx

280
539.3
5.87
xx

281
499.5
5.62
xx

282
497.6
5.58
xx

283
531.4
5.89
xxx

284
607.3
6.29
xxxx

285
567.3
5.99
xxx

286
565.4
5.93
xxx

287
583.5
6.02
xxxx

288
579.6
6.18
xxx

289
515.3
5.58
xx

290
620.5
5.44
xx

291
620.5
5.38
x

292
531.5
5.22
xx

293
559.5
5.74
xx

294
607.4
6.06
xx

295
557.4
5.61
xx

296
534.4
7.27
xx

297
544.5
7.42
xx

298
559.4
6.59
xx

299
549.4
6.42
xx

300
567.3
6.52
xx

301
635.5
7.34
xx

302
593.5
6.02
xxx

303
573.4
5.47
xx

304
481.4
5.47
xx

305
521.5
6.10
xxx

306
641.4
7.38
xx

307
655.3
7.59
xx

308
485.3
5.17
x

309
553.3
5.82
xx

310
535.3
5.72
xx

311
553.5
5.39
x

312
621.2
6.06
xx

313
603.4
5.94
xx

314
572.3
4.91
x

315
574.5
7.69
xx

316
584.5
7.83
xx

317
617.7
7.04
xx

318
627.5
7.11
xxx

319
582.3
7.44
xx

320
592.4
7.55
xx

321
588.4
8.00
xx

322
598.4
8.15
xx

323
568.1
7.28
xx

324
578.3
7.45
xx

325
519.2
5.93
xx

326
511.2
5.94
xxx

327
540.3
5.61
xx

328
523.2
5.37
xx

329
498.4
5.49
xx

330
481.5
5.27
x

331
514.3
5.52
x

332
514.2
5.42
x

333
505.4
5.27
x

334
480.3
5.33
x

335
514.4
5.65
x

336
514.4
5.62
xx

337
514.3
5.63
x

338
477.3
5.35
x

339
531.5
5.65
x

340
480.4
5.38
x

341
487.2
5.55
xx

342
527.3
5.96
xx

343
587.2
6.33
xxx

344
567.3
6.12
xxx

345
577.2
6.31
xxxx

346
443.2
5.43
xx

347
435.3
5.46
xx

348
503.1
5.58
xx

349
511.4
5.73
xxx

350
493.7
5.71
xxx

351
427.3
5.04
x

352
423.4
5.28
x

353
427.3
5.13
x

354
423.3
5.32
x

355
489.4
6.42
xx

356
589.4
5.92
xx

357
581.3
6.03
x

358
480.4
5.33
x

359
555.4
5.81
xxx

360
612.6
5.49
x

361
620.5
—
x

362
595.4
6.12
xx

363
637.2
6.30
x

364
505.1
6.46
xx

365
485.2
6.26
xx

366
491.2
5.69
xx

367
573.1
6.07
xx

368
565.2
6.88
xxx

369
491.2
5.69
xx

370
483.4
5.77
xxx

371
559.1
6.12
xx

372
539.2
5.84
xx

373
473.3
5.29
xx

374
473.2
5.21
x

375
549.4
6.03
xx

376
621.4
6.13
xxx

377
493.3
5.32
xx

378
587.2
6.17
xxx

379
577.4
6.04
xxx

380
559.3
6.01
xxx

381
551.3
5.99
xxx

382
551.4
6.04
xxxx

383
555.3
6.19
xxx

384
575.4
6.11
xxx

385
589.3
6.06
xxx

386
443.6
5.36
xx

387
459.9
5.66
xx

388
503.2
5.74
xx

389
511.4
5.65
xxx

390
527.3
5.95
xxx

391
573.2
6.07
xxx

392
483.3
5.97
xx

393
465.4
5.81
xx

394
475.3
5.98
xx

395
623.2
6.41
xxxx

396
607.4
6.17
xxxx

397
585.4
6.12
xxx

398
573.2
6.12
xxx

399
563.4
5.95
xx

400
581.3
6.12
xx

401
479.1
5.68
x

402
487.4
5.45
xx

403
551.5
6.42
xxx

404
525.3
6.31
xx

405
487.3
5.69
x

406
473.4
5.51
xx

407
487.4
5.40
x

408
568.1
5.91
x

409
601.3
6.08
xxx

410
533.3
5.82
x

411
622.3
6.90
x

412
579.3
6.60
x

413
555.4
