Methods of modulating activity of mc5 receptor and treatment of conditions related to thereof

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics, namely, deals with compounds of formula , suitable for reduction of regulation of biological activity of melanocortin-5 receptor (MC5R). Such diseases and/or conditions include, but are not limited by, acne, seborrhoea, seborrheic dermatitis, cancer and inflammatory diseases.

EFFECT: compounds of claimed invention can be applied for treatment of diseases and/or conditions, in which reducing regulation of MC5R is favourable.

3 cl, 109 ex, 7 tbl

 

Field of the INVENTION

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

Background of the INVENTION

Melanocortin-5 receptor (MC5R) is coupled with G-protein receptor (GPCR) belonging to the family of melanocortin receptors. There are five melanocortin receptors that have been identified and cloned to date. MC1R, MC2R, MC3R, MC4R and MC5R. Melanocortin receptors are involved in various physiological functions, providing a number of opportunities for therapeutic intervention in the physiological processes by changing (i.e., statistically significant increase or decrease) or modulation (e.g., up regulation or down regulation) signaling activity of the melanocortin receptor.

Published reviews of the melanocortin receptors and their potential as targets for therapy (Wikberg 2001; Bohm 2006). The members of the family of melanocortin receptors regulated natural peptide AGON�Stam, such as AST (adrenocorticotropic hormone), and melanocyte-stimulating hormone (α-, β-, γ-MSH) derived from proopiomelanocortin (ROMs), and peptide antagonists such as Agouti-signaling protein (ASP) and Agouti-related protein (AGRP). MC1R is widely expressed and is associated with pigmentation in melanocytes and inflammatory responses in many cells involved in the immune system. MC2R is different from other melanocortin receptors that it binds only asthma, but not MSH ligands. He is highly expressed in adrenal gland and regulates the synthesis of corticosteroids. MC3R is found in the brain, as well as in other places in the body and, as it turns out, plays a role in the regulation of energy homeostasis and possible sexual dysfunction. MC4R is found almost exclusively in the brain, sometimes reported his presence in other places. It is closely related to power control, and is also associated with sexual desire. MC5R is widely expressed in peripheral tissues, especially in exocrine glands, some of the receptor is also expressed in the brain. Taking into account the scope of activity associated with melanocortin receptors, is necessary when aiming at a target of one of these receptors be done selectively to avoid side effects associated with antagonism or agonism another recepto�and in this family.

MC5R cloned and expressively from many species, including humans in 1993 (although called MC2 in this document) (Chhajlani 1993), rat in 1994 (Griffon 1994), mice in 1994 (Gantz 1994; Labbe 1994) and in 1995 (Fathi 1995), the representative of the dog (Houseknecht 2003), the rhesus monkey (Huang 2000), sheep (Barrett 1994), striped pertino (Ringholm 2002), silver carp (Cerdá-Reverter 2003), prickly shark (Klovins 2004), rainbow trout (Haitina 2004) and chicken (Ling 2004), using the MC5R gene, also identified in pigs (Kim 2000). Published patents covering MC5R sequence in humans (Wikberg 2002), mice (Yamada 1997), the rhesus monkey (Fong 2003) and dogs (Houseknecht 2003).

A number of studies associated with MC5R regulation of sebum, as summarized in 2006 (Zhang 2006). Mouse MC5R-deficient, reduced sebum production, as shown by the inability to remove water from their fur and a reduced amount of sebum, extracted from their wool. Largely these mice the rest were generally healthy, with no easily noticeable violations (appearance, behavior, growth, muscle mass, fat mass, reproduction, levels of basal and stress induced corticosterone, glucose and insulin) (Chen 1997). Further research has identified the reduction of pheromone that causes changes in aggressive behavior between mice (Caldwell 2002; Morgan 2004a; Morgan 2004b; Morgan 2006). Mice that ROMs-production�water native peptide ligands MC5R "knocked out", exhibit a similar phenotype (Yaswen 1999). Rats, injected with α-MSH, were increased by 30 to 37% of normal sebum production, while the removal of the intermediate pituitary (source MSH). was caused by the reduced sebum 35%, which was restored after the administration of α-MSH (Thody 1973). Synergistic effect between a-MSH and testosterone was observed in rats, while testosterone increases sebaceous gland and cell volumes (probably through increased proliferation), α-MSH increases groovetune skin, and the combination increases the excretion of fat (Thody 1975a; Thody 1975b).

Through the detection of MC5R transcripts in microarcsecond sebaceous glands (Thiboutot 2000), detection of MC5R in human facial sebaceous glands staining using immune markers (Hatta 2001), detection of MC5R mRNA and MC5R in human sebaceous glands, cultured human sebocyti and rat preputial cells (Thiboutot 2000) and detection of MC5R in the form punctate particles in the sebaceous glands staining polyclonal antibodies have been shown at the cellular level the human sebocyti Express MC5R, which is visible in differentiated but not in undifferentiated sebocyti (Zhang 2006). MC5R mRNA is also detected in sebaceous glands from the skin of wild type mice, but not in sections of the skin "MC5R-knockout" mice (Chen 1997). Processing human�fir sebocyti recently isolated toxin (TMS), extract pituitary of the ox (TIME), α-MSH or NDP-MSH increases the formation of lipid droplets, the synthesis of squalene and the expression of MC5R (Zhang 2003; Zhang 2006). At the time, as MC1R and MC5R found in fat cells, treatment of primary sebocyte cell culture human NDP-MSH or TIME was caused by the significant increase in the expression of MC5R compared to serum-free conditions, correlating with differentiation sebocyti. Immortalisant line of fat cells (SZ-95, TSS-1 and SEB-1) also demonstrate the expression of MC5R (Jeong 2007; Smith 2007a; Phan 2007). These studies suggest that MC5R antagonists can be used in the reduction of sebum in mammals and, consequently, in the treatment of conditions associated with excess sebum secretion.

It was discovered that a family of 1,2,4-thiadiazoline derivatives with antagonistic activity of MC5R (138-320 nm) reduce saloobrazovanie as in cultures of human cells of sebocyti and when applied topically to human skin grafted onto immunodeficient mice (Eisinger 2003a-d; 2006a, b).

Excess sebum secretion, or seborrhea, is a common ailment, Sebaceous glands are found in most parts of the body with dense concentrations of large glands on the face, the hairy part of the scalp and upper torso (Simpson and Cunliffe p43.1). Sebum secretion in part, dependent on androgenic hormones, in�Sogno 35 partially mediated by 5α-reductase, which recycles the testosterone to 5α-DHT (dihydrotestosterone). Sebum consists of a species-specific mixture of lipids. In humans it consists of approximately 58% of glycerides, 26% of complex wax esters, 12% squalene and 4% cholesterol/esters of cholesterol (Simpson and Cunliffe p43.5). The presence of squalene is almost an exclusive feature of human sebum. The function of sebum is not clearly defined, but it is believed that it has fungistatic properties and plays a role in moisture loss from the epidermis and its water repellent ability (Simpson and Cunliffe p43.6; Danby 2005; Porter 2001; Shuster 1976; Kligm''an 1963).

Excess sebum secretion associated with the development of acne vulgaris. Ordinary acne is a common disease that affects about 80% of the world's population at some stage in their life. The person more likely to develop acne than any other disease, although the severity varies considerably (Simpson and Cunliffe p43.16). Acne peaks in prevalence and severity in adolescents aged 14-19 years, with approximately 35-40% of the affected, but a significant number of patients (7-24%), it continues beyond 25 years of age (Simpson and Cunliffe p43.15). Of patients treated from acne, one study found that 80% still had symptoms in 30-40 years of age (Simpson and Cunliffe p43.16). Despite the fact that acne n� is a life-threatening disease it can greatly affect the quality of life of patients (Follador 2006), while one study of patients with severe acne shows a similar effect as the more serious chronic medical conditions such as asthma, epilepsy, diabetes, back pain or arthritis (Mallon 1999).

It is believed that four main factors involved in the pathogenesis of acne: (i) increased production of sebum (seborrhea), (ii) hyperuricuria/zakuporivanija duct relating to the hair follicle and sebaceous gland (acne), (iii) infection of the duct R. acnes, and (iv) duct inflammation relating to the hair follicle and sebaceous gland (Simpson and Cunliffe p43.15; Williams 2006). Several studies have shown a clear link between increased production of sebum and the presence and severity of acne (Simpson and Cunliffe p43.17; Youn 2005; Pierard 1987; Harris 1983; Cotterill 1981; Thody 1975; Pochi 1964). A study in 2007 determined the relationship between sebum excretion and the development of acne in children pre-adolescent (Mourelatos 2007). Sebum is a key nutrient R. acnes, thus reducing sebum will reduce subsequent bacterial infection and the inflammatory response.

Androgenic sex hormones apparently play a role in the development of acne, with a strong relationship with the production of sebum (Makrantonaki 2007). Pills two oral contraceptives approved by the FDA (Commission p� the control of drugs and nutrients) for the treatment of acne vulgaris (Harper 2005), and these compounds apparently function by reducing androgen-mediated saloobrazovanie. Diet (Cordain 2005; Smith 2007b), stress (Zouboulis 2004) and genetic factors (Goulden 1999, Bataille 2006) may also play a role in acne, again potentially through increased sebum production.

Current methods of treatment of acne vulgaris are focused primarily on the treatment of infections and inflammatory stages of the disease with the help of a large number of different compositions Metodista antibiotics (for example, benzoyl peroxide, tetracycline, erythromycin, clindamycin) and retinoids (e.g., retinoic acid, isotretinoin, adapalene, tazarotene), or used singly, or in combination, some of them also have anti-inflammatory effects (Simpson and Cunliffe p43.36-43.38). Many of these treatments have limited effectiveness, especially in severe cases of acne Growing problem is the development of antibiotic-resistant strains of P acnes (Simpson and Cunliffe P43 37, 43 46, Williams 2006). As Metodista retinoids and benzoyl peroxide cause skin irritation, and retinoids, may cause photosensitivity (Williams 2006). Oral treatments include isotretinoin, antibiotics, hormones and steroids. It has been shown that females antiandrogens reduce the production of sebum (approx�proximately 40 to 80%, although no placebo control group) and reduce acne (Simpson and Cunliffe P43-44; Burke 1984, Goodfellow 1984) based on Laser and UV therapy are gaining ground is assumed to operate by heating the sebaceous glands and subsequent reduction of saloobrazovanie, with a decrease in both saloobrazovanie and measured lesions of acne (Jih 2006, Bhardwaj 2005). Many of therapies that is suitable for acne, only oral isotretinoin and hormonal therapy acting through regulation of the sebaceous glands to reduce sebum (Clarke 2007).

The most effective treatment of acne, oral isotretinoin (13-CIS-retinoic acid, Roaccutane, Accutane), was introduced in 1983 and still remains the most clinically effective therapy against acne. This is the only known treatment with strong suppressive activity on the production of fat reducing sebum excretion up to 90% after 8-12 weeks of therapy (60-70% after 2 weeks) (Simpson and Cunliffe P43-47, Jones 1983, Goldstein 1982, King 1982). Metodista retinoids, in contrast, have no effect on sebum production. Oral isotretinoin is anti-inflammatory, reduces the appearance of acne and reduce the infection of R. acnes. The mechanism of action is still unclear, and, apparently, an important role is played by the metabolites of isotretinoin. Isotretinoin induces apoptosis and cessation TC�exact cycle in human immortalizing SEB-1 sebocytes cell culture (Nelson 2006). Unfortunately, oral isotretinoin has serious side effects; largely it is a teratogen and that it needs a registration scheme for use in the United States. The FDA issued a warning against online purchase isotretinoin. During the treatment also recommend the study of blood lipids, deposited on an empty stomach, and liver function (Williams 2006). Isotretinoin was associated (although not significantly) with adverse psychological effects, including suicide and depression (Marqueling 2005).

Other forms of acne such as nodular acne or lightning acne, can also react to a substance that reduces sebum. Seborrhea, or excess production of sebum, often associated with severe acne condition. Seborrheic dermatitis (SD) is a skin disease associated with rich sebum areas of the scalp, face and torso with scaly, flaky, itchy redness of the skin, affecting 3-5% of the population; dandruff is a mild form of dermatitis that affects 15-20% of the population. Seborrhea and diabetes occur more frequently in patients with Parkinson's disease or affective disorders (paralysis of the facial nerve, damage was performed, poliomyelitis, syringomyelia, quadriplegia, unilateral damage in Gusarova ganglia and those with HIV/AIDS) (Plewig 1999). Studies have shown�, what seborrheic dermatitis is also associated with chronic alcoholic pancreatitis, hepatitis C and various cancers. It also usually occurs in patients with genetic disorders such as down syndrome, Hailey-Hailey's disease and cardio-Fazio-cutaneous syndrome (Gupta 2004). To treat these symptoms MC5R antagonists can be used.

Although few in number, but described various tumors involving the sebaceous glands or fat cells (for example, Ide, 1999; Mariappan 2004; Kruse 2003). Syndrome Muir-Torre includes adenoma sebaceous glands associated with the internal adenocarcinoma (usually the colon, breast, ovarian or prostate). Preventing the differentiation of fat cells may provide effective treatment for the relief of tumor growth. For this purpose, had used oral isotretinoin (Graefe 2000). Sebaceous gland hyperplasia is a benign hyperplasia of the sebaceous glands, forming a small yellowish papules on the surface of the skin, usually the face. The disease is associated with excessive proliferation of undifferentiated sebocyti, but not with excessive samoobrazovaniem. Ectopic sebaceous glands (pellets Fordyce) are similar yellow papules that are found in the mouth or on the body of the penis. And they both respond to oral isotretinoin. Effective treatment mo�et to provide a compound which reduced the proliferation of sebocyti.

a-MSH demonstrated immunosuppressive effects on people, suppressing a number of inflammatory responses, and MC5R was involved in these immunomodulatory activity. It was found that MC5R mRNA is expressed at high levels in human CD4+ T-helper (TA) cells and at moderate levels in human peripheral blood leukocytes (Andersen 2005). In mice MC5R identified in lymphoid organs (Labbe, 1994) and MC5R found on the surface of murine Pro-b-limfozitah cells where he was, as it turned out, mediates α-MSH activation of the JAK2 signaling pathway, enhancing cell proliferation (Buggy 1998). Induction of CD25+ CD4+ regulatory T-cells with α-MSH also, as it turns out, is through MC5R (Taylor 2001).

Due to the above reasons it would be desirable to do MC5R antagonists that could be applied in a number of therapeutic areas. Therapeutic regulation of biological signal transduction comprises modulation MC5R-mediated cellular events, including, inter alia, inhibition or potentiation of interactions among MC5R-binding and activation or deactivation of molecules or other substances that regulate MC5R activity. The increased ability of such regulation MC5R can facilitate the development of ways modelerov�Oia sebum or other biological processes and treatment of conditions associated with such pathways, such as acne, as described above.

Still need to develop better methods of modulating the activity of MC5R, which will facilitate the treatment of MC5R-bound States.

BRIEF description of the INVENTION

The present invention provides a method of down regulating the activity of MC5R or a fragment, analogue or functional equivalent, at which MC5R or a fragment or analogue or functional equivalent is exposed to the compounds of formula (I):

,

where

Y is a group of the formula -(CR9R10)n-;

X is selected from the group comprising-C(=O)-, -OC(=O)-, -NHC(=O)-, -(CR11R12)sand-S(=O)2-;

R is a group of amino acid side chain;

R1selected from the group comprising H, optionally substituted C1-C12alkyl, optionally substituted C2-C12of alkenyl, optionally substituted C2-C12alkynyl, optionally substituted C1-C12heteroalkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C2-C12heteroseksualci, optionally substituted C6-C18aryl and, optionally substituted C1-C18heteroaryl;

R2and R3each independently selected from the group comprising H, optionally substituted C1-C12alkyl, optionally substituted C2-C12of alkenyl, optionally substituted C2-C12alkynyl, optionally substituted C1-C12heteroalkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C2-C12heteroseksualci, optionally substituted C6-C18aryl and, optionally substituted C1-C18heteroaryl;

each R5aand R5bindependently selected from the group including H, halogen, C1-C12alkyl, C1-C12hydroxyalkyl and C1-C12haloalkyl, or

one or more of R5aand R5btaken together with one or more of R6, R7and R8and the atoms to which they are attached form a part selected from the group including optional substituted C3-C12cycloalkyl, optionally substituted C2-C12heteroseksualci, optionally substituted C6-C18aryl and, optionally substituted C1-C18heteroaryl;

R6, R7and R8each independently selected from the group including H, halogen, hydroxy, optionally substituted C1-C12alkyl, optionally substituted C2-C12al�Anil, optional substituted C2-C12alkynyl, optionally substituted C1-C12heteroalkyl, optionally substituted C1-C10heteroalkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C2-C12heteroseksualci, optionally substituted C6-C18aryl, optionally substituted C1-C18heteroaryl, optionally substituted amino, optionally substituted carboxy, C1-C12alkyloxy and, optionally substituted thio, or

(a) taken together with the carbon atom to which they are attached, two or more of R6, R7and R8form part selected from the group including optional substituted C2-C12of alkenyl, optionally substituted C3-C12cycloalkyl, optionally substituted C2-C12heteroseksualci, optionally substituted C6-C18aryl and, optionally substituted C1-C18heteroaryl, or

(b) one or more of R6, R7and R8taken together with one or more of R5aand R5band the atoms to which they are attached form a part selected from the group including optional substituted C3-C12cycloalkyl, optionally substituted C2-C12heteroseksualci, optional Sames�nny 6-C18aryl and, optionally substituted C1-C18heteroaryl;

each R9and R10independently selected from the group comprising H, optionally substituted C1-C12alkyl, optionally substituted C6-C18aryl and, optionally substituted C1-C18heteroaryl;

each R11and R12independently selected from the group comprising H and, optionally substituted C1-C12alkyl;

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

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

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

or its pharmaceutically acceptable salt or a prodrug.

In one embodiment, the implementation of MC5R or a fragment or analogue or functional equivalent is in the cell, and the method includes the stage at which the cell is exposed to a compound of formula (I). In one embodiment of the present invention provides a method of down regulating the activity of MC5R or a fragment or analogue or functional equivalent in the mammal, the mammal is administered MC5R-modulating amount of a compound of this invention.

In another aspect the present invention provides the use connected�I of formula (I) when a down-regulation of the activity of MC5R or a fragment, analogue or functional equivalent.

In another aspect the present invention provides use of a compound of formula (I) in the preparation of a medicinal product for down regulating the activity of MC5R or a fragment or analogue or functional equivalent of a mammal.

In another aspect the present invention provides a method of treating, preventing or controlling a condition associated with the activity of MC5R or a fragment, analogue or functional equivalent of a mammal, the method includes a stage on which administered a therapeutically effective amount of a compound of formula (I). The connection can be by any method known in the art, although in one aspect the compound is applied 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 including acne, seborrhea and seborrheic dermatitis. In one embodiment, the implementation status is a common acne. In one embodiment of the compound of formula (I) is administered together with a second active substance. In one embodiment, the implementation of the second active substance selected from the group comprising antibiotics, retinoids, anti-androgens and steroids.

In yet another aspect, the invention provides a method of reducing sebum mammal, wherein the method includes a stage on which the mammal is administered a therapeutically effective amount of a compound of formula (I). The compound of this invention can be entered by any way known in the art, although in one aspect the compound is applied topically. In another aspect the compound is administered orally. In another aspect the compound is administered parenterally.

In another aspect the invention provides use of a compound of formula (I) in the preparation of a medicinal product to reduce sebum by the mammal. In one embodiment, the implementation of drug fit � use topically. In another embodiment of the drug to adapt to the introduction of oral. In another embodiment, the implementation of the compound is administered parenterally.

DETAILED DESCRIPTION of the INVENTION

This description uses a number of expressions that are well known to the person skilled in the art. However, for the purposes of clarity will be determined by a number of expressions.

As used here, the expression "unsubstituted" means that there is no Deputy or that the only Deputy is hydrogen.

The expression "optional substituted", as used throughout the description, means that the group may or may not optionally be substituted or fused (so as to form a condensed polycyclic system), with one or more not hydrogen replacing groups. In certain embodiments, the substituting groups are one or more groups independently selected from the group comprising halogen, =O, =S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkenyl, heteroseksualci, geteroseksualen, aryl, heteroaryl, cycloalkyl al Kil, geterotsiklicheskie, heteroallyl, arylalkyl, cycloalkenyl, geterotsiklicheskikh, arylalkyl, heteroallyl, cycloalkylcarbonyl, heterotic�alkylglycerols, arylheteroacetic, heteroarylboronic, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, alkyloxyalkyl, alkyloxyalkyl, alkyloxyaryl, alkyloxyalkyl, allyloxycarbonyl, alkylaminocarbonyl, alkenylacyl, alkyloxy, cycloalkane, cycloalkenyl, heteroseksualci, geteroseksualnoe, aryloxy, phenoxy, benzyloxy, heteroaromatic, arylalkyl, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfonylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfonyl, arylsulfonyl, aminocarbonylmethyl, -C(=O)HE, -C(=O)Ra, -C(=O)ORa, C(=O)NRaRb, C(=NOH)Ra, C(=NRa)NRbRc, NRaRb, NRaC(=O)Rb, NRaC(=O)ORb, NRaC(=O)NRbRc, NRaC(=NRb)NRcRd, NRBSO2Rb, -SRa, SO2NRaRb, -ORaOC(=O)NRaRbOS(=O)Raand acyl,

where Ra, Rb, Rcand Rdeach independently selected from the group including H, C1-C12alkyl, C1-C12haloalkyl, S2-C12of alkenyl, C2-C12alkenyl, C1-C10heteroalkyl, S3-C12cycloalkyl, S3-C12cycloalkenyl, S1-C12heteroseksualci, S1-C12geteroseksualen�l, With6-C18aryl, C1-C18heteroaryl and acyl, or any two or more of Ra, Rb, Rcand Rdtaken together with the atoms to which they are attached, form a heterocyclic ring system with 3 to 12 ring atoms.

In one embodiment, the implementation of each of the optional Deputy independently selected from the group comprising: halogen, =O, =S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkenyl, heteroseksualci, geteroseksualen, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, alkyloxyaryl, alkyloxyalkyl, alkenylacyl, alkyloxy, cycloalkane, cycloalkenyl, heteroseksualci, geteroseksualnoe, aryloxy, heteroaromatic, arylalkyl, heteroallyl, arylalkyl, 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, CH2CH3HE founded3, CF3, OCF3, NO2NH2and CN.

The expression "group of the amino acid side chain" represents a natural or unnatural group of the side chain, present in the protein. The expression includes an hour�and the side chain, present in naturally occurring proteins, including naturally occurring part of the amino acid side chain identified in table 1 below.

Table 1.
Part of the amino acid side chain
Part of the amino acid side chainAmino acid
HGlycine
CH3Alanine
CH(CH3)2Valine
CH2CH(CH3)2Leucine
CH(CH3)CH2CH3Isoleucine
(CH2)4NH3+Lysine
(CH2)3NHC(NH2NH2+Arginine
CH2-(imidazol-4-yl)Histidine
CH2COO-Aspartic acid
CH2CH2COO-Glutamic acid
CH2CONH2Asparagine
CH2CH2CONH2Glutamine
CH2PhPhenylalanine
CH2C6H4OHTyrosine
CH2(Indolin-3-yl)Tryptophan
CH2SHCysteine
CH2CH2SCH3Methionine
CH2OHSerine
CH(Oh)CH3Threonine

In addition to naturally occurring groups of amino acid side chains, as identified above, the expression also includes their derivatives or analogues. As used here, the expression, derivative or analog of the amino group of the side chain includes modifications and variations of the naturally occurring groups of the side chain. According to the above table, the majority of naturally occurring amino groups�islotes side chain can be classified as alkyl, aryl, arylalkyl or heteroalkyl parts. As such derivative groups of the amino acid side chain include straight or branched, cyclic or acyclic alkyl, aryl, heteroaryl, heteroallyl, arylalkyl or heteroalkyl parts.

Groups of amino acid side chain, as discussed above, also includes an optional substituted derivatives of alkyl, aryl, arylalkyl, heteroaryl, heteroarylboronic or heteroalkyl parts. The optional substituents can be chosen from the group defined above. For example, the optional substituents can be selected, but not limited to, HE, Cl, Br, F, COOH, COORZ, CONH2NH2, NHRZ, NRZRZ, SH, SRZ, SO2RZ, SO2H and SORZwhere RZrepresents an alkyl, aryl or arylalkyl part.

In the definitions of a number of substituents below found that "the group may be a terminal group or a bridging group. It is assumed that this means that the use of the expression has to introduce the situation, where the group is a connecting link between two other portions of the molecule, and, where it is the terminal portion. The use of the expression alkyl as an example, in some publications used�Xia expression "alkylene" for the bridging group, and therefore in these other publications there is a distinction between the expressions "alkyl" (terminal group) and "alkylene" (bridging group), In this application not made such a distinction, and most groups may constitute or bridging group or a terminal group.

Multiple expressions begin with the index register, showing a certain amount of carbon atoms present in the part. For example, index register "C1-C6"before the expression "alkyl" indicates that the alkyl portion has 1-6 carbon atoms. In addition, index register "C1-C18"before the expression "heteroaryl" shows that the heteroaromatic ring may have 1-18 carbon atoms in the composition the total number of atoms in the ring system.

"Acyl" means R-C(=O)-group in which the R group may be an alkyl, cycloalkyl, geteroseksualnoe, 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 linked to the remainder of the molecule through the carbonyl carbon.

"Acylamino" means R-C(=O)-NH-group in which the R group may be an alkyl, cycloalkyl, geteroseksualnoe, �sterile or heteroaryl group, as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule via the nitrogen atom.

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

"Alkenylamine" refers to an alkenyl-O-group in which alkenyl is as defined here. Preferred alkenylamine groups are C1-C6alkenylamine group. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule through the oxygen atom.

"Alkyl" as a group or part of GRU�PY refers to straight or branched aliphatic hydrocarbon group, preferably With1-C14alkyl, more preferably C1-C10alkyl, most preferably C1-C6if not stated otherwise. Examples of suitable straight and branched C1-C6alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, hexyl and the like. The group may be a terminal group or a bridging group.

"Alkylamino" includes monoalkylamines, and dialkylamino, if not specified. "Monoalkylamines" means alkyl-NH-group in which alkyl is as defined here. "Dialkylamino" means (alkyl)2N-group in which each alkyl may be the same or different, and each represents a as defined herein for alkyl. The alkyl group preferably represents C1-C6alkyl group". The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule via the nitrogen atom.

"Alkylaminocarbonyl" refers to a group of the formula (Alkyl)x(H)yNC(=O)-, in which x is 1 or 2, and x+y=2. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule via� carbonyl carbon.

"Alkyloxy" refers to alkyl-O-group in which alkyl is as defined here. Preferably alkyloxy represents 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 alkyloxy-alkyl-group in which alkyloxy and the alkyl part are as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule through the alkyl group.

"Alkyloxyaryl" refers to alkyloxy-aryl-group in which alkyloxy and aryl parts are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule through an aryl group.

"Allyloxycarbonyl" refers to alkyl-O-C(=O)-group in which alkyl is as defined here. Alkyl group are preferably C1-C6alkyl group. Examples include, but are not limited to, methoxycarbonyl and ethoxycarbonyl. The group may be a terminal group or a bridging group. EU�and the group is a terminal group, it is linked to the remainder of the molecule through the carbonyl carbon.

"Alkyloxyalkyl" refers to alkyloxy-cycloalkyl-group in which alkyloxy and cycloalkyl part are as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule via cycloalkyl group.

"Alkyloxyalkyl" refers to alkyloxy-heteroaryl-group in which alkyloxy and heteroaryl portion are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule through the heteroaryl group.

"Alkyloxyalkyl" refers to alkyloxy-heteroseksualci-group in which alkyloxy and geteroseksualnoe part are as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule via geteroseksualnoe group.

"Alkylsulfonyl" means alkyl-S(=O)-group in which alkyl is as defined here. The alkyl group preferably represents C1-C6alkyl�ing group. Approximate alkylsulfonyl groups include, but are 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 linked to the remainder of the molecule via a sulfur atom.

"Alkylsulfonyl" refers to alkyl-S(=O)2-group in which alkyl is as defined above. The alkyl group preferably represents C1-C6alkyl group. Examples include, but are not limited to, methyl-sulfonyl and ethylsulfonyl. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule via a 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 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, ethinyl and PROPYNYL. The group may be a terminal group or a bridging group.

"Alkyloxy" refers to alkynyl-O-group in which alkenyl is, how do�Leno here. Preferred alkylalkoxy groups are C1-C6alkyloxy group. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule through the oxygen atom.

"Aminoalkyl" means 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 linked to the remainder of the molecule through the alkyl group.

"Aminosulfonyl" means NH2-S(=O)2group. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule via a sulfur atom.

"Aryl" as a group or part of a group means (i) optional substituted monocyclic or fused polycyclic, aromatic carbon cycle (ring structure having ring atoms, all of which are carbon), preferably having 5-12 atoms in the ring. Examples of aryl groups include phenyl, naphthyl and the like; (ii) the optional substituted partially saturated bicyclic aromatic carbocyclic portion, in which phenyl and C5-7cyclo�lilina 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. Basically aryl group is a C6-C18the aryl group.

"Arylalkyl" means an aryl-alkenyl-group in which the aryl and alkenyl are as defined herein. Approximate arylalkylamine groups include generally. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule through the alkenyl group.

"Arylalkyl" means aryl-alkyl-group in which the aryl and alkyl parts are as defined herein. Preferred arylalkyl groups contain a C1-5the alkyl part. Approximate arylalkyl groups include benzyl, phenetyl, 1-naphthalenethiol and 2-naphthalenethiol. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule through the alkyl group.

"Arylalkyl" refers to aryl-alkyl-O-group in which alkyl and aryl are as defined herein. The group may be a terminal group remotecopy group. If the group is a terminal group, it is linked to the remainder of the molecule through the oxygen atom.

"Arylamino" includes monoarylamino and diarylamino, if not specified. Monoarylamino means a group of the formula N-, in which aryl is as defined here. Diarylamino means a group of formula (aryl)2N-, where each aryl may be the same or different, and each represents a 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 linked to the remainder of the molecule via the nitrogen atom.

"Arylheteroacetic" means aryl-heteroalkyl-group, in which aryl and heteroalkyl part are as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule via heteroalkyl group.

"Aryloxy" refers to aryl-O-group wherein aryl is as defined here. Preferably aryloxy represents C6-C18aryloxy, more preferably6-C10aryloxy. The group may be a terminal group or a bridging group. If the group is Terminalo� group it is linked to the remainder of the molecule through the oxygen atom.

"Arylsulfonyl" means an aryl-S(=O)2-the 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 linked to the remainder of the molecule via a sulfur atom.

"Connection" is a connection between atoms in the compound or molecule. The relationship may represent a single bond, double bond or triple bond.

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

"Cycloalkenyl" means non-aromatic monocyclic or mnogonitochnoy-ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms in the ring.

Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. Cycloalkenyl group may be substituted by one or more groups of substituents. The group may be a terminal group or a bridging group.

"Cycloalkyl" refers to nasionalisme or merged or spirobicyclic, carbon cycle, preferably containing from 3 to 9 carbons in the ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise indicated. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems, such as the position, and polycyclic systems such as adamantane. The group may be a terminal group or a bridging group.

"Cycloalkenyl" means cycloalkyl-alkyl-group in which cycloalkyl and the alkyl part are as defined here. Approximate monocyclohexyl 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 linked to the remainder of the molecule through the alkyl group.

"Cycloalkylcarbonyl" means cycloalkyl-alkenyl-group in which cycloalkyl and the alkenyl portion are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule through the alkenyl group.

"Cycloalkylcarbonyl" means cycloalkyl-heteroalkyl-the group in which cycloalkyl and heteroarm�price parts are, as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule via heteroalkyl group.

"Cycloalkane" refers to cycloalkyl-O-group in which cycloalkyl represents, as defined here. Preferably cycloalkane represents C1-C6cycloalkane. Examples include, but are not limited to, cyclopropane and CYCLOBUTANE. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule through the oxygen atom.

"Cycloalkenyl" refers to cycloalkenyl-O-group in which cycloalkenyl represents, as defined here. Preferably cycloalkenyl represents C1-C6cycloalkenyl. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule through the oxygen atom.

"Haloalkyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms replaced by halogen atom selected from the group comprising fluorine, chlorine, bromine and iodine. Haloalkyl group typically has the formula nH(2n+1-m)Xmwhere each X is independently selected from the group comprising F, Cl, Br and I. In groups of this type n is typically 1-10, more preferably 1-6, most preferably 1-3. m is usually equal 1-6, more preferably 1-3. Examples of haloalkyl include vermeil, deformity and trifluoromethyl.

"Haloalkyl" refers to an alkenyl group as defined herein in which one or more of the hydrogen atoms replaced by halogen atom, independently selected from the group comprising F, Cl, Br and I.

"Haloalkyl" refers to Salcininkai group as defined herein in which one or more hydrogen atoms are substituted by a halogen atom, independently selected from the group comprising F, Cl, Br and I.

"Halogen" represents chlorine, fluorine, bromine or iodine.

"Heteroalkyl" refers to an alkyl group with straight or branched chain, preferably having 2-14 carbons, more preferably 2-10 carbons in the chain, one or more of which is substituted with a heteroatom selected from S, O, P and N. the Approximate heteroalkyl 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 by itself or as part of a group refers to groups containing an aromatic ring (preferably 5 or 6 membered �romantic ring), having one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms representing carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulfur. Examples of heteroaryl include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphto[2,3-b]thiophene, furan, isoindole, santolan, phenoxathiin, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthiridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, fenesin, thiazole, isothiazol, phenothiazines, oxazol, isooctanol, furazan, phenoxazine, 2-, 3 - or 4 - pyridyl, 2-, 3-, 4-, 5- or 8 - chinolin, 1-, 3-, 4 - or 5 - ethenolysis 1-, 2 - or 3 - indole and 2 - or 3-thienyl. The group may be a terminal group or a bridging group.

"Heteroaromatic" means heteroaryl-alkyl group, in which heteroaryl and alkyl parts are as defined herein. Preferred, heteroallyl groups contain a lower alkyl part. Approximate heteroarylboronic groups include pyridylmethyl. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule via a�kilou group.

"Heteroarylboronic" means heteroaryl-alkenyl-group in which the heteroaryl and alkenyl portion are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule through the alkenyl group.

"Heteroarylboronic" means heteroaryl-heteroalkyl-group, which heteroaryl and heteroalkyl part are as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule via heteroalkyl group.

"Heteroaromatic" refers to heteroaryl-O-group in which heteroaryl represents, as defined here. Preferably heteroaromatic represents C1-C12heteroepitaxy. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked 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 and� group, include nitrogen, sulfur and oxygen as a ring atom. Examples of heterocyclic parts include heteroseksualci, geteroseksualen and heteroaryl.