6.00
xx

414
555.4
6.10
xxx

415
607.5
6.60
xxx

416
539.4
6.32
xx

417
593.5
6.26
xxx

418
525.3
6.03
xx

419
601.3
6.09
xxx

420
533.2
5.81
xx

421
627.4
7.20
x

422
601.3
6.10
xxx

423
609.4
7.64
xx

424
613.4
6.31
xxx

425
575.3
6.26
xxxx

426
537.4
5.98
xxx

427
525.1
5.96
xxx

428
561.4
6.26
xxxx

429
559.1
6.11
xxx

430
545.1
6.01
xxx

431
569.3
5.92
xx

432
645.3
6.28
xxxx

433
640.2
6.70
xxx

434
622.3
6.49
xx

435
613.4
7.03
xx

436
603.2
7.23
xxx

437
587.2
7.01
x

438
561.4
6.88
xxx

439
545.1
6.68
xx

440
589.4
6.24
xxx

441
573.1
5.95
xxx

442
559.1
5.90
xx

443
627.4
6.56
xx

444
493.2
5.68
x

445
493.2
5.71
x

446
561.4
5.93
x

447
561.4
6.09
xx

448
581.3
6.93
xx

449
547.3
6.00
xxx

450
561.2
5.92
xxx

451
567.2
6.94
xx

452
581.2
6.45
xxx

453
593.3
6.56
xx

454
547.2
6.12
xxx

455
574.3
5.67
xxx

456
555.3
6.15
xxx

457
555.3
6.25
xxx

458
607.2
6.20
xxx

459
539.2
5.90
x

460
607.3
6.11
xx

461
539.1
5.94
x

462
577.1
6.37
xxxx

463
561.1
6.17
xxx

464
549.2
6.28
xxxx

465
507.2
6.00
xxx

466
583.3
6.38
xx

467
595.2
6.50
xxxx

468
560.3
5.64
xxx

469
575.2
6.62
xxx

470
575.2
6.27
xxxx

471
573.2
6.28
xxxx

472
547.2
5.96
xxx

473
617.2
6.52
xxx

474
520.2
7.40
xx

475
534.3
7.66
xxx

476
587.4
6.55
xxx

477
575.2
5.82
xxx

478
603.4
5.98
xxx

479
573.1
6.32
xxx

480
573.1
6.18
xxxx

481
561.2
6.21
xxx

482
651.3
6.85
x

483
571.1
7.11
xx

484
583.3
6.98
xx

485
575.2
6.06
xxx

486
593.4
6.01
xxx

487
549.2
5.87
xxx

488
563.3
6.05
xxx

489
457.2
5.64
x

490
457.2
5.78
x

491
525.2
6.05
xxx

492
525.3
6.13
xxx

493
535.2
6.33
xx

494
535.2
6.50
x

495
491.3
5.63
xx

496
533.2
5.94
xxx

497
533.1
6.44
xxx

498
603.3
6.44
xxx

499
603.2
7.15
xxx

500
603.2
6.96
xxx

501
473.1
5.99
xx

502
473.2
6.09
xx

503
541.2
6.34
xxx

504
541.1
6.43
xxx

505
574.2
8.16
x

506
548.3
7.86
xxx

507
633.4
5.66
xx

508
591.1
6.36
xxxx

509
536.2
6.57
xxx

510
522.4
6.72
xxx

511
598.2
7.49
x

512
520.1
7.36
x

513
455.2
5.16
x

514
523.3
6.09
xx

515
471.1
5.53
xxxx

516
539.3
6.11
xxx

517
539.2
6.19
xxxx

518
519.3
5.72
xx

519
496.3
4.91
xxx

520
494.4
4.65
xx

521
595.3
6.30
xxx

522
492.2
6.16
x

523
595.3
6.39
xx

524
545.2
5.91
xxx

525
523.0
5.88
xx

526
471.1
5.79
xx

527
539.3
6.14
xxx

528
573.1
6.50
x

529
564.5
6.60
xx

530
587.2
6.61
xx

531
601.3
7.03
x

532
589.3
6.59
xxx

533
592.3
7.08
xx

534
567.3
6.34
xxx

535
574.2
6.14
xxx

536
601.3
6.69
xxx

537
591.3
7.24
xx

538
535.3
6.94
xxx

539
535.3
6.37
xxx

540
573.1
6.13
xx

541
519.2
5.98
xx

542
587.1
6.34
xx

543
597.1
6.61