"Heteroseksualci" refers to heteroseksualci as defined herein, but containing at least one double bond. The group may be a terminal group or a bridging group.

"Heteroseksualci" refers to a saturated monocyclic, bicyclic or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably 1 to 3 heteroatom, at least one ring. Each ring represents preferably 3-10 membered, more preferably 4 to 7 membered. Examples of suitable geterotsiklicheskikh substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrofuranyl, piperidyl, piperazin, tetrahydropyranyl, morpholino, 1,3-diazepan, 1,4-diazepan, 1,4-oxazepan and 1,4-Ossetian. The group may be a terminal group or a bridging group.

"Geterotsiklicheskikh" refers to heteroseksualci-alkyl-group in which geteroseksualnoe and the alkyl part are as defined here. Approximate geterotsiklicheskikh groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrofuranyl) methyl. The group may p�establet a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule through the alkyl group.

"Geterotsiklicheskikh" refers to heteroseksualci-alkenyl-group in which geteroseksualnoe and the alkenyl portion are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule through the alkenyl group.

"Geterotsiklicheskikh" means heteroseksualci-heteroalkyl-the group in which geteroseksualnoe and heteroalkyl part are as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule via heteroalkyl group.

"Heteroseksualci" refers to heteroseksualci-O-group in which heteroseksualci represents, as defined here. Preferably heteroseksualci represents C1-C6geterotsiklicheskie. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule through the oxygen atom.

"Geterotsiklicheskikh" refers to GE�eroticaolder-O-group, in which heteroseksualci represents, as defined here. Preferably geteroseksualnoe represents C1-C6heterocyclizations. The group may be a terminal group or a bridging group. If the group is a terminal group, it is linked 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 are substituted by HE group. Hydroxyalkyl group typically has the formula CnH(2n+1-x)(OH)x. In groups of this type n is typically equal to 1-10, more preferably 1-6, most preferably 1-3. X usually equals 1-6, more preferably 1-3.

"Lower alkyl" as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched with 1-6 carbon atoms in the chain, more preferably 1-4 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 R-S(=O)-group in which the R group may be a HE, alkyl, cycloalkyl, geteroseksualnoe, aryl or heteroaryl group as defined herein. GRU�PA can be a terminal group or a bridging group. If the group is a terminal group, it is linked to the remainder of the molecule via a sulfur atom.

"Sulfonylamino" means R-S(=O)-NH-group in which the R group may be a HE, alkyl, cycloalkyl, geteroseksualnoe, 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 linked to the remainder of the molecule via the nitrogen atom.

"Sulfonyl" means R-S(=O)2-the group in which the R group may be a HE, alkyl, cycloalkyl, geteroseksualnoe; 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 linked to the remainder of the molecule via a sulfur atom.

"Sulfonylamino" means 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 linked to the remainder of the molecule via the nitrogen atom.

It is clear that included in the family of compounds of formula (I) are isomeric forms including diastereomers, enantiomers, tautomers, and geometrical isomers in "E" or "Z" configurational isomer or a mixture of E and isomers. It is also clear that some isomeric forms, such as diastereoisomers, enantiomers and geometric isomers are possible to divide a physical and/or chemical methods and specialists in this field of technology.

Some of the compounds of the disclosed embodiments may exist as single stereoisomers, racemates and/or mixtures of enantiomers and/or diastereomers. It is assumed that all such separate stereoisomers, racemate and mixtures thereof are implied as being in the scope described and claimed the essence of this invention.

The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of formula (I) where 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 compounds of the invention include isotopes of hydrogen, such as2H and3H, carbon, such as11C,13C and14C, chlorine, such as36Cl, fluorine, such as18F, iodine, such as123I and125I, nitrogen, such as13N and15N, oxygen, such as15Oh,17O and18Oh, phosphorus, such as32P and sulfur, such as35S.

Certain isotopically-labeled compounds of Fort�uly (I), for example incorporating a radioactive isotope, applied in the studies of tissue distribution of the drug and/or substrate. The radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.,14With, and is particularly suitable for this purpose due to the simplicity of their inclusion and light detection methods.

Substitution of heavier isotopes such as deuterium, i.e.,2H, can provide 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 as11C,18F,15O and13N, can be applicable in studies of Positron Emission Tomography (PET) to verify the employment of the receptor substrate.

Isotope-labeled compounds of formula (I) can generally be prepared by conventional methods known to the person skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopically-labeled reagents instead of the previously used unlabeled reagent.

Additionally, Formula (I) is intended to encompass, where applicable, solvated; and desolvation�e forms of compounds. Thus, each formula includes compounds having the specified structure, including hydrated and non hydrated form.

The expression "pharmaceutically acceptable salt" refers to salts that retain the desired biological activity of the above compounds, and include pharmaceutically acceptable salts accession acid salt and the base is connected. Suitable pharmaceutically acceptable salts accession acid compounds of the formula (I) can be prepared from inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric and phosphoric acid. Suitable organic acids can be choose 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, alkylsulfonate, arylsulfonate. For more 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 substances that are solids, the person skilled in the art it is clear that patentable compounds, substances and salts to exis�engaged in different crystal or polymorphic forms, all of which, as implied, are within the scope of this invention and are set by formulas.

"Prodrug" means a compound that undergoes transformation into a compound of formula (I) in a biological system, usually by metabolic means (e.g. by hydrolysis, recovery or oxidation). For example, ether Prodrug of a compound of formula (I) containing a hydroxyl group, can be convert by hydrolysis in vivo to the original molecule. Suitable esters of compounds of formula (I) containing a hydroxyl group are, for example, acetates, citrates, lactates, tartrates, malonate, oxalates, salicylates, propionates, succinates, fumarate, maleate, methylene-bis-β-hydroxynaphthoate, gentisate, isethionate, di-p-toluoyltartaric, methansulfonate, econsultancy, benzolsulfonat, R-toluensulfonate, cyclohexylsulfamate and salts of quinic acid. As another example, the ester Prodrug of a compound of formula (I) containing carboxypropyl, can be converted by hydrolysis in vivo to the original molecule. (Examples of ester prodrug are those described by F. J. leinweber know, Drug Metab. Res., 18:379, 1987). Similarly, the acyl prodrug of a compound of formula (I) containing an amino group can be converted by hydrolysis in vivo to the original molecule (most of the examples PR�drugs for these and other functional groups, including amines 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 expression "therapeutically effective amount" or "effective amount" is an amount sufficient to perform a useful or desired clinical results. An effective amount can be entered for one or more introductions. An effective amount is usually sufficient to temporarily facilitate, improve, stabilize, reverse, slow or delay the development of the disease state.

The phrase "functional equivalent" is intended the inclusion of specific variants of the receptor described herein. It will become clear that receptors can have isoforms such that while the primary, secondary, tertiary or Quaternary structure of the receptor isoforms differs from the prototype receptor; molecule podderjivaet biological activity at the receptor level. Isoforms may result from normal allelic variation within a population and include mutations such as amino acid substitution, deletion, addition, truncation or duplication. Also included in the expression "functional equivalent" options are formed at the transcriptional level.

In methods and applications of this invention it should be noted that some�rye from compounds of formula (I), are more active than others and, therefore, it is desirable to use these compounds in methods and applications of this invention.

In methods and applications of this invention, the preferred stereochemistry at the 3 and 5 positions of the ring of compounds of formula (I) is 3S, 5S diastereoisomer. Accordingly, in one embodiment of the methods and applications of this invention applied to the compound of formula (I) is a compound of formula (Ia):

,

where R, R1, R2, R3, R5a, R5bR6, R7, R8, X, Y and r are as defined in formula 1, or pharmaceutically acceptable salt or prodrug.

In methods and applications of this invention are particularly applicable subpopulation of compounds of formula (I) are compounds of formula (Ib) as shown below.

,

where

R1, R2, R3, R5a, R5b, R6, R7, R8, X, Y and r are as defined above,

Z is a group of the formula -(CR13R14)q-;

R4selected from the group including H, C1-C12alkyl, optionally substituted C2-C12of alkenyl, optionally substituted C2-C12alkynyl, optionally substituted C3-C12/sub> cycloalkyl, optionally substituted C6-C18aryl, optionally substituted C1-C18heteroaryl, NR4aR4b, C(=O)R15, C(=O)NR16R17, -C(=NR16)NR17R18, SR20SC(=O)R20, SO2R20, OR20, ONR16R17, OCR17R18R20, OC(=O)R20, OC(=O)OR20, OC(=O)NR16R17and ONR16C(NR17)NR18R19,

R4aselected from the group comprising H, optionally substituted C1-C12alkyl, optionally substituted C2-C12of alkenyl, optionally substituted C2-C12alkynyl, optionally substituted C1-C12heteroalkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C2-C12heteroseksualci, optionally substituted C6-C18aryl, optionally substituted C1-C18heteroaryl, C(=O)R15a, C(=O)NR15aR16a, C(=O)OR15a, SO2R15a, C(=O)H, -C(=NR15a)-NR16aR17aand OR15a,

R4bselected from the group comprising H, optionally substituted C1-C12alkyl, optionally substituted C2-C12of alkenyl, optionally substituted C2-C12alkynyl, optionally substituted C1-C12heteroalkyl, optionally substituted C3-C12qi�loukil, optional substituted C2-C12heteroseksualci, optionally substituted C6-C18aryl, optionally substituted C1-C18heteroaryl, C(=O)R15a, C(=O)NR15aR16a, C(=O)OR15aor

R4aand R4btaken together with the nitrogen atom to which they are attached, form an optional substituted heterocyclic part, or

one of R4aand R4btaken together with any R13or R14and the atoms to which they are attached, form an optional substituted heterocyclic;

R13and R14each independently selected from the group including H, halogen, HE, WITH1-C12alkyl, C6-C18aryl, C1-C12hydroxyalkyl, S1-C12haloalkyl, S1-C12alkyloxy and C1-C12haloalkoxy, or

taken together with the carbon to which they are attached, R13and R14form an optional substituted C3-C12cycloalkyl, or optionally substituted C1-C12geteroseksualnoe group, or

one of R13and R14taken together with one of R4aand R4band the atoms to which they are attached, form an optional substituted heterocyclic part, or

one of R13and R14taken together with one of R15, R16, R17, R18/sup> , R19or R20and the atoms to which they are attached, form an optional substituted cyclic part;

each R15, R15a, R16, R16a, R17, R17a, R18, R19and R20independently selected from the group comprising H, optionally substituted C1-C12alkyl, optionally substituted C1-C12heteroalkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C2-C12heteroseksualci, optionally substituted C6-C18aryl and, optionally substituted C1-C18heteroaryl, or

any two of R15, R15a, R16, R16a, R17, R17a, R18, R19and R20taken together with the atoms to which they are attached, form an optional substituted cyclic group, or

one of R15, R16, R17, R18, R19and R20taken together with one of R13and R14and the atoms to which they are attached, form an optional substituted cyclic part;

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

or its pharmaceutically acceptable salt or a prodrug.

In methods and applications of the present invention is particularly suitable subgroup of the compounds of formula (I) are compounds where Y p�establet a group of the formula -(CR 9R10)n-. In one embodiment, the implementation of suitable compounds n is 1 and Y is-CR9R10-. In another embodiment, the implementation of suitable compounds n is 2 and Y is-CR9R10CR9R10-.

In one embodiment of the compounds suitable for use in the present invention, each R9and R10independently selected from N and CH3. In one particular embodiment of the R9and R10both represent N. Accordingly, in one embodiment of the compounds suitable for use in the present invention, Y represents-CH2-. In another embodiment of the compounds suitable for use in the present invention, Y represents-CH2CH2-. In yet another embodiment of the compounds suitable for use in the present invention, Y represents-C(CH3)2-.

In one embodiment of the compounds suitable for use in the present invention, R2represents H or C1-C6alkyl. In a specific embodiment, the implementation of R2represents N.

In one embodiment of the compounds suitable for use in the present invention, R3represents H or C1-C6alkyl. In a VA�iante implementation of R 3represents N.

In one embodiment of the compounds suitable for use in the present invention, X is selected from the group comprising-C(=O)- and -(CR11R12)s-. In one particular embodiment of the X represents-C(=O)-. In one embodiment of the compounds suitable for use in the present invention, X represents -(CR11R12)s-, s is 1. In another embodiment of the compounds suitable for use in the present invention, X represents -(CR11R12)s-, s is 2. In one form, each of these embodiments, R11and R12each independently selected from the group comprising H and C1-C6alkyl. In a specific embodiment, the implementation of both R11and R12represent N, and s is equal to 1 so that X represents-CH2-.

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

,

where R1, R4, R5a, R5b, R6, R7, R8and r are as defined above.

In one embodiment of the compounds suitable for use in the present invention, in particular compounds of formula (Ib and Ic), R4selected from the group including H, C1-C12alkyl, optionally substituted C2-C12of alkenyl, optionally substituted C2-C12alkynyl, S3-C12cycloalkyl, optionally substituted C6-C18aryl, optionally substituted With-associated With1-C18heteroaryl, C(=O)R15, C(=O)NR16R17, -C(=NR16)NR17R18, SR20SC(=O)R20, SO2R20, OR20, ONR16R17, OCR17R18R20, OC(=O)R20, OC(=O)OR20, OC(=O)NR16R17and ONR16C(=NR17)NR18R19.

In one particular embodiment of the R4optional substituted C1-C18heteroaryl. In another embodiment, the implementation of R4optional substituted C3-C12cycloalkyl. In another embodiment, the implementation of R4represents C1-C12alkyl.

In another specific embodiment, the implementation of R4represents C(=O)NR16R17.

In another specific embodiment, the implementation of R4represents C(=O)NR16R17and R16and R17taken together with the nitrogen atom to which they are attached, form an optional substituted C2-C12geteroseksualnoe group. In certain embodiments, R15and R16, satyavrata with the nitrogen atom, to which they are attached, form an optional substituted geteroseksualnoe group selected from the group comprising piperidine-1-yl, pyrrolidin-1-yl, azetidin-1-yl, morpholine-4-yl, piperazine-1-yl, 4-methyl-piperazine-1-yl and 1-basepanel.

In one embodiment of the compounds suitable for use in the present invention, R16selected from the group comprising H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2With(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl and phenyl, or halogenated derivative.

In one embodiment of the compounds suitable for use in the present invention, R17selected from the group comprising H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2With(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl and phenyl, or halogenated derivative.

In one embodiment of the methods and applications of this invention applied to the compound of formula (I) represents in which R4=NR4aR4b. ACC�tstone applicable sub-group of compounds for use in methods and applications of this invention are compounds of formula (Id):

,

where R1, R4a, R4b, R5a, R5b, R6, R7, R8, Z and r are as defined for formula (I).

In one embodiment of the compounds suitable for use in the present invention, r is selected from the group including 1, 2, 3 and 4. In one particular embodiment, the implementation of r is 1. In another specific embodiment, the implementation of r is equal to 2. In yet another specific embodiment, the implementation of r is 3. In yet another specific embodiment, the implementation of r equal to 4.

In one embodiment of the compounds suitable for use in the present invention, R5aand R5bindependently selected from N and C1-C6of alkyl. In one embodiment, the implementation of R5aand R5beach independently selected from N and CH3. In one particular embodiment of the R5aand R5bboth represent N. In yet another variant implementation, at least one of R5aand R5btaken together with at least one of R6, R7and R8and the atoms to which they are attached, form an optional substituted cycloalkyl group. In one particular embodiment of the at least one of R5aand R5btaken together with at least one of R6, R7and R8and the atoms to which �nor attached, forms pirazinokarbazolovogo cyclohexyl group.

In one embodiment of the compounds of this invention, Y is a CH2, R2represents H, R3represents H, R5aand R5brepresent H, and X represents-C(=O)- and r is 1. This provides compounds of formula (II).

,

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

In one embodiment of the compounds of this invention, Y is a CH2, R2represents H, R3represents H, R5aand R5brepresents H, X represents-C(=O)-, R4represents NR4aR4band r is 1. This provides compounds of formula (IIa).

,

where R1, R4a, R4b, R6, R7, R8and Z are as defined for formula (I).

In the compounds of the invention Z is a group of the formula -(CR13R14)q-. In one embodiment of the compounds suitable for use in the present invention, in particular compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (II) and formula (In), R13and R14independently selected from N and C1-C6of alkyl. In about�nom embodiment of the R 13and R14each independently selected from N and CH3. In one particular embodiment of the R13and R14both represent N. In yet another variant implementation, at least one of R13and R14taken together with at least one of R4aand R4band the atoms to which they are attached, form an optional substituted geteroseksualnoe group. In one embodiment, the implementation of Z represents -(CH2)q-.

In one embodiment of the compounds suitable for use in the present invention, q is an integer selected from the group comprising 0, 1, 2, 3, 4 and 5. In one particular embodiment, the implementation of q is 1. In another specific embodiment, the implementation of q is 2, in another embodiment, the implementation of q is 3, and in yet another embodiment, the implementation of q equals 4.

Compounds in which R7, R13and R14represent N, and q is 1-4, lead to the compounds (IIIa), (IIIb), (IIIc) and (IIId), respectively.

,

where R1, R4a, R4b, R6and R8are as defined for formula (I).

,

where R1, R4a, R4b, R6and R8are as defined for formula (I).

,

where R1 , R4a, R4b, R6and R8are as defined for formula (I).

,

where R1, R4a, R4b, R6and R8are as defined for formula (I).

In one form of the compounds suitable for use in the present invention, R4aselected from the group including 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)2With(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl and phenyl, or halogenated derivative. In one form of the compounds suitable for use in the present invention, R4bselected from the group comprising H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2With(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl and phenyl, or halogenated derivative.

In another form of the compounds suitable for use in the present invention, R4aand R4btaken together with the atom and�OTA, to which they are attached, form an optional substituted C2-C12geteroseksualnoe group, optionally substituted C2-C12geteroseksualnoe group, or optionally substituted C1-C18heteroaryl group.

In a particular embodiment of the compounds suitable for use in the present invention, R4aand R4btaken together with the nitrogen atom to which they are attached, form an optional substituted geteroseksualnoe group selected from the group comprising piperidine-1-yl, pyrrolidin-1-yl, azetidin-1-yl, piperazine-1-yl, morpholine-4-yl and azepin-1-yl.

In one embodiment of the methods and applications of this invention, the compound of formula (I) is that in which one of R4aand R4btaken 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 optional substituted C2-C12geteroseksualnoe group. In a specific embodiment, the implementation of one of R4aand R4btaken 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 optional substituted geteroseksualnoe group selected from the group including piperidinyl, PIR�original, azetidinol, morpholinyl, piperazinyl and azepane.

Specific examples NR4aR4bin compounds, which are applicable in the methods and applications of this invention include:

In one embodiment of the compounds suitable for use in the present invention, R7represents N.

In one embodiment of the compounds suitable for use in the present invention, R6and R8each independently selected from the group comprising H, optionally substituted C1-C12alkyl, optionally substituted C2-C12of alkenyl, facul�effective substituted C 6-C18aryl and, optionally substituted C1-C18heteroaryl.

In one particular embodiment of the compounds suitable for use in the present invention, R6selected from the group comprising 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 particular embodiment of the compounds suitable for use in the present invention, R6represents an optional substituted phenyl, or optionally substituted C1-C18heteroaryl.

In one particular embodiment of the compounds suitable for use in the present invention, R8selected from the group comprising 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 particular embodiment of the compounds suitable for use in the present invention, R 8is methyl, ethyl, phenyl, or optionally substituted C1-C5heteroaryl.

In one particular embodiment of the compounds suitable for use in the present invention, R6, R7and R8taken together with the carbon to which they are attached form a part selected from the group including optional substituted C2-C12of alkenyl, optionally substituted C3-C12cycloalkyl, optionally substituted C2-C12heteroseksualci, optionally substituted C6-C18aryl and, optionally substituted C1-C18heteroaryl.

In one particular embodiment of the compounds suitable for use in the present invention, R6, R7and R8taken together with the carbon to which they are attached, form an optional substituted C6-C18the aryl group.

In one particular embodiment of the compounds of this invention and, in particular, compounds of formula (I), (II) (IIa) (IIIa), (IIIb), (IIIc) and (IIId), R6, R7and R8taken together with the carbon atom to which they are attached, form a disubstituted phenyl group.

In one embodiment of the disubstituted phenyl group is a 2,4-disubstituted Hairdryer-1-ilen group or 3,5-dosagesin�Yu fen-1-ilen group. A large number of substituents may be present at disubstituted phenyl group as defined above. The examples, in particular, 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 particular embodiment of the disubstituted phenyl group is a 3,5-dichlorophen-1-ilen group.

In one particular embodiment of the compounds suitable for use in the present invention, R1selected from the group including optional substituted C2-C12of alkenyl, optionally substituted C6-C18aryl and, optionally substituted C1-C18heteroaryl.

In one particular embodiment of the compounds suitable for use in the present invention, R1represents an optional substituted C6-C18aryl. With6-C18aryl can be monocyclic, bicyclic or polycyclic part. In certain embodiments, C6-C18aryl represents sobemoviruses part. In certain embodiments, C6-C18aryl is a bicyclic part.

In one particular embodiment of the R1represents an optional substituted C6-C18aryl selected from the group including optional substituted phenyl, biphenyl and, optionally substituted naphthyl. Parts can be unsubstituted or can be substituted by one or more optional substituents. A large number of optional substituents can 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, MHz, cyano, phenoxy, hydroxy, methoxy, ethoxy, pyrrol-1-yl and 3,5-dimethyl-pyrazol-1-yl.

The substituents can be located at any substitutable position around the aryl ring available for replacement, as will be clear to the person skilled in the art. Examples of suitable optional 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-Chlo�-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-debtor-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-tert-butyl-phenyl, 2,4-dimethoxy-phenyl and 3,4-methylenedioxy-phenyl.

In the case where R1represents an optional substituted biphenyl, the point of attachment of R1the remainder of the molecule can be 2-, 3 - or 4 - position relative to the attachment point of the second phenyl ring. As such, the biphenyl may be optional substituted bifen-2-yl, or optionally substituted bifen-3-yl, or optionally substituted bifen-4-yl. Mostly optional substituted biphenyl represents a optional substituted bifen-4-yl. Optional substituted biphenyl can be substituted in any suitable position.

In the case where R1represents an optional substituted naphthyl, the point of attachment of R1the remainder of the molecule can be in 1 or 2 position. As such, the naphthyl may be optional substituted�th naft-1-yl, or optional substituted naft-2-yl. Mostly optional substituted naphthyl represents a optional substituted naft-2-yl. Optional substituted naphthyl may be substituted in any suitable position. Examples of suitable optional substituted naft-2 sludges include, but are not limited to, 6-fluoro-naft-2-yl, 6-bromo-naft-2-yl, 6-chloro-naft-2-yl, CH-methoxy-naft-2-yl, 3-methoxy-naft-2-yl, 6-methoxy-naft-2-yl, 1-hydroxy-naft-2-yl and 6-amino-naft-2-yl.

In one particular embodiment of the compounds suitable for use in the present invention, R1represents an optional substituted C1-C18heteroaryl. With1-C18heteroaryl may be a monocyclic, bicyclic or polycyclic part. In certain embodiments, C1-C18heteroaryl represents a monocyclic part. In certain embodiments, C1-C18heteroaryl is a bicyclic portion. Examples of suitable heteroaryl parts include, but are not limited to, indole-2-yl, indol-3-yl, quinolin-2-yl quinoline-3-yl, isoquinoline-3-yl, quinoxaline-2-yl, benzo[b]furan-2-yl, benzo[b]thiophene-2-yl, benzo[b]thiophene-5-yl, thiazol-4-yl, benzimidazol-5-yl, benzotriazole-5-yl, furan-2-yl, benzo[d]thiazol-6-yl, pyrazol-1-yl, pyrazol-4-yl and thiophene-2-yl. He� can also be optional substituted, as discussed above.

In one particular embodiment of the compounds suitable for use in the present invention, R1represents an optional substituted C2-C12of alkenyl. Optional substituted of alkenyl can contain one or more double bonds with each double bond being independently in the E or Z configuration. In one embodiment of the present invention the alkenyl contains one double bond, which is in the E configuration.

In one particular form of this embodiment R1represents an optional substituted C2-C12of alkenyl of the formula:

,

R1aselected from the group including H, halogen and, optionally substituted C1-C12alkyl;

R1band R1ceach independently selected from the group including H, halogen, optionally substituted C1-C12alkyl, optionally substituted C2-C12of alkenyl, optionally substituted C2-C12alkynyl, optionally substituted C1-C12heteroalkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C2-C12heteroseksualci, optionally substituted C6-C18aryl and, optionally substituted C1-C18heteroaryl.

In one form of this embodiment R 1arepresents N. In one form of this embodiment R1brepresents N. This provides compounds where R1formula:

.

In one embodiment of the compounds of this invention R10represents an optional substituted C6-C18aryl. With6-C18aryl can be monocyclic, bicyclic or polycyclic part. In certain embodiments, C6-C18aryl represents monocyclic part. In certain embodiments, C6-C18aryl is a bicyclic part.

In one particular embodiment of the R10represents an optional substituted C6-C18aryl selected from the group including optional substituted phenyl optional substituted naphthyl. Parts can be unsubstituted or can be substituted by one or more optional substituents. A large number of optional substituents can 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, PHE�Teal, 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.

The substituents can be located at any substitutable position around the aryl ring available for replacement, as will be clear to the person skilled in the art. Examples of suitable optional 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-debtor-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-tert-butyl-phenyl, 2,4-dimethoxy-phenyl and 3,4-methylenedioxy-phenyl.

Certain compounds suitable for use in the methods and applications of this invention include the following:

or their pharmaceutically acceptable salt or a prodrug.

� to help the reader the names of compounds that are suitable for use in 5 the present invention, as discussed above, are the following:

(14) N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(25) N-(((3S,5S)-3-(2-(diethylamino)ethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naptime

(31) N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naptime

(33) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-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-naptime

(38) N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(39) N-(((3S,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(49) N-(((33,58)-3-(2-aminoethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(50) N-((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-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-naptime

(60) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-6-bromo-N-methyl-2-naptime

(62) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-4-methyl-2-oxo-1,4-diazepan-5-yl)methyl)-6-bromo-2-naptime

(63) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(64) N-(((3S,5S)--(2,2-diphenylether)-2-oxo-3-(3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(65) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-(isopropylamino)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(67) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-(3-methylguanine)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(71) (E)-N-(((3S,5S)-3-butyl-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide

(79) N-((S)-1-((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalene-2-yl)ethyl)acetamide

(81) (S)-2-acetamido-N-((S)-1-((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalene-2-yl)ethyl)-3-(1H-imidazol-5-yl)propanamide

(83) propyl (S)-1-((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalene-2-yl)ethylcarbamate

(85) N-((R)-1-((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalene-2-yl)ethyl)acetamide

(86) (S)-2-acetamido-N-((R)-1-((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalene-2-yl)ethyl)-3-(1H-imidazol-4-yl)propanamide

(87) propyl (R)-1-((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalene-2-yl)ethylcarbamate

(102) N-(((3R,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(103) N-(((3R,5R)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(104) N-(((3S,5R)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(105) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-�co-1,4-diazepan-5-yl)methyl)-2-naptime

(106) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)biphenyl-4-carboxamide

(107) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-1H-indole-2-carboxamide

(108) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)biphenyl-4-carboxamide

(109) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-1H-indole-2-carboxamide

(110) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(naphthalene-2-yl)acetamide

(111) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-1,2,3,4-tetrahydronaphthalen-2-carboxamide

(112) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)quinoline-3-carboxamide

(113) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)quinoxaline-2-carboxamide

(114) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)isoquinoline-3-carboxamide

(115) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide

(116) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)quinoline-2-carboxamide

(117) N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalene-1-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(118) N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalene-1-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(naphthalene-2-yl)acetamide

(119) N-(((3S5S)-3-(4-aminobutyl)-1-(naphthalene-1-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1-naptime

(120) N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalene-1-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(1H-indol-3-yl)acetamide

(121) N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalene-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(biphenyl-4-yl)acetamide

(122) N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalene-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(123) N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalene-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(naphthalene-2-yl)acetamide

(124) N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalene-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1-naptime

(125) N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalene-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(naphthalene-1-yl)acetamide

(126) N-(((3S,5S)-3-(4-aminobutyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(127) (S)-N-(((3S,5S)-3-(4-aminobutyl)-1-(2,2-diphenylether)-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-diphenylether)-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-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)benzofuran-2-carboxamide

(130) (R)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-(3-methylguanine)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide

(131) (S)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide

(132) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-Diaz�EN-5-yl)methyl)benzofuran-2-carboxamide

(133) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2,3-dihydro-1H-indene-2-carboxamide

(134) (R)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3 cantinori)-2-oxo-1,4-diazepan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide

(135) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)benzo[b]thiophene-2-carboxamide

(136) of 2,4-dichloro-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide

(137) of 2,5-dichloro-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide

(138) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide

(139) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)cyclohexanecarboxylic

(140) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-phenoxybenzamide

(141) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-4-phenoxybenzamide

(142) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-1H-indole-2-carboxamide

(143) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-phenylpropanamide

(144) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dimethylbenzamide

(145) 4-tert-butyl-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)Benza�ID

(146) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2,4-dimethoxybenzamide

(147) 2-cyclohexyl-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)acetamide

(148) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)benzo[d][1,3]dioxol-5-carboxamide

(149) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-1H-benzo[d]imidazole-5-carboxamide

(150) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-1H-benzo[d][1,2,3]triazole-5-carboxamide

(151) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)cyclopentanecarboxylic

(152) 3,4-dichloro-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide

(153) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)cinnamamide

(154) 3,5-dichloro-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide

(155) 2-(2,4-dichlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)acetamide

(156) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-1-methoxy-2-naptime

(157) 2-(3,4-dichlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)acetamide

(158) N-((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)--methoxy-2-naptime

(159) N-(((3S,5S)-1-(2,2-diphenylether)-3-(2-(guanidinium)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(160) (E)-3-(2,4-dichlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidino-propyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide

(161) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-adamantane-1-carboxamide

(162) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-phenoxyacetamide

(163) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-methoxy-2-naptime

(164) 4-bromo-N-((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide

(165) (S)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-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-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide

(167) (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(thiophene-2-yl)acrylamide

(168) (R)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-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-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-hydroxyphenyl)acrylamide

(170) (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2-methoxyphenyl)acrylamide

(171) (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanido�propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-R-tolylacetic

(172) (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2-(trifluoromethyl)phenyl)acrylamide

(173) (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(3-fluorophenyl)acrylamide

(174) (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-methyl-3-phenylacrylate

(175) N-(((3S,5S)-1 -(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-phenylcyclopropanecarboxylic

(176) 2-(2,4-dichlorophenoxy)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)acetamide

(177) (E)-3-(3-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide

(178) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)benzo[d]thiazole-6-carboxamide

(179) N-(((33,58)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-5-phenylfuro-2-carboxamide

(180) (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(3-methoxyphenyl)acrylamide

(181) 6-bromo-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(182) N-(((3S,5S)-3-(3-guanidinopropionic)-2-oxo-1-phenethyl-1,4-diazepan-5-yl)methyl)-2-naptime

(183) N-(((3S,5S)-1-(3,4-dichlorophenacyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(184) N-(((3S,5S)-1-(2,4-dichlorophenacyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5�)methyl)-2-naptime

(185) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)benzo[b]thiophene-5-carboxamide

(186) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide

(187) (E)-N-(((38,53)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-Diazepan-5-yl)methyl)-3-(4-methoxyphenyl)acrylamide

(188) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naptime

(189) (E)-3-(2-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide

(190) (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2-hydroxyphenyl)acrylamide

(191) (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-m-tolylacetic

(192) (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(3-(trifluoromethyl)phenyl)acrylamide

(193) (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(3-hydroxyphenyl)acrylamide

(194) (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2-fluorophenyl)acrylamide

(195) (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-o-tolylacetic

(196) (Z)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-fluoro-3-phenylacrylate

(197) N-((1-(2,2-diphenylether)-2-oxo-3-piperidine-4-yl)-1,4-diazepan-5-yl)methyl)-2-naptime

(198) N-((1-(2,2-diphenylether)-2-oxo-3-(piperidine-4-ylmethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(199) (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide

(200) (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-(trifluoromethyl)phenyl)acrylamide

(201) N-(((3S,5S)-1-(2,2-diphenylpropyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(202) N-(((3S,5S)-1-(cyclohexylmethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(203) N-(((3S,5S)-1-(1-adamantylamine)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(204) N-(((3S,5S)-1-((S)-1,1-diphenylpropane-2-yl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(205) N-(((3S,5S)-1-((R)-1,1-diphenylpropane-2-yl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(206) N-(((3S,5S)-1-cyclohexyl-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(207) N-(((3S,5S)-1-((R)-1-fluoro-1,1-diphenylpropane-2-yl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(208) (E)-3-(2,6-differenl)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide

(209) (E)-3-(2-chloro-6-fluorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide

(210) (E)-3-(4-bromophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide

(211) (E)-N-(((3S,5S)-1-(2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-ethoxyphenyl)acrylamide

(212) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-6-bromo-2-naptime

(213) N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylether)-2-oxo-1,4-diazepan-6-yl)methyl)cinnamamide

(214) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide

(215) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-1,4-dimethoxy-2-naptime

(216) N-(((3S,5S)-3-(3-(3,3-dimethylguanidine)propyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(217) N-(((3S,58)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-6-hydroxy-2-naptime

(218) 6-amino-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(219) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-R-tolylacetic

(220) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide

(221) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naptime

(222) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-ethylhexanate

(223) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dimethylbenzamide

(224) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide

(225) N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepa�-5-yl)methyl)-2-ethylhexanate

(226) N-(((3S,5S)-3-(3-(cyclohexylamino)propyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(227) N-(((3S,5S)-3-(3-guanidinopropionic)-1 -(naphthalene-2-yl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(228) N-(((3S,5S)-1-((9H-fluoren-9-yl)methyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(229) N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(pyridin-3-ylmethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(230) N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(pyridin-4-ylmethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(231) (E)-N-(((3S,5S)-3-(3-(cyclohexylamino)propyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide

(232) N-(((3S,5S)-1-(2,2-diphenylether)-3-(4-(isopropylamino)butyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(233) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2,4-differenl)acrylamide

(234) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-cyanophenyl)acrylamide

(235) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-6-yl)methyl)-3-(naphthalene-2-yl)acrylamide

(236) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(4-pertenece)acetamide

(237) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-5-(4-chlorophenyl)furan-2-carboxamide

(238) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-4-(1H-pyrrol-1-yl)benzamide

(239) N-(((3S,5S)-3-(3-aminopropyl�)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-oxo-1-phenylpyrrolidine-3-carboxamide

(240) N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-5-(4-chlorophenyl isoxazol-3-carboxamide

(241) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-5-(furan-2-yl isoxazol-3-carboxamide