x

544
673.0
7.50
x

545
618.4
—
x

546
533.1
6.20
xxx

547
603.1
6.57
xxx

548
513.3
6.00
xxx

549
581.2
6.22
xxx

550
581.0
6.33
xxxx

551
473.3
6.03
xx

552
541.1
6.36
xxx

553
625.4
6.57
xxx

554
577.2
6.30
xxx

555
603.1
6.45
xxx

556
589.1
6.23
xxx

557
554.3
6.02
xx

558
587.1
6.50
x

559
457.0
5.73
x

560
525.2
6.20
xxx

561
637.0
6.75
xxx

562
613.3
7.03
xxx

563
607.2
—
xx

564
589.5
6.19
xxx

565
574.8
6.27
xxxx

566
618.9
6.74
xxx

567
587.7
6.19
xxxx

568
596.9
6.20
xxx

569
578.0
6.38
xxxx

570
597.0
6.42
xxx

571
626.9
6.70
xxxx

572
591.9
6.61
xxxx

573
559.0
6.03
xxxx

574
612.8
7.04
xx

575
644.9
6.79
xxx

576
570.9
6.04
xxx

577
570.8
6.21
xxx

578
618.8
6.61
xxxx

579
579.9
6.39
xxxx

580
575.4
6.40
xx

581
575.2
6.26
xxx

582
575.2
6.11
xxx

583
575.1
6.21
xx

584
575.2
6.25
xx

585
575.4
6.27
x

x = <10 μM;

xx = <1 μM,

xxx = <100 nM,

xxxx = <10 nM

Example 105
MC5R Radioligand Binding Assay Using MC5 Receptors From Other Species

Radioligand binding and cAMP assays were also conducted using membranes and cells expressing MC5R cloned from other species (mouse MC5R membranes were obtained from Euroscreen; canine, rhesus monkey, cyno monkey and guinea pig MC5 receptors were cloned and expressed from cDNA libraries and transiently transfected as described in Examples 107 and 109. Plasma membranes from the cells were tested in the radioligand assay as in Example 102.

Example 106
Activity of Selected Compounds: Other Species MC5R

Representative compounds of the present invention were tested for binding to MC5R from other species, as described in Example 105, the results are listed in Table 5.

TABLE 5

Binding of Selected Compounds to MC5R from Different Species

rhesus

human

canine
rhesus
monkey

MC5R
mouse
MC5R
monkey
MC5R

human MC5R
(whole
MC5R
(whole
MC5R
(whole

(membrane)
cells)
(membrane)
cells)
(membranes)
cells)

Cpd.
IC₅₀(nM)
IC₅₀(nM)
IC₅₀(nM)
IC₅₀(nM)
IC₅₀(nM)
IC₅₀(nM)

105
57
219
4000
6400
6027
3000

64
30
127
—
13000
7307
>5000

These results show the selectivity of the compounds of the invention for human MC5R in comparison to MC5R in other species. Whilst there is activity in other species it is significantly reduced in comparison to human MC5R, which would not be expected given the high receptor homology between species.

Example 107
Human MC1R, MC3R and MC4R Radioligand Binding Assay

Radioligand binding assays were carried out using commercial or in-house prepared hMC1R, hMC3R and hMC4R membranes and [¹²⁵I] NDP-MSH, as per the hMC5R procedure in Example 102.