(242) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-6-yl)methyl)-2-phenylthiazol-4-carboxamide

(243) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-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-diphenylether)-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-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(246) N-(((3S,5S)-1-(2-(bicyclo[2.2.1]heptane-2-yl)ethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(247) N-(((3S,5S)-1-(2,2-bis(4-methoxyphenyl)ethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(248) N-(((3S,5S)-3-(3-(benzylamino)propyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(249) N-(((3S,5S)-3-(3-(cyclopentylamine)propyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(250) N-(((3S,5S)-3-(3-(temporalelement)propyl)-1 -(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(251) N-(((3S,5S)-3-(3-(bicyclobutane)propyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(252) N-(((3S,5S)-1-benzyl-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthas�d

(253) N-(((3S,5S)-1-(2,2-bis(4-fluorophenyl)ethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(254) N-(((3S,5S)-3-(3-guanidinopropionic)-1-(naphthalene-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(255) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(5-methylthiophene-2-yl)acrylamide

(256) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-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-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)-N-methylacrylamide

(258) (E)-N-(((3S,5S)-3-(3-aminopropyl)-1 -(2,2-diphenylether)-4-methyl-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide

(259) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-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-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-bromophenyl)acrylamide

(261) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-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-diphenylether)-2-oxo-3-(3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)acrylamide

(263) N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(264) N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(3-(pyrrolidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(265) N-(((3S,5S)-3-(3-(azetidin-1-yl)propyl)-1-(2,2-diphenylether)-2-oxo-1,4-di�sepan-5-yl)methyl)-2-naptime

(266) N-(((3S,5S)-3-(3-guanidinopropionic)-1-(naphthalene-1-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(267) N-(((3S,5S)-3-(3-guanidinopropionic)-1-(2-(naphthalene-2-yl)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(268) N-(((3S,5S)-1-((S)-2-acetamido-2-phenylethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(269) N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)cinnamamide

(270) N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-3,4-dimethylbenzamide

(271) 3,4-dichloro-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)benzamide

(272) N-(((3S,5S)-1-((S)-2-(cyclobutanecarboxylic)-2-phenylethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(273) N-(((3S,5S)-1-((S)-2-(cyclohexanecarbonyl)-2-phenylethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(274) N-(((3S,5S)-3-(aminomethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(275) (E)-N-(((3S,5S)-3-(aminomethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide

(276) (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide

(277) (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-R-tolylacetic

(278) N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(piperidine-1-ylmethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(279) (E)-3-(4-chlorophenyl)-N-(((3S,5's)-1-(2,2-diphenylether)-2-oxo-3-(piperidine-1-ylmethyl)-1,4-diazepan-5-yl)methyl)acrylamide

(280) N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide

(281) N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dimethylbenzamide

(282) N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)cinnamamide

(283) (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide

(284) 3,4-dichloro-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide

(285) N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3,4-dimethylbenzamide

(286) N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)cinnamamide

(287) (E)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide

(288) (E)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-R-tolylacetic

(289) N-(((3S,5S)-1-(3,5-dimethylbenzyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(290) N-((3S,5S)-1-((S)-2-benzamide-2-phenylethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(291) N-(((3S,5S)-1-((R)-2-benzamide-2-phenylethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(292) N-(((3S,5S)-3-(3-guanidinopropionic)-1-(2-methoxy-2-phenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(293) N-(((3S,5S)-3-(3-guanidinopropionic)-2-oxo-1-(2-phenyl-2-propox�ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(294) N-(((3S,5S)-1-(2-(benzyloxy)-2-phenylethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(295) N-(((3S,5S)-1-(2-(allyloxy)-2-phenylethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(296) N-(((3S,5S)-3-butyl-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(297) (E)-N-(((3S,5S)-3-butyl-1-(2,2-diphenylether)-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-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide

(299) N-(((3S,5S)-3-(3-amino-3-oxopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(300) (E)-N-(((3S,5S)-3-(3-acetamidophenyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-R-tolylacetic

(301) N-(3-((2S,7S)-4-(2,2-diphenylether)-3-oxo-7-(((E)-3-R-tolylacetic)methyl)-1,4-diazepan-2-yl)propyl)cyclohexanecarboxylic

(302) N-(((3S,5S)-3-(3-guanidinopropionic)-2-oxo-1-(2-phenoxy-2-phenylethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(303) ethyl 3-((3S,5S)-5-((2-naptime)methyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-1-yl)-2-phenylpropanoate

(304) N-(((3S,5S)-1-(2-ethylbutyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(305) N-(((3S,5S)-1-((3,5-dimethylcyclohexyl)methyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(306) N-(2-((2S,7S)-7-(((E)-3-(4-chlorophenyl)acrylamide)methyl)-4-(2,2-diphenylether)-3-oxo-1,4-diazepan-2-yl)ethyl)cyclohexanecarboxylic

(307) (E)-3-(4-chlorophenyl)-N-(((3S,5S)--(2-(2-cyclohexylamino)ethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide

(308) N-(2-((3S,5R)-1-(2,2-diphenylether)-2-oxo-3-(2-aminoethyl)-1,4-diazepan-5-yl)ethyl)benzamide

(309) 3,4-dichloro-N-(2-((3S,5R)-1-(2,2-diphenylether)-2-oxo-3-(2-aminoethyl)-1,4-diazepan-5-yl)ethyl)benzamide

(310) N-(2-((3S,5R)-1-(2,2-diphenylether)-2-oxo-3-(2-aminoethyl)-1,4-diazepan-5-yl)ethyl)-2-naptime

(311) N-(2-((3S,5R)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)ethyl)benzamide

(312) 3,4-dichloro-N-(2-((38,5 R)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)ethyl)benzamide

(313) N-(2-((3S,5R)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)ethyl)-2-naptime

(314) N-(((3S,5S)-1-(3-(dimethylamino)-3-oxo-2-phenylpropyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(315) N-(((3S,5S)-3-(cyclohexylmethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(316) N-(((3S,5S)-3-(2-aminoethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(317) N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(3-oxo-3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(318) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(3-oxo-3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)acrylamide

(319) N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-phenethyl-1,4-diazepan-5-yl)methyl)-2-naptime

(320) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-phenethyl-1,4-diazepan-5-yl)methyl)acrylamide

(321) N-((3S,5S)-3-(2-cyclohexylethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(322) (E)-3(4-chlorophenyl)-N-(((3S,5S)-3-(2-cyclohexylethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide

(323) N-(((3S,5S)-3-benzyl-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(324) (E)-N-(((3S,5S)-3-benzyl-1-(2,2-diphenylether)-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-terbisil)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(328) N-(((3S,5S)-1-(3,5-diferensial)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(329) N-(((3S,5S)-3-(3-aminopropyl)-1-(3-chloro-5-terbisil)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(330) N-(((3S,5S)-3-(3-aminopropyl)-1-(3,5-diferensial)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(331) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(332) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,6-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(333) N-(((3S,5S)-3-(3-amiprol)-1-(3,5-dimethoxybenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(334) N-(((3S,5S)-3-(3-aminopropyl)-1-(2-chlorbenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(335) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,3-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(336) N-(((3S,5S)-3-(3-aminopropyl)-1-(2,4-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(337) N-(((3S,5S)-3-(3-aminopropyl)-1-(3,4-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl-2-naptime

(338) N-(((3S,5S)-3-(3-aminopropyl)-1-(3-fluoro-5-methylbenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(339) N-(((3S,5S)-3-(3-aminopropyl)-1-(3-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(340) N-(((3S,5S)-3-(3-aminopropyl)-1-(4-chlorbenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(341) N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-(2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(342) N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-((1-phenylcyclohexyl)methyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(343) 3,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide

(344) N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(345) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide

(346) N-(((3S,5S)-3-(2-aminopropyl)-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-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide

(349) 3,4-dichloro-N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide

(350) N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(351) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-4-chloro-3-ferb�NSAID

(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-(2,3-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-chloro-4-fermentated

(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-(piperidine-1-ylmethyl)-1,4-diazepan-5-yl)methyl)acrylamide

(356) N-(2-((3S,5R)-1-(2,2-diphenylether)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)-1,4-diazepan-5-yl)ethyl)-2-naptime

(357) N-(((3S,5S)-3-(3-aminopropyl)-1-(3,5-bis(trifluoromethyl)benzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(358) N-(((3S,5S)-3-(3-aminopropyl)-1-(3-chlorbenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(359) N-(((3S,5S)-2-oxo-1-(2-phenylbutyl)-3-(3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(360) N-(((3S,5S)-3-(3-guanidinopropionic)-2-oxo-1-(3-oxo-2-phenyl-3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(361) N-(((3S,5S)-3-(3-guanidinopropionic)-2-oxo-1-(3-oxo-2-phenyl-3-(phenylamino)propyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(362) 3,4-dichloro-N-(2-((3S,5R)-1-(2,2-diphenylether)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)ethyl)benzamide

(363) 3,4-dichloro-N-(2-((3S,5R)-3-(2-(diisopropylaminoethyl)ethyl)-1-(2,2-diphenylether)-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-OK�about-1,4-diazepan-5-yl)methyl)-2-naptime

(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-(piperidine-1-ylmethyl)-1,4-diazepan-5-yl)methyl)benzamide

(368) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(piperidine-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-naptime

(373) N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-((S)-2-phenylpropyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(374) N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-((R)-2-phenylpropyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(375) N-(((3S,5S)-3-(2-(dimethylamino)ethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(376) N-(((3S,5S)-1 -(2,2-diphenylether)-2-oxo-3-(3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naptime

(377) N-(((3S,5S)-3-(3-aminopropyl)-1-(3,5-diethylphenyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(378) (E)-3-(4-chlorophenyl)-N^-(((3S,5S)-3-(2-(diethylamino)ethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide

(379) N-(((3S,5S)-3-(2-(diethylamino)ethyl)-1-(2,2-diphenylether)-2-oxo-1,4-dia�epan-5-yl)methyl)-2-naptime

(380) 3,4-dichloro-N-(((3S,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidine-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-(piperidine-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-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide

(383) N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-b-chloro-2-naptime

(384) N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(385) N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(386) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naptime

(387) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naptime

(388) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-bromo-2-naptime

(389) N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naptime

(390) 6-chloro-N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(391) 6-bromo-N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(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-diazep�n-5-yl)methyl)-2-naptime

(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-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(396) N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naptime

(397) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-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-diphenylether)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide

(399) N-(((3S,5S)-1-(2,2-diphenylether)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(400) of 3,4-dichloro-N-(((3S,5S)-1-(2,2-diphenylether)-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-naptime

(402) N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(403) 3,4-dichloro-N-(((3S,5S)-1-((3,5-dimethylcyclohexyl)methyl)-2-oxo-3-(2-(piperidine-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-naptime

(406) N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

<> (407) N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-((R)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(408) (E)-N-(((3S,5S)-3-((1H-imidazol-4-yl)methyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide

(409) 3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)propanamide

(410) N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)propanamide

(411) N-(((28,78)-7-((((E)-3-(4-chlorophenyl)acrylamide)methyl)-4-(2,2-diphenylether)-3-oxo-1,4-diazepan-2-yl)methyl)picolinate

(412) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-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-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(414) N-(((3S,5S)-1-((S)-3-methyl-2-phenylbutyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(415) (E)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-(4-isopropylphenyl)acrylamide

(416) (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-6-yl)methyl)-3-(4-isopropylphenyl)acrylamide

(417) (E)-3-(2,4-dimethylphenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide

(418) (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-6-yl)methyl)-3-(2,4-dimethylphenyl)acrylamide

(419) (E)-3-(2,4-differenl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-�l)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide

(420) (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2,4-differenl)acrylamide

(421) N-(((28,78)-7-((((E)-3-(4-chlorophenyl)acrylamide)methyl)-4-(2,2-diphenylether)-3-oxo-1,4-diazepan-2-yl)methyl)cyclohexanecarboxylic

(422) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-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-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide

(424) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-3-(2-(2,5-dimethylpyrrole-1-yl)ethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide

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

(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-naptime

(429) 3,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide

(430) of 3,4-dichloro-N-(((33,53)-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-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methylcarbamate

(432) (E)-3-(4-bromophenyl)-N-(((3S,5S)-1-(2,2-dif�retil)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide

(433) 5-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl isoxazol-3-carboxamide

(434) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-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-diphenylether)-2-oxo-3-(2-oxo-2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide

(436) 6-chloro-N-(((3S,5S)-2-oxo-3-(3-oxo-3-(piperidine-1-yl)propyl)-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(437) 3,4-dichloro-N-(((3S,5S)-2-oxo-3-(3-oxo-3-(piperidine-1-yl)propyl)-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide

(438) 6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(piperidine-1-ylmethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(439) 3,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(piperidine-1-ylmethyl)-1,4-diazepan-5-yl)methyl)benzamide

(440) 6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(441) 3,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)benzamide

(442) (E)-N-(2-((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-6-yl)propan-2-yl)-3-(4-chlorophenyl)acrylamide

(443) (E)-3-(4-chlorophenyl)-N-(2-((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-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-naptime

(445) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-(4-harfe�yl)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(446) N-(((3S,5S)-1-((R)-2-(4-chlorophenyl)propyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(447) N-(((3S,5S)-1-((S)-2-(4-chlorophenyl)propyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(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-diphenylether)hexahydro-1H-imidazo[1,5-d][1,4]diazepin-6(5H)-he

(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-methylpiperazin-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-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(457) N-(((3S,5S)-2-oxo-1-((S)-2-phenylpentyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(458) N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-4-(trifluoromethyl)benzamide

p> (459) N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-4-(trifluoromethyl)benzamide

(460) N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-(trifluoromethyl)benzamide

(461) N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-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-naptime

(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-naptime

(465) N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naptime

(466) N-(((3S,5S)-3-(2-aminobenzyl)-1 -(2,2-diphenylether)-2-oxo-1,4-diazepan-6-yl)methyl)-2-naptime

(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-(piperazine-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-(diisopropylaminoethyl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide

(471) 3,4-dichloro-N-(((3S,5S)-3-(2-(4-demerol-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide

(472) (S)-6-chloro--((2-oxo-1 -(2-phenylbutyl)-3-(piperidine-4-yl)-1,4-diazepan-5-yl)methyl)-2-naptime

(473) (S)-6-chloro-N-(3-(1-isobutylpyrazine-4-yl)-2-oxo-1-(2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(474) N-(((3S,5S)-3-butyl-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naptime

(475) 6-chloro-N-(((3S,5S)-3-isopentyl-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(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-hydroxypiperidine-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide

(478) 1-(2-((2S,7S)-7-((3,4-dichlorobenzamide)methyl)-3-oxo-4-((S)-2-phenylbutyl)-1,4-diazepan-2-yl)ethyl)piperidine-4-carboxylic acid

(479) N-(((3S,5S)-3-(2-(azepin-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-demerol-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-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)benzyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(483) N-(((3S,5S)-3-(3-(butyl(methyl)amino)-3-oxopropyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(484) N-(((3S,5S)-3-(3-(cyclohexylamino)-3-oxopropyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(485) 6-chloro-N-((3-(1-ethylpiperazin-4-yl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naft�

(486) (3S,5S)-5-((3,4-dichloraniline)methyl)-1-(2,2-diphenylether)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-2-he

(487) 6-chloro-N-(((3S,5S)-3-(2-guanidinate)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(488) 6-chloro-N-(((3S,5S)-3-(2-(3-methylguanine)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(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-(piperidine-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-(piperidine-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-naptime

(494) N-(((3R,5R)-3-(2-amino-2-methylpropyl")-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naptime

(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-naptime

(498) 6-chloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(499) 6-chloro-N-(((3S,5S)-3-(2-methyl-2-(Pieper�DIN-1-yl)propyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(500) 6-chloro-N-(((3R,5R)-3-(2-methyl-2-(piperidine-1-yl)propyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(501) N-(((3S,5S)-3-(2-aminoethyl)-1-((R)-2-ethyl-3-methylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naptime

(502) N-(((3S,5S)-3-(2-aminoethyl)-1-((S)-2-ethyl-3-methylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naptime

(503) 6-chloro-N-(((3S,5S)-1-((R)-2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(504) 6-chloro-N-(((3S,5S)-1-((S)-2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(505) 6-chloro-N-(((3S,5S)-3-(2-cyclohexylethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(506) 6-chloro-N-(((3S,5S)-3-hexyl-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(507) 6-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methylcarbamoyl)-2-naftalina acid

(508) 6-chloro-N-(((3S,5S)-3-(2-(3-isopropylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(509) 6-chloro-N-(((3S,5S)-3-(4-hydroxybutyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(510) 6-chloro-N-(((3S,5S)-3-(2-methoxyethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(511) N-(((3S,5S)-3-(2-(benzyloxy)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-6-yl)methyl)-6-chloro-2-naptime

(512) 6-chloro-N-(((3S,5S)-3-isobutyl-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(513) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethyl-3-methylbu�-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-(piperidine-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-naptime

(516) 6-chloro-N-(((3S,5S)-1-((R)-2-ethyl-3-methylbut-3-enyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(517) 6-chloro-N-(((3S,5S)-1-((S)-2-ethyl-3-methylbut-3-enyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(518) N-(((3S,5S)-1-(cyclohexylmethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)biphenyl-4-carboxamide

(519) N-(((3S,5S)-1-(cyclohexylmethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(1H-indol-3-yl)acetamide

(520) N-(((3S,5S)-1-(cyclohexylmethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)quinoline-3-carboxamide

(521) of 3,4-dichloro-N-(((3S,5S)-3-(2-(4,4-deformability-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-deformability-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide

(524) (3S,5S)-5-((3,4-dichloraniline)methyl)-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-2-he

(525) 3,4-dichloro-N-(((3S,5S)-1-(2-cyclopropylethyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide

(526) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-cyclopropylethyl)-2-oxo-1,4-diazepan-yl)methyl)-6-chloro-2-naptime

(527) 6-chloro-N-(((3S,5S)-1-(2-cyclopropylethyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(528) 3,4-dichloro-N-(((3S,5S)-3-(2-(2,5-dioxopiperidin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide

(529) 6-chlor-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(3-ureidopropionic)-1,4-diazepan-5-yl)methyl)-2-naptime

(530) 3,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(1,1,1-tryptophan-2-ylamino)ethyl)-1,4-diazepan-5-yl)methyl)benzamide

(531) 3,4-dichloro-N-(((3S,5S)-3-(2-(3,3-dimethyl-2,5-dioxopiperidin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide

(532) N-(((3S,5S)-3-(2-(azepin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naptime

(533) 6-chloro-N-(((3S,5S)-3-(2-(3-isopropylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(534) N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)biphenyl-4-carboxamide

(535) N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-phenylthiazol-4-carboxamide

(536) 4'-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)biphenyl-2-carboxamide

(537) 6-chloro-N-(((3S,5S)-3-(2-(N-isopropylacrylamide)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(538) 6-chloro-N-(((3S,5S)-3-((isopropylamino)methyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(539) 6-chloro-N-(((3S,5S)-3-(guanidinate)-2-oxo-1-((S)-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(540) 2-(2,4-dichlorophenyl)-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-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-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide

(543) 3,4-dichloro-N-(((3S,5S)-1-(2,4-dichlorobenzyl)-3-(2-(methylsulfonyl)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide

(544) 3,4-dichloro-N-(((3S,5S)-1-(2,4-dichlorobenzyl)-3-(2-(4-methylphenylsulfonyl)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide

(545) N-(((3S,5S)-3-(2-((S)-2-amino-3-methylbutanoyl)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-naptime

(547) 6-chloro-N-(((3S,5S)-1-(2,4-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(548) N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-(2-(thiophene-3-yl)butyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naptime

(549) 6-chloro-N-(((3S,5S)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1-((R)-2-(thiophene-3-yl)butyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(550) 6-chloro-N-(((3S,5S)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1-((S)-2-(thiophene-3-yl)butyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(551) N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethyl-2-methylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naptime

(552) 6-chloro-N-(((3S,5S)-1-(2-ethyl-2-methylbutyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphtha�ID

(553) 6-chloro-N-(((3S,5S)-1-(2,2-diphenylether)-3-(2-morpholinoethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(554) 6-chloro-N-(((3S,5S)-3-(2-morpholinoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(555) 6-chloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(2-morpholinoethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(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-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acetamide

(558) 1-(4-chlorbenzyl)-3-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-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-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide

(561) 6-chloro-N-(((3S,5S)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1-(2,3,5-trichlorobenzoyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(562) 6-chloro-N-(((3S,5S)-3-(2-(1-methylethylacetate)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(563) - butyl 2-((2S,7S)-7-((6-chloro-2-naptime)methyl)-3-oxo-4-((S)-2-phenylbutyl)-1,4-diazepan-2-yl)ethylcarbamate

(564) (8)-6-chloro-N-((3-(1-isopropylpiperazine-4-yl)-2-oxo-1-(2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

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

(566) 5-(4-chlorophenyl-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl isoxazol-3-carboxamide

(567) 2,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide

(568) N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-6-methoxy-2-naptime

(569) 6-chloro-N-(([5-13C,a 415N](3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)[13C]methyl)-2-naptime

(570) N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-1-methoxy-2-naptime

(571) (E)-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-(4-(triptoreline)phenyl)acrylamide

(572) 5-(4-chlorophenyl)-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl isoxazol-3-carboxamide

(573) 2,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-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-(piperidine-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-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-(3-fluoro-4-(triptoreline)phenyl)acrylamide

(576) 6-methoxy-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(577) 1-methoxy-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(578) (E)-3-(3-fluoro-4-(triptoreline)phenyl)-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,-diazepan-5-yl)methyl)acrylamide

(579) 6-chloro-N-(([5,6,6-2H3](3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)[2H2]methyl)-2-naptime

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

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

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

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

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

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

As indicated previously, the compounds of formula (I) are MC5R antagonists and therefore can be used to modulate the activity of MC5R or a fragment or analogue or functional equivalent by subjecting MC5R or a fragment or analogue or functional equivalent effects of the compounds of this invention. This can occur in vitro in tests where the desired reduction regulation of activity of MC5R, however, is typically more useful when used in down-regulation activity of MC5R in the patient. The magnitude of down-regulation, beacause� compounds of this invention, will vary from connection to connection and will also depend on the amount of input connections. In one embodiment, the implementation of the magnitude of down-regulation is at least 10%. In another embodiment, the implementation of the magnitude of down-regulation is at least 20%. In yet another embodiment of the magnitude of down-regulation is at least 50%.

Accordingly, the methods of this invention can be applied in the treatment of any condition in which modulation of the activity of MC5R or a fragment or analogue or functional equivalent will lead to a beneficial effect on this condition. As such compounds, suitable for use in the present invention, can 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 of a mammal, where the modulating MC5R number of compounds of this invention administered to a mammal. One condition associated with the activity of MC5R, is a redundant sebum secretion and States associated with it. In one embodiment of the method the condition is selected from the group including acne, seborrhea and seborrheic dermatitis. In one embodiment of the acne W�t from the group including acne vulgaris, acne, nodular acne and lightning eels. In one particular embodiment of the condition is a common acne.

For example, down regulation of MC5R reduces sebum and thus, can be used in the treatment or prevention of a number of States in which the observed excess sebum secretion, namely, acne, seborrhea and seborrheic dermatitis.

The methods of this invention can be also useful in the treatment, prevention or control of a number of conditions that relate to biological processes, controlled MC5R, such as diseases associated with inflammation. Compounds of formula (I) can be also suitable for the treatment or prevention of cancers such as syndrome Muir-Torre or other cancerous tumors the sebaceous glands.

Through its influence on the secretion of a compound of formula (1) may also find use in the treatment, where it is desirable reduced sebum secretion, namely in cosmetic treatments. The compounds can thus be used in methods of reducing sebum mammal, wherein the method includes the stage at which administered an effective amount of a compound of formula (I).

Compounds of formula (I) can be used in the treatment of conditions in any species in which PR�ststue MC5R, most usually mammals. Examples of species in which they find MC5R and, consequently, species in which it is possible to use compounds that include humans, rats, mice, dogs, rhesus monkeys, sheep, striped percino, silver carp, prickly shark, rainbow trout and chicken. In a particular embodiment of the mammal is a human.

The introduction of the compounds of formula (I) to a patient, such as humans, can be implemented through local application, by any of the conventional methods for enteral administration, such as oral or rectal, or by parenteral administration such as subcutaneous, intramuscular, intravenous and intradermal methods of application. The injection may be in the form of an injection loading dose of a substance, or by continuous or intermittent infusion. Active compound normally included in a pharmaceutically acceptable carrier or diluent and in an amount sufficient to deliver to a patient a therapeutically effective dose.

In applying the compounds of formula (I) can be entered in any shape or form, which makes the compound bioavailable. The person skilled in the art for preparing formulations can readily select the proper form and type of administration, depending on the individual characteristics of the selected connection state to�e should be treated, the stage of the condition that should be treated, and other relevant circumstances. The authors refer to Remingtons Pharmaceutical Sciences, 19thedition, Mack Publishing Co. (1995) for further details.

Compounds of formula (I) can be administered alone or in the form of pharmaceutical compositions together with pharmaceutically acceptable carrier, diluent or excipient. Compounds of formula (I), despite the fact that effective and themselves, usually drawn up and introduced in the form of their pharmaceutically acceptable salts, as these forms are typically more stable, easier to crystallize and have increased solubility.

However, compounds generally used in the form of pharmaceutical compositions, which are prepared depending on the desired type of administration. The composition is prepared in the manner well known in the art.

The compound of formula (I) are usually combined with a carrier to obtain a pharmaceutical form suitable for a particular patient to be treated, and the particular method of administration. For example, a composition intended for oral administration to humans may contain from about 0.5 mg to about 5 g of the compounds of this invention, composed with an appropriate and suitable amount of carrier material which may vary from approximately 5 to approximately 99,95%�the components of the total composition. Typical dosage forms will generally contain from about 1 mg to about 500 mg of the compounds of this invention, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg of the Compounds of this invention may also be made for local delivery formulations, such as solutions, ointments, lotions, gels, creams, microemulsions or transdermal patches. For example, these compositions may contain from 0.005 to 5% (weight/weight or weight/volume) of compounds of this invention.

Compounds of formula (I) may be used or entered together with one or more additional drug(s). The compounds of this invention can be used in conjunction with one or more other pharmaceutically active compounds, such as other treatment against acne. In one embodiment, the implementation of other pharmaceutically active substance is selected from the group including antibiotics, retinoids, antiandrogens, and steroids. Examples of other pharmaceutically active compounds, which can be combined with the compound of formula (I) and enter in a simultaneous or sequential combinations thereof, may include, by way of non-limiting examples, other substances against acne, such as oral retinoids (e.g., isotretinoin), retinoids (e.g., isotretinoin, adapalene, tazarotene), Perera� - to-date or topical antibiotics (e.g., clindamycin, erythromycin, minocycline, tetracycline, benzoylperoxide) or hormonal therapy (e.g., drospirenone, norgestimate - ethinyl estradiol, cyproterone acetate). As indicated, these components can be administered in a single composition or in separate compositions. When administered in separate formulations of the compounds of this invention can be introduced sequentially or simultaneously with another drug(s).

Pharmaceutical compositions suitable for use in this invention for parenteral injection, contain a pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for conversion immediately before use in sterile injectable solutions or dispersion. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or mediums include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) and suitable mixtures, vegetable oils (such as olive oil), and injectable organic esters, such as ethyloleate. Appropriate fluidity can be maintained, for example, through the application of covering materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by applying surface�STN-active substances.

These compositions may also contain auxiliary agents such as preservatives, moisturizing agents, emulsifying agents and dispersing agents. Preventing exposure to microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, fenolcarbonove acid and the like. Can also be a desired inclusion isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of injectable pharmaceutical forms may cause the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

If necessary, and for more effective distribution, the compounds can be included in a slow-release or targeted delivery systems such as polymer matrices, liposomes and microspheres.

Injectable formulations can be sterilized, for example, by filtration through inhibiting bacteria filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. � such solid dosage forms the active compound is mixed, at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalciumphosphate and/or a) fillers or diluents, 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 manioc starch, alginic acid, certain silicates and sodium carbonate, (e) the dissolution retarders, such as paraffin, f) absorption accelerators such as Quaternary ammonium compounds, g) wetting agents such as, for example, cetyl, sperti glycerylmonostearate, 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 can also be used as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as you�homomolecular the polyethylene glycols and the like.

Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric-coating tablets and other coatings well known in the field of pharmaceutical preparation. They can contain optional mud components and can also include a composition that they release the active ingredient(s), or preferably, in certain parts of the intestine, optional, prolonged way. Examples of molding compositions that can be used include polymeric substances and waxes.

If necessary, and for more effective distribution, the compounds can be included in a 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 fillers.

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, solubilizers of veshestva emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed oil, ground nut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters sorbitan and mixtures thereof.

Besides inert diluents, oral compositions can also include adjuvants, such as moisturizing agents, emulsifying and suspendresume substances, sweetening, flavoring and otdushivayut substances.

Suspensions, in addition to the active compounds, may contain suspendresume substances, as, for example, ethoxylated isostearyl alcohols, polyoxyethylenated and sorbitane esters, microcrystalline cellulose, aluminum Metagalaxy, bentonite, agar-agar and tragakant and mixtures thereof.

Compositions for rectal or vaginal injection 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, polyethyleneglycol or a suppository wax which are solid at room temperature but liquid at temperature�re body and, therefore melt in the rectum or vaginal cavity and release the active connection.

For topical application, the active substance may be in the form of ointment, cream, suspension, lotion, powder, solution, paste, gel, spray solution, aerosol or oil. Alternatively, the composition may be delivered via liposomes, nanosomes, ribosome or nutri-diffuser environment. On the other hand, the composition may include a transdermal patch or dressing such as a bandage impregnated with an active ingredient and, optionally one or more carriers or diluents. For administration in the form of a transdermal delivery system, an introduction the dosage will, of course, more continuous, and not intermittent in the course regimens. Methods of producing compositions for topical application are known in the art.

Compositions used for topical application, usually contain a pharmaceutically acceptable carrier, which may be any environment that is toxicologically and pharmaceutically acceptable. Conventional pharmaceutically acceptable carriers that can be used in the compositions of this invention include water, ethanol, acetone, isopropyl alcohol, stearyl alcohol, freons, polyvinylpyrrolidone, propylene glycol, polyethylene glycol, fragrances, gel-�roguerouge materials, mineral oil, stearic acid, spermaceti, sorbitan, monolet, Polysorbate, "twins", sorbitol, methylcellulose, percolator, mineral oil (liquid paraffin oil), which can be any type of petroleum based product; modified or unmodified vegetable oils such as peanut oil, wheat germ oil, linseed oil, jojoba oil, oil of apricot pits, walnut oil, palm oil, pistachio oil, sesame oil, rapeseed oil, juniper oil, oil from corn germ, peach seed oil, poppy seed oil, pine oil, castor oil, oil from soybeans, safflower oil, coconut oil, hazelnut oil, grapeseed oil, avocado oil, soybean oil, sweet almond oil, oil of Calafell, castor oil, olive oil, sunflower oil, or animal oils such as whale oil, seal oil, manhattanie fat, fat, halibut liver, cod liver oil, cod, tuna, turtle fat, fat horse's hoof, sheep's paws, mink, otter, marmot and the like; synthetic oils such as silicone oil, such as dimethylpolysiloxane; alkyl and alkenyl esters of fatty acids, such as isopropylene esters of myristic, palmitic and stearic acids and fatty ester�, which are solid at room temperature; waxes such as lanolin wax, candlelike wax, spermaceti, cocoa butter, karite butter, silicone waxes, hydrogenated oils which are solid at room temperature, sugar glycerides, oleate, myristate, linoleates, stearates, paraffin, beeswax, Carnauba wax, ozocerite, candlelike wax, microcrystalline wax; fatty alcohols such as lauryl, cetyl, ministerului, stearyl, palmately and alerby alcohols; polyoxyethylated fatty alcohols; and wax esters, lanolin and its derivatives, perhydrosqualene and saturated esters, Etisalat, isopropylpalmitate, alkalinity, such as isopropyl myristate, mutiliated and deterministic, existiert, triglyceride esters, triglycerides octinomos and decanoas acid, cetirizine, stearylamine (purcellin oil), fatty acids, polyhydric alcohols, polyether derivatives, fatty acid monoglycerides, polyethylene glycol, propylene glycol, alkylalkoxysilane, ammoniumnitrate, Soaps of fatty acids and hydrogenated polyisobutene and mixtures of waxes and oils.

Compositions for topical application can be in various forms. However, the composition may often take the form of water �whether oil solution, or dispersion, or emulsion, or gel, or cream. The emulsion may be an emulsion of the type oil-in-water or emulsion of the type water-in-oil.

The oil phase of emulsions of the type water-in-oil or oil-in-water can contain, 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, oil of apricot pits, oil of a tree or jojoba oil; d) silicone oils such as Dimethicone, cyclomethicone or acidimeter; (e) fatty acid esters, such as isopropylpalmitate, isopropyl myristate, distilled, glyceridae and testosteronediet; (f) fatty alcohols such as cetyl alcohol or stearyl alcohol and their mixture (for example, clearily alcohol); (g) polypropylene glycol or polyethylene glycol esters, for example, PPG-14 butyl ether; or h) mixtures thereof.

Used emulsifiers can be any emulsifiers known in the art for use in emulsions of the type water-in-oil or oil-in-water. Known cosmetically acceptable emulsifiers include: (a) sesquioleate, such as servicesecurity available commercially, for example, under the trade name Arlacel 83 (ICI), or polyglyceryl-2-sesquioleate; b) ethoxylated esters of origin�water of natural oils, such as polyethoxysiloxane ester of hydrogenated castor oil available commercially, for example, under the trade name Arlacel 989 (ICI); (C) silicone emulsifiers such as siliconpower available commercially, for example, under the trade name Abil stock WS08 (Th. Goldschmidt AG); (d) anionic emulsifiers such as fatty acid Soaps, e.g., potassium stearate and sulfates of fatty acids, for example, cetostearyl sodium, commercially available under the trade name Dehydag (Henkel); (e) ethoxylated fatty alcohols, for example, the emulsifiers available commercially under the trade name Brij (ICI); (f) esters sorbitan, for example, the emulsifiers available commercially under the trade name Span (ICI); (g) ethoxylated esters sorbitan, 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 triglycerides, for example, the emulsifiers available commercially under the trade name Labrafil (Alfa Chem.); (j) non-ionic self emulsifiable 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 n�title Tefose (Alfa Chem.); l) methylglucose esters such as polyglycerol-3 methylglucose distearate, commercially available under the name Tegocare 450 (Degussa Goldschmidt); or (m) mixtures thereof.