In-house plasma membranes were prepared from transfected mammalian cells (prepared as in Example 109, using plasmid DNA containing the human MC1R, MC3R or MC4R gene or other gene of interest in a plasmid vector with a mammalian origin of replication):

Adherent cells were washed with warm Hanks buffered saline solution (HBSS). 1 mL of cold HBSS was added to each flask and the cells were scraped off with a rubber policeman. The scraped cells were added to a 50 mL tube on ice. The plates were then rinsed twice with 5 mL cold HBSS and this was also added to the tube. The cells were centrifuged at 1000×g for 5 mins in a bench top centrifuge and the supernatant was decanted. The remaining cell pellet was resuspended in 0.25 M sucrose. The cell suspension was centrifuged again as previously and the pellet resuspended in 5 mL of 0.25 M sucrose containing protease inhibitors. The cells were homogenised by a 10 second pulse with an Ika disperser followed by 30 seconds on ice. The homogenisation and ice incubation was repeated three times. The mixture was then centrifuged at 1260×g for 5 mins. The supernatant was decanted into another centrifuge tube, to which a buffer containing 50 mM Tris, pH 7.4, 12,5 mM MgCl₂, 5 mM EGTA and protease inhibitors was added to make the volume up to 30 mL. This was centrifuged at 30,000×g for 90 mins at 4° C. The resulting pellet was resuspended in 1 mL of the buffer above also containing 10% glycerol. Membranes were aliquoted into cryovials which were snap-frozen in a dry-ice/ethanol bath before being stored at −80° C. until required for use.

Example 108
Selectivity of Selected Compounds: hMCR Binding

Representative compounds of the present invention were tested for binding in the hMC1R, hMC3R, hMC4R and hMC5R assays, as in Examples 102 and 107, as listed in Table 6.

TABLE 6

hMCR Binding Selectivity of Selected Compounds

human MC5R
human MC1R
human MC3R
human MC4R

Cpd.
IC₅₀(nM)
IC₅₀(nM)
IC₅₀(nM)
IC₅₀(nM)

105
57
6660
1750
3280

64
31
9220
2240
3490

33
9
2850
1500
6060

348
150
20000
1830
20000

These results demonstrate the selectivity of the compounds of the invention for human MC5R in comparison to other receptor subtypes of the human melanocortin receptor family.

Example 109
Inhibition or Stimulation of cAMP Signal in Cells Expressing Human MC5R
Transient Transfection of Mammalian Cell Lines:

The mammalian cell line, human embryonic kidney cells (HEK 293), were maintained in Dulbeccos Modified Eagle's medium (DMEM) with 5% fetal bovine serum, L-glutamine, high glucose and antibiotics/antimycotics. On the day prior to transfection, cells were passaged using trypsin/EDTA and seeded into 75 cm²flasks so that they would be approximately 90% confluent the next day. The next day, the cell media was replaced with fresh antibiotic/antimycotic-containing DMEM. Approximately 100 μl of the transfection lipid Turbofectin 8.0 (Origene Technologies, MD, USA), was diluted in 1.0 mL of serum and antibiotic/antimycotic-free OptiMEM in a sterile 15 mL tube and incubated for 5 mins at room temperature. Following incubation, approximately 10-20 μg of plasmid DNA expressing the gene of interest (for example: pCMV6-XL4:Homo sapiens melanocortin 5 receptor (Origene Technologies, MD, USA)) was diluted into the transfection mix and incubated for a further 30 mins at room temperature. The DNA/lipid solution was then added drop-wise to the media covering the cells while rocking the flask gently. 24 hrs post-transfection, the cells were passaged and seeded directly into two, 75 cm²flasks and left to recover. 48 hrs post transfection, cells were harvested for use in assays with cell dissociation solution.

Cyclic-Adenosine Monophosphate [cAMP] Stimulation Assay:

HEK 293 cells transiently expressing the melanocortin MC5 receptor were suspended in stimulation buffer (Hanks buffered saline solution (HBSS), 0.1% bovine serum albumin, protease inhibitors and 0.5 mM 3-Isobutyl-1-methylxanthine) at 4×10⁶cells/mL. 5 μl of cells, plus the compounds/peptides as described below, were added to wells of a 384-well plate as soon as possible after resuspension.