Gels for local application can be aqueous or nonaqueous. Water gels are preferred. The gel will contain a thickener or gelling substance to impart sufficient viscosity to the gel. A number of thickeners can be used in accordance with the nature of the liquid carrier and the desired viscosity, and they are listed below. A particularly suitable thickening agent is a copolymer acryloyldimethyltaurate acid (or its salts), preferably a copolymer of this monomer with another vinyl monomer. For example, the thickener is a copolymer salt acryloyldimethyltaurate acid with another vinyl monomer. Salt may be a salt of alkali metals group 1, but more preferably is an ammonium salt. Examples of suitable copolymer thickeners are: (i) ammonium acryloyldimethyltaurate 1 vinylpyrrolidone copolymer, i.e. a copolymer of ammonium acryloyldimethyltaurate and vinylpyrrolidone (1-vinyl-2-pyrrolidone).

The composition may further include other active ingredients of skin care products that are well known in the art, which can be effective to support normalno� functioning of the skin. One group of preferred compositions include hydrolyzed milk protein to regulate sebum production.

The composition may further include other components that are well known to those skilled in the art, such as softeners, humectants, stabilizing emulsion, salts, preservatives, chelating complexing substances or compounds (binding compound), abrasives, antioxidants, stabilizers, pH controllers, surfactants, thickeners, diluents, flavoring and coloring agents.

Compositions for topical application may preferably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such amplifiers dermal penetration include dimethylsulfoxide and related analogs.

The amount of the administered compounds will preferably be treated to improve or alleviate the condition. A therapeutically effective amount can easily be determined by the attending diagnostician through the use of conventional techniques and by observing results obtained under analogous circumstances. In determining therapeutically effective amount should consider a number of factors, including, but without limitation, species of animal, its size�, the age and General health, sex, diet, the specific condition involved, the severity of the condition, the response of the patient to treatment, the specific input connection, type of administration, the bioavailability of the drug administered, the selected dosage, the use of other medications and other relevant circumstances.

Preferred dosage will be in the region of about 0.01 to 300 mg per kilogram of body weight per day. A more preferred dosage will be in the region of 0.1 - 100 mg per kilogram of body weight per day, more preferably 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 numerous curioso a day.

SYNTHESIS of COMPOUNDS FOR USE IN the PRESENT INVENTION

The General approach to the synthesis of the compounds for use in the present invention flows through the key intermediate product And produced as described in schemes 1 or 2.

Figure 1 amino acid-derived V-N(R2)-Y-CO2H (V=R1X or a protective group of the amine R1) are converted to amide Weinrebe via activation of the carboxyl group and amidation of the N-methylmethanamine. The addition of the vinyl Grignard reagent produces aminoalkylindole, which is subjected to a paired Pris�Union with R 6R7R8C(CR5aR5b)rNH2amine component (shown as WNH2for the sake of simplicity). The resulting secondary amine acelerou under standard conditions of peptide compounds with a protected amino acid P2-NHCH(U)-CO2H, where U represents either the final side chain R protected final side chain R-P3or predecessor, who needs chemical modification to generate the end of the side chain R. the Removal of the protective group, R2with subsequent intramolecular reductive amination of a ketone using standard conditions of recovery, such as H2/Pd catalyst, NaBH4, NaBH3CN or NaBH(OAc)3, with the formation of the key intermediate product A. If Y=CH2or CH2CH2then A is formed as the predominant diastereoisomer. If V=R1X and U=R, And is the final product.

Scheme 1: Synthesis of intermediate product And by intramolecular reductive amination

In figure 2 an alternative path to the desired intermediate product And starts with the same formation of amide Weinrebe, vinyl accession Grignard and amine conjugate connection. At this stage, the secondary amine is protected with a protective group of the amine R4. Ketone �ATEM recovery miniroot protected aminalonum ether, H2NCH(U)-CO2R5producing a mixture of diastereomers, which is carried out through the subsequent stages of the reaction. Ring system is obtained by removing the protective groups R4and R5with the subsequent formation of the amide bond using standard peptide reagents of the connection. Alternatively, the protective group R4remove and reach cyclization by means of thermal or base-induced cyclization with P^protected ester. Cyclization produces a mixture of two diastereoisomers, A and b, of which the preferred diastereomers And can be separated by chromatography.

Scheme 2: Synthesis of intermediate product And by intramolecular reductive amination

The key intermediate product And may constitute the final product, if U=R and V=R1X, but in other cases, turns into the final product, as shown in schemes 3, 4 and 5.

In scheme 3, where V=R1X, the final product is obtained by modifying the side chain of U, for example, removal of the protective group, R3or removal of the protective group, R3, followed by additional chemical modification.

Figure 3: V=R1X

In figure 4, where V=R1, the final product is obtained by removal of the protective group �1, followed by introduction of the substituent R1X. If U=R, it produces the final product.Alternatively, the side chain U then modified to obtain the final R groups, as in the diagram 3.

Scheme 4: V=P1

In scheme 5, where V=R1, the final product is obtained, first, by modifying the side chain of U to obtain the final R groups as in scheme 3. This is accomplished by removing the protective group P1, followed by introduction of the substituent R1X.

Scheme 5: V=P1

It is also possible to modify the under W, if necessary, during the sequences of these reactions.

Examples

The following examples are intended to show the disclosed variants of implementation, and should not be construed as limiting them. Additional connections beyond those described below, can be obtained by the following the above schemes reactions, as noted above, or suitable variations or modifications. All of the source materials described in the Examples below, commercially available or easily synthesized by experts in this field.

Equipment

Analysis of HPLC (high performance liquid chromatography) was performed on the treatment system Agilent series 1100, with a Phenomenex Synergi 4µ Max-RP 80A, 50×2.00 mm analytical HPLC column, detection �of ICA by UV. In the standard analysis used a flow rate of 1 ml/min with 0.05% trifluoroacetic acid (TFA) in water (solvent A) and 0.05% TFA in 90:10 acetonitrile:water (solvent B), using a gradient from 5% (initial) to 95% b for 9 minutes. Mass spectra were obtained on an Applied Biosystems MDS Sciex API 2000 LC/MS/MS triple quadrupole mass spectrometer and analyzed yourspouse mass spectrometry (ISMS). Preparative HPLC was performed on Waters Delta Prep 3000 HPLC system with detection of peaks by UV (Waters model 486 custom absorption detector), using a Phenomenex Luna C5 10µ 100A, 250×21,20 mm (20 mg scale), Phenomenex Luna 15u 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 column. The solvent system used different gradients of 0.05% TFA in water (solvent A) and 0.05% TFA in 90:10 acetonitrile:water (solvent B).

The following examples 1-7 offer General synthesis procedures that can be followed for carrying out the transformations described in schemes 1-5. For the formation of different end products using these techniques or need to change the variable group on the source material, or change variable group at one of the reactants, depending on the nature of the reaction. The person skilled in the art it will be clear from reading the General methods of how to change or source material, or the reagents used in methods� for producing different end products. In addition, depending on the starting materials and reagents, may need and/or desire to make minor modifications described in the General methods in order to provide the most easy synthesis of the desired end product.

Example 1 - General procedure - formation of the amide Weinrebe

THIEF (benzotriazole-1-yl-oxy-Tris-(dimethylamino)-phosphodiester phosphate) reagent (100 mmol) and diisopropylethylamine (DIPEA) (100 mmol) was added to a stirred solution of amino acid (1) (100 mmol) in dichloromethane (DCM) (100 ml). The solution was then stirred at room temperature for 10 min, before adding the pre-mixed solution of N,O-dimethylhydroxylamine hydrochloride (100 mmol) and DIPEA (100 mmol) followed by stirring at room temperature overnight. DCM is then removed by rotary evaporation and the residue is absorbed in ethyl acetate (EtOAc) (200 ml). The organic phase is then washed with 1N HCl (3×100 ml), H2O (3×100 ml), saturated aqueous solution of NaHCO3(3×100 ml) and brine (1×10 ml). The organic phase was then dried (MgSO4) and EtOAc was removed to obtain an amide Weinrebe (2) in the form of a white solid or oil.

Example 2 - General procedure - attaching vinyl Grignard to Amida Weinreb for the formation of α,β-unsaturated ketone�in the formulas (3)

To Amida Weinrebe (2) (15 mmol) in DCM (10 ml) at (FF add vinylmania (45 mmol) in THF (45 ml). The reaction was stirred for 2 hours and checked by means of HPLC. The reaction is then cooled rapidly by adding thereto a mixture of ice and 1M HCl (200 ml). The aqueous mixture was 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 was dried (MgSO4): to a solution of α,β-unsaturated ketone (3). α,β-Unsaturated ketone (3) can distinguish rotary evaporation or it can be used in solution without further purification. If the purpose is to use the α,β-unsaturated ketone (3) in the solution, the volume reduced to 100 ml using rotary evaporation and stored for future use.

Example 3 General method - conjugate of the accession of the amine to the α,β-unsaturated ketones of the formula (3) to obtain the compounds of formula (4)

To Aminu W-NH2(7,4 mmol) in DCM (10 ml) was added a solution of α,β-unsaturated ketone (3) (5,7 mmol) in DCM (50 ml). The solution was stirred at room temperature for 15 minutes or until until the analysis does not show that all of (3) is used up. A solution of compound (4) is directly used without purification for subsequent reactions.

Example 4 General method of acelerou�tion of aminoketone (4)

Amino acid P2-NHCH(U)-CO2H (15 mmol) and DIC (15 mmol) was added to a solution of DCM containing 10 mmol adduct 4 mated connection. The reaction was stirred at room temperature overnight. DCM was removed using rotary evaporation, and the residue was then subjected to column chromatography on silica gel, using white spirit:EtOAc to obtain 5.

Alternatively, DIC can be replaced by HATU (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate) (15 mmol) and DIPEA (15 mmol). The reaction was stirred at room temperature overnight. DCM was removed using rotary evaporation, and the residue absorb in EtOAc (100 ml). The organic layer was washed with saturated sodium bicarbonate solution (2×100 ml), saturated aqueous ammonium chloride (2×100 ml) and brine (2×100 ml). The organic phase was dried and the solvent removed under reduced pressure. The residue is subjected to column chromatography on silica gel using petroleum ether:EtOAc to obtain 5.

Example 5 General procedure - the removal of the protective group, R2and cyclization

The method selected for removal of the protective group P2, will vary depending on the specific nature of the protective group. As will be appreciated by the person skilled in the art, can be used�ü greater number of possible protective groups, and the person skilled in the art will easily be able to determine a suitable method for removing any protective groups of methods known in the art. However, in order to help the reader, are common methods of removal of the most well-known protective groups. R2=Fmoc: compound 5 (2 mmol) in DCM (3 ml) was added diethylamine (20 mmol). The reaction was stirred at room temperature for 1 hour. DCM and diethylamine are then removed using rotary evaporation. DCM (5 ml) and then added triacetoxyborohydride sodium (3 mmol) and the reaction was stirred overnight at room temperature. The organic phase is washed with saturated sodium bicarbonate solution (25 ml), dried (MgSO4and remove DCM to obtain cyklinowanie product A. It can be cleaned flash chromatography on silica gel or used without purification.

R2=Boc: To the compound 5 (2 mmol) in DCM (3 ml) was added TFA (3 ml) and the reaction was stirred at room temperature for 2 hours. DCM and TFA then removed using rotary evaporation. Then add DCM (5 ml) and triacetoxyborohydride sodium (3 mmol) and the reaction was stirred overnight at room temperature. The organic phase is washed with saturated sodium bicarbonate solution (25 ml), dried (MgSO4and remove DCM to obtain cyklinowanie producta. Can be cleared flash chromatography on silica gel or used without purification.

R2=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 (pounds per square inch)) within 24 hours. The mixture was then filtered through a pad of Celite and the filtrate concentrated under reduced pressure to obtain crude product. To obtain And can be applied purification using flash chromatography on silica gel (100% EtOAc).

Example 6 General procedure - the removal of the protective group, R1and deriving c R1X

The method selected for removing the protective group P1, will vary depending on the specific nature of the protective group. As will be appreciated by the person skilled in the art, it is possible to apply a large number of possible protective groups, and the person skilled in the art will easily be able to determine a suitable method for removing any protective groups of methods known in the art. However, in order to help the reader, are common methods of removal of the most well-known protective groups.

The removal of the protective groups, R1=Cbz:

To cyklinowanie product A (1 mmol) in methanol (5 ml) was added catalytic Pd/C. the Reaction was stirred in the atmosphere nitric acid�and all night. The reaction mixture was filtered through Celite, and the methanol is removed with rotary evaporation to obtain the free amine. Amine can be used in subsequent reactions without purification.

The removal of the protective groups, R1=Boc:

To cyklinowanie product A (1 mmol) in DCM (1 ml) was added TFA (1 ml) and the reaction was stirred at room temperature for 2 hours. The solvent was removed using rotary evaporation to obtain the amine TFA salt, which can be used in subsequent reactions without purification.

The removal of the protective groups, R1=Alloc:

To cyklinowanie product A (1 mmol) in DCM (6 ml) was added 1,3-dimethylbarbituric acid (0.2 mmol) and palladium tetranitroaniline (10 mg). The reaction is evacuated and stirred at room temperature for 1 hour. DCM was removed under reduced pressure to obtain the crude free amine, which can be used in subsequent reactions without purification.

Obtaining derivatives with R1X when X=C(=O):

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

Example 7 General procedure - modifying U by removing the protective �the group R 3and dialkylamide the dibromide

The methodology selected for modifying U by removing the protective group and obtaining the derivatives will vary depending on the specific nature of the group U. As will be appreciated by the person skilled in the art, a large number of possible variations, and the person skilled in the art will easily be able to determine a suitable method for turning in the necessary R group. However, in order to help the reader, is one common method of inoculation, usually used for the following examples.

R3=Boc:

The protected amine (1 mmol) in DCM (5 ml) was added TFA (5 ml) and the reaction was stirred at room temperature for 2 hours. Add DCM (20 ml) and the solution washed with saturated sodium bicarbonate solution (20 ml), dried (MgSO4) and evaporated to obtain the crude amine. To the crude amine is added DMF (dimethylformamide) (0.5 ml), potassium carbonate (50 mg) and 1,5-dibromethane (5 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, then add DCM (20 ml), the organic layer washed with saturated sodium bicarbonate solution (20 ml) and N2About (20 ml), dried (MgSO4) and evaporated. The residue can be cleaned preparative HPLC to obtain piperidineacetate. The purified product is isolated in the form of TFA salt, but easily converted to the free base by neutralization of aqueous NaHCO3and extraction into an organic solvent, or optionally converted to HCl salt by acidification 1N HCl.

Example 8 - Synthesis of compound 8 N-(2-(methoxy(methyl)amino)-2-oxoethyl)-2-naftalina

To a mixture of 2-natoinal acid (5.8 g, or 33.7 mmol), 2-amino-N-methoxy-N-methylacetamide (Gly amide Weinrebe; prepared from Boc-Gly amide Weinrebe 15 as in Example 43) (3.8 g, to 32.1 mmol) and DIPEA (12.0 ml, 68.9 per mmol) in DCM (70 ml) was added THIEF (14,9 g, or 33.7 mmol) in one portion at room temperature. The resulting mixture was stirred for 1 hour, then was added a saturated aqueous solution of NaHCO3. 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 obtain crude product, which was used in subsequent reactions without further purification.

Example 9 - Synthesis of compound 9 N-(2-(methoxy(methyl)amino)-2-oxoethyl)-2-naftalina

To a solution of 8 (3.5 g, 12,85 mmol) in dry THF (10 ml) was slowly added a solution of vinylmania in THF (1 M, 31 ml) at 0°C. After addition the resulting mixture was stirred at room temperature for 1 hour, satanville in ice-cold 20 a solution of 1 N HCl (50 ml). The aqueous layer was extracted with DCM (3 x 80 ml) and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to obtain crude product. MS (ESI) 240 (M+1); HPLC tR5.46 minutes.

Example 10 - Synthesis of compound 10 N-(4-(3,5-dichloraniline)-2-oxobutyl)-2-naftalina

To a solution of 3,5-dichloraniline (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 then, until all 9 have not used up (within one hour) and then used directly in subsequent reactions. MS (ESI) 415 (M+1); HPLC tR6,00 minutes.

Example 11 - Synthesis of compound 11 (S)-N-(4-(5-(3-Pbf-guanidino)-2-(Fmoc-amino)-N-(3,5-dichlorobenzyl)pentanolide)-2-oxobutyl)-2-naftalina

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 the addition of DIC (12,5 µl, 0,082 mmol) at room temperature. The resulting mixture was stirred for 2 hours, then the solvent was removed under reduced pressure. The residue was filtered through a short plug of silica gel, elwira DCM EtOAc followed to obtain the desired product 11 in the form of a white solid. It was used in the next stage without additional clean�Ki. MS (ESI) 1045 (M+1); HPLC tR9.99 minutes.

Example 12 - Synthesis of compound 12 (S)-N-(4-(5-(3-Pbf-guanidino)-2-amino-N-(3,5-dichlorobenzyl)pentanolide)-2-oxobutyl)-2-naftalina

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 minutes. Excess diethylamine was removed under reduced pressure to obtain the desired free amine 12. It was used in the next stage without additional purification. MS (ESI) 823 (M+1); HPLC tR7,49 minutes.

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-naftalina

Aminoketone 12 (44 mg, 0,053 mmol) in DCM (2 ml) were cyclically added NaBH(SLA)3(40 mg, 0.18 mmol) in one portion at room temperature. The resulting mixture was stirred for 3 hours followed by the addition of saturated aqueous NaHCOs 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, elwira DCM with further EtOAc, then EtOAc/IPA (9:1) to obtain the target product 13 in the form of a white solid. It was used on the trail�the next stage without additional purification. MS (ESI) 807 (M+1); HPLC tR7.75 minutes.