To detect antagonist activity, test compounds at varying concentrations were diluted in stimulation buffer at four times concentrate and 2.5 μl was added to wells containing cells. 2.5 μl of a four times required concentration of NDP-MSH or alpha-MSH was added to all wells containing compounds. Negative control wells contained two times concentrated NDP-MSH or alpha-MSH alone without compound.

To detect agonist activity, test compounds at varying concentrations were diluted in stimulation buffer at two times concentrate and 5 μl was added to wells containing cells. Positive control wells contained NDP-MSH or alpha-MSH alone (no compound) at two times concentrate

Basal level (of cAMP) control wells contained stimulation buffer only (no agonist or compounds). Known concentrations of cAMP (standards) in stimulation buffer were included on the plate, but no cells were added to these wells. The plate was then incubated for 30 mins at 37° C. with gentle shaking. After incubation, 10 μl of lysis buffer (10% Tween 20, 1 M HEPES, 0.1% BSA, protease inhibitors, ddH₂O) was added to all wells to be measured. Detection of cAMP was then achieved using the Alphascreen cAMP kit (Perkin Elmer, USA), briefly described as follows. A dilution of 10 μl acceptor beads/mL of lysis buffer was prepared in low light conditions. 5 μl of diluted acceptor beads were added to each well to be measured, then the plate was incubated for 30 mins at room temperature, in the dark, with gentle shaking. In low light conditions, donor beads were diluted at 10 μl/mL of lysis buffer, to which 0.75 μl biotinylated cAMP/mL of lysis buffer was added. This mixture was allowed to incubate for 30 mins at room temperature (in the dark) before proceeding with the assay. Following incubation, 5 μl/mL of biotinylated cAMP/Donor bead mix were added per well in low light conditions and the plate was incubated in the dark, at room temperature, for a further hr. Plates were read on an Envision plate reader (Perkin Elmer) after 1 hr and ˜16 hrs incubation. cAMP concentration in the cells was determined by the use of a ‘standard curve’ generated from the output of known cAMP concentrations as described below.

Each assay plate contained a “standard curve” of known concentrations of cAMP, in 10 fold dilutions. This is an essential part of the assay as there is high inter-plate variability. The plates were read on an Envision multilabel plate reader fitted with Alphascreen technology and the raw data was imported into GraphPad Prism 4 software (GraphPad, USA) for analysis. A curve was fitted to the known concentrations using non-linear regression, specifically using a sigmoidal dose-response equation (Y=Bottom+(Bottom 30 (Top-Bottom)/1+10^{log EC50−X}), where the equation shows the response as a function of the logarithm of concentration. X is the logarithm of peptide/compound concentration and Y is the response. Also considered in this equation are bottom plateau, top plateau of the curve and EC₅₀(effective concentration, 50%)

Example 110
Activity of Selected Compounds: hMC5R

Representative compounds of the present invention were tested for agonism or antagonism of the hMC5R, as in Example 109, results are listed in Table 7.

TABLE 7

Agonism and Antagonism of hMC5 by Selected Compounds

human
human MC5R IC₅₀

MC5R EC₅₀
(cAMP, antagonism of

(cAMP, agonism)
10⁻⁶M alpha-MSH)

Cpd.
(nM)
(nM)

105
>10000
400

64
>10000
70

33
>10000
190

348
>10000
94

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The details of specific embodiments described in this invention are not to be construed as limitations. Various equivalents and modifications may be made without departing from the essence and scope of this invention, and it is understood that such equivalent embodiments are part of this invention.

Number	Date	Country
61032912	Feb 2008	US
61032894	Feb 2008	US
61032898	Feb 2008	US

METHODS OF MODULATING THE ACTIVITY OF THE MC5 RECEPTOR AND TREATMENT OF CONDITIONS RELATED TO THIS RECEPTOR

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