Example 14 - Synthesis of compound 14 N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naftalina

A solution of TFA/DCM (2:1) (1 ml) with 5% H2O added to 13 at room temperature and the resulting mixture was stirred for 4 hours. The solvent was removed under reduced pressure and the residue was purified using preparative HPLC (100% H2O to MeCN/H2O 9:1, gradient) to obtain 14 (7,6 mg) in the form of a white solid (TFA salt). Total output (9) was approximately 18%. MS (ESI) 556,2 (M+1); HPLC tR5.74 minutes.

Example 15 - Synthesis of compound 15 tert-butyl 2-(methoxy(methyl)amino)-2-oxoethylidene (Boc-Gly amide Weinrebe)

To a stirred mixture of Boc-Gly-OH (20 g, to 114.1 mmol), DIPEA (19.8 ml, to 114.1 mmol) and the THIEF (50,5 g, to 114.1 mmol) in DCM (20 ml) was added a pre-mixed solution of N,O-dimethylhydroxylamine (11.2 g, to 114.1 mmol) and DIPEA (19.8 ml, to 114.1 mmol) in DCM (20 ml) at room temperature. The resulting mixture was stirred for 16 hours, then washed with 1N HCl (3×120 ml), H2O (3×120 ml), a saturated aqueous solution of NaHCO3(3×120 ml) and brine (40 ml), dried over MgSO4, filtered and concentrated under reduced pressure to obtain 15 in the form of a white solid (20 g, 80%), which inform�do in the next stage without additional purification. MS(ESI) 219 (M+1); HPLC tR4.12 minutes.

Example 16 - Synthesis of compound 16 tert-butyl 2-exabot-3-talkabout

At 0°C a solution of vinylmania in THF (184 ml, 1 M) was added in one portion to Amida Weinreb 15 (20 g, to 91.6 mmol) under nitrogen with stirring. The resulting mixture was allowed to stir for 2 hours and poured into a mixture of 1N HCl/ice (400 ml). The aqueous mixture was extracted with DCM (5[100 ml), the combined DCM extract was washed with 1N HCl (2×100 ml), a saturated aqueous solution of NaHCO3(100 ml) and brine (100 ml), then dried over MgSO4. The solvent was removed under reduced pressure, received the ketone 16 (12.9 g, 76%) in the form of a pale yellow oil, which was used for next step without further purification. MS(ESI) 186 (M+1); HPLC tR4,19 minutes.

Example 17 - Synthesis of compound 17 tert-butyl 4-(2,2-diphenylethylamine)-2-oxobutyrate

To peremeshivaem a solution of 2,2-diphenylethylamine (0.33 g, of 1.66 mmol) in DCM (10 ml) was added α,β-unsaturated ketone 16 (0.31 g, of 1.66 mmol) at room temperature. The stirring was continued for 2 hours; the crude reaction mixture 17 was used in the next stage without purification. MS(ESI) 383 (M+1); HPLC tR5,98 minutes

Example 18 - Synthesis of compound 18 (S)-tert-butyl 3-methyl-4,8-diokso-10-phenyl-2,9-dioxa-3,7-diabadikan-6-carboxylate

To a suspension of the salt of Cbz-L-Asp-OtBu-DCHA (10.1 g, 20.0 mmol), N,O-dimethylhydroxylamine-HCl (5.9 g, of 60.5 mmol) and DIPEA (12.0 ml, 68.9 per mmol) in DCM (150 ml) was added THIEF (10,6 g, 24,0 mmol) in one portion at room temperature. The resulting suspension was stirred for 3 hours, then added H2O (100 ml). The organic layer was washed with 1 N HCl (2×100 ml), a saturated aqueous solution of NaHCO3(2×100 ml) and brine (3×100 ml) and then dried over MgSO4, filtered and concentrated under reduced pressure to obtain crude product. Purification using flash chromatography on silica gel (pet. ether/ EtOAc 1:2) gave 18 (6.4 g, 87%) in the form of a colorless oil. MS (ESI) 367 (M+1); HPLC tR6,87 minutes.

Example 19 - Synthesis of compound 19 (S)-3-methyl-4,8-diokso-10-phenyl-2,9-dioxa-3,7-diabadikan-6-carboxylic acid

Compound 18 (300 mg, 0,82 mmol) was dissolved in TFA/DCM (1:1) solution (2 ml) and the resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue re-dissolved in DCM (10 ml). This solution was washed with 1 N HCl (1×10 ml) and the organic layer dried over MgSO4, filtered and concentrated under reduced pressure to obtain crude product 19 (235 mg, 92%) which was used in subsequent reactions without further purification. MS (ESI) 311 (M+1); HPLC t 4,96 minutes.

Example 20 - Synthesis of compound 20 (S)-benzyl 8-(2,2-diphenylether)-3,16,16-trimethyl-4,7,11,14-tetraoxo-2,15-dioxo-3,8,13-triazapentadiene-6-ylcarbamate

Compound 20 was obtained from compound 17 and 19, following the method of Example 5. MS (ESI) 675 (M+1); HPLC tR8,31 minutes.

Example 21 - Synthesis of compound 21 tert-butyl ((3S,5S)-1-(2,2-diphenylether)-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 stirred at room temperature under hydrogen (30 psi) for 24 hours. The mixture was then filtered through a pad of Celite and the filtrate concentrated under reduced pressure to obtain crude product. Purification using flash chromatography on silica gel (100% of EtOAc) gave 21 (175 mg, 65% over 3 steps) in the form of a white solid. MS (ESI) 525 (M+1); HPLC tR6.24 minutes.

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

Compound 21 (175 mg, 0,333 mmol) was dissolved in TFA/DCM (1;1) solution (1 ml) and the resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue re-dissolved in EtOAc (20 ml). Saturated aqueous Sol�R NaHCO 3(10 ml) and brine (10 ml) was 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 obtain crude product 22 (120 mg, 85%) in the form of a yellow solid, which was used in subsequent reactions without further purification. MS (ESI) 425 (M+1); HPLC tR5,20 minutes.

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

To a solution of 22 (50 mg, the amount of 0.118 mmol) and 6-fluoro-2-natoinal 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 hours, then the solvent was removed under reduced pressure to obtain crude product. Cleaning with flss chromatography on silica gel (elwira petroleum ether: EtOAc (1:1), then EtOAc) gave 23 (29 mg, 41%) in the form of a white solid. MS (ESI) 597 (M+1); HPLC tR6.75 minutes.

Example 24 - Synthesis of compound 24 N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-oxoethyl)-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naftalina

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 those�ture, and the resulting suspension was stirred overnight. This slurry was then slowly poured into a cold (0°C) 0.4 M aqueous solution of KHSO4(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), a saturated aqueous solution of NaHCO3(1×6 ml) and brine (1×6 ml). The organic solution is then dried over MgSO4, filtered and concentrated under reduced pressure to obtain crude product 24 (24 mg, 91%) which was used in subsequent reactions without further purification. MS (ESI) 538 (M+1); HPLC tR6,41 minutes.

Example 25 - Synthesis of compound 25 N-(((3S,5S)-3-(2-(diethylamino)ethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naftalina

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 minutes to the above solution was added NaBH(SLA)3(20 mg, 0,090 mmol) in one portion and the resulting suspension was stirred for 10 minutes. To the suspension was added a saturated aqueous NaHCOs solution (4 ml) 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 obtain crude product. This crude product is clean,�or by means of preparative HPLC (100% H 2O to MeCN/H2O 9:1, gradient) to obtain 25 in the form of a white solid (TFA salt). MS (ESI) 595,3 (M+1); HPLC tR6,22 minutes.

Example 26 - Synthesis of compound 26 benzyl 2-(methoxy(methyl)amino)-2-oxoethylidene

To Cbz-glycine (10 g, 47,8 mmol, Aldrich) in DCM (100 ml) was added THIEF reagent (21.5 g, to 48.6 mmol) and DIPEA (6.5 ml, 46,0 mmol). After stirring at room temperature for 10 minutes was added N,O-dimethylhydroxylamine (4,9 g, a 50.2 mmol) and DIPEA (6.5 ml, 46,0 mmol). The reaction was stirred at room temperature overnight. DCM was removed using rotary evaporation and the residue absorbed 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 EtOAc was removed to obtain an amide Weinrebe 26 in the form of a white solid (7.78 g, 64%).

Example 27 - Synthesis of compound 27 benzyl 2-exabot-3-talkabout

To Amida Weinreb 26 (3,89 g, for 15.42 mmol) in DCM (10 ml) at 0°C was added vinylmania (45 mmol) in THF (45 ml). The reaction was stirred for 2 hours and checked using 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 in�was dried (MgSO 4) and the volume reduced to 100 ml using rotary evaporation. 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-diphenylether)-2,2-dimethyl-18-phenyl-4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-trasaction-8-ylcarbamate

To 2,2-diphenylethylamine (0.95 g, 7.4 mmol) in DCM (10 ml) was added RA-unsaturated ketone 27 (5,7 mmol) in DCM (75 ml). After stirring at room temperature for 15 minutes was added Fmoc-L-2,4-diaminobutane acid(BOC)-IT (2.4 g, 8,55 mmol) and DIC (of 0.87 ml, 5.6 mmol). The reaction was stirred at room temperature overnight. DCM was removed using rotary evaporation and the residue was subjected to column chromatography on silica gel with the use of white spirit:EtOAc (1:1 to 0:1) to obtain 28 (1.5 g, 31%)

Alternative, 2,2-diphenylethylamine (0,97 g, 7.4 mmol) in DCM (20 ml) was added α,β-unsaturated ketone 27 (5,95 mmol) in DCM (40 ml). After stirring at room temperature for 15 minutes was added Fmoc-L-2,4-diaminobutane acid(BOC)-IT (2.4 g, 8,55 mmol), DIPEA (2.5 ml) and HATU (2.3 g, 6.0 mmol). The reaction was stirred at room temperature overnight. DCM was removed using rotary evaporation and the residue absorbed in EtOAc (100 ml). The organic layer was washed with saturated sodium bicarbonate solution (2×100 ml), saturated solution of chloride of ammo�ia (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 with the use of white spirit:EtOAc (3:1 to 1:1 to 0:1) to obtain 28 (0.86 g, 17%),

Example 29 - Synthesis of compound 29 (3S,5S)-3-(2-tert-butoxycarbonylamino)-5-(benzyloxycarbonylamino)-1-(2,2-diphenylether)-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 hour. DCM and diethylamine was removed using rotary evaporation. Added DCM (5 ml), triacetoxyborohydride sodium (0.4 g, 1.9 mmol) and the reaction was stirred overnight at room temperature. The organic phase is washed with saturated sodium bicarbonate solution (25 ml), dried (MgSO4) and the DCM removed to obtain cyklinowanie product 29, which was used for next step without purification.

Example 30 - Synthesis of compound 30 (3S,5S)-3-(2-tert-butoxycarbonylamino)-5-aminomethyl-1 -(2,2-diphenylether)-1,4-diazepan-2-one

To cyklinowanie product 29 in methanol (5 ml) was added catalytic Pd/C. the Reaction was stirred under hydrogen atmosphere overnight. The reaction mixture was filtered through Celite and the methanol was removed using rotary evaporation to obtain the amine 30 (0.7 g, 83% and� 28).

Example 31 - Synthesis of compound 31 N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naftalina

To Aminu 30 (0.08 g, 0.17 mmol) in DCM (1 ml) was added DIPEA (0.25 ml), THIEF reagent (0.08 g, 0.18 mmol) and 6-fluoro-2-natoinal acid (0.06 g, 0,32 mmol). The reaction was stirred at room temperature for 2 hours. TFA (1 ml) was added and the reaction stirred at room temperature for 2 hours. Rotary evaporation and preparative HPLC received 31 (0.05 g, 54%). MS (ESI) to 539.3 (M+1); HPLC tRmin 5,92

Example 32 - Synthesis of compound 32 6-chloro-2-natoinal acid

A suspension of 6-bromo-2-natoinal 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 boiling under argon in the dark for 4 hours. After cooling to room temperature the solution was decanted into water H2About (200 ml) and the resulting mixture was extracted with EtOAc (2×500 ml). The combined organic layers then washed with H2O (4×500 ml), then brine (1×500 ml), dried over MgSO4, filtered and concentrated under reduced pressure to dry condition. The residue was ground into powder with CHsCN and the obtained solid substance was then precrystallization from EtOAc to obtain pure product 32 (2.2 g, 93%) in the form of a dirty-white solid. �ASH t R6,47 minutes.

Example 33 - Synthesis of compound 33 (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide

To the amine(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-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 hours. The solvent was removed under high vacuum and the residue was purified using preparative HPLC to obtain 8 mg (~30%) of 33 in the form of TFA salt. MS (ESI) 599,4 (M+1); HPLC tRminutes 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-trasaction-ylcarbamate

To 2-phenylbutyraldehyde (0.26 g, 1.4 mmol) in DCM (10 ml) and DIPEA (0.25 ml, 1.8 mmol) was added α,β-unsaturated ketone 27 (1,06 mmol) in DCM (20 ml). After stirring at room temperature for 15 minutes was added Fmoc-diaminobutane acid(BOC)-HE (0.7 g, 1.56 mmol) and DIC (0.25 ml, of 1.61 mmol). The reaction was stirred at room temperature overnight. DCM was removed using rotary evaporation and the residue was subjected to column chromatography on silica gel using white spirit:EtOAc (1:1-0:1), giving compound 34 as a mixture of diastereomer� (0.17 g, 21%).

Example 35 - Synthesis of compound 35 (3S,5S)-3-(2-tert-butoxycarbonylamino)-5-(benzyloxycarbonylamino)-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 hour. DCM and diethylamine was removed using rotary evaporation. DCM (5 ml) and triacetoxyborohydride sodium (0.1 g, 0.47 mmol) was added and the reaction was stirred overnight at room temperature. The organic phase is washed with saturated sodium bicarbonate solution (25 ml), dried (MgSO4) and DCM was removed to obtain cyklinowanie product 35 as a mixture of diastereomers (0.11 g, 100%).

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

To cyklinowanie 35 product (0.11 g) in methanol (5 ml) was added catalytic Pd/C. the Reaction was stirred under hydrogen atmosphere overnight. The reaction mixture was filtered through Celite and the methanol was removed using rotary evaporation to obtain 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-naftopidil)-1-(2-phenylbutyl)-1,4-diazepan-2-one

To amine 36 (0.02 mg, 0,05 mmol) in DCM (1 ml) was added DIPEA (1 ml, 0,7 mmol), THIEF reagent (0.02 mg, or 0.045 mmol) and 2-natoinal acid (0.015 mg, 0,09 mmol). The reaction was stirred at room temperature for 2 hours. Added TFA (1 ml) and the reaction was stirred at room temperature for 2 hours. Rotary evaporation and preparative HPLC received 37 as a mixture of diastereomers (13,4 mg, 57%). MS (ESI) 473,4 (M+1); HPLC tR5,59 minutes.

Example 38 - Synthesis of compounds 38-39 N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthalide and N-(((3S,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naftalina

Prepared from compound 37 by means of alkylation, as in Example 33. Preparative HPLC purification separated the two diastereoisomer. Proper configuration established by repeated synthesis of compounds with (3)-2-phenylbutyramide 43 or (S)-2-phenylethylamine. 38: MS (ESI) 541,3 (M+1); HPLC tR5.78 minutes; 39: MS (ESI) 541,3 (M+1); HPLC tR5,67 minutes.

Example 39 - Synthesis of compound 40 (S)-2-phenylbutane

To a suspension of sodium borohydride (2,36 g, of 62.4 mmol) in THF (50 ml) was slowly added a solution of (S)-2-fenilmaslana acid (4,27 g, for 26.0 mmol) in THF (40 ml) at 0°C. the Mixture was stirred until then, until you stopped the formation of gas. A solution of iodine (6,60 g of 26.0 mmol) in THF (40 ml) then slowly d�bavili at 0°C. After adding the resulting mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction solution is then slowly poured into a solution of 1 N HCl (280 ml) and the resulting mixture was diluted with EtOAc (250 ml). The aqueous layer was extracted with EtOAc (150 ml × 3) and combined organic layers then washed with saturated NaHCO3(water.), 0.5 M Na2S2O3(water.) and salt solution. This organic solution was dried over MgSO4, filtered and concentrated under reduced pressure to obtain crude product. Purification using flash chromatography on silica gel (petroleum ether: EtOAc 4:1) was obtained the desired product 40 in the form of a colorless oil in quantitative yield. HPLC tR5.24 minutes.

Example 40 - Synthesis of compound 41 (S)-1-mesilate-phenylbutane

To a mixture of 40 (3.9 g, for 26.0 mmol) and triethylamine (5.5 ml, 39.5 mmol) in DCM (90 ml) was slowly added a solution of methanesulfonamide (4,47 g, 39,0 mmol) in DCM (30 ml) at 0°C. After addition the resulting mixture was allowed to warm to room temperature and stirred for 2 hours. Then the above mixture was added 1 N HCl (70 ml) 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 �the force to obtain the crude product 41 in the form of a colorless oil. This untreated lose-was used in the next stage without additional purification. HPLC tR6.48 minutes.

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

A suspension of 41 (5,93 g of 26.0 mmol) and sodium azide (5.7 g, 78,0 mmol) in DMF (60 ml) was heated at 85°C for 3 hours. After cooling to room temperature the mixture was diluted with H2O (200 ml) and was extracted with EtOAc (250 ml). The organic layer was then washed with H2O (4×150 ml) and then brine (150 ml), dried over MgSO4, filtered and concentrated under reduced pressure to obtain crude product. Purification using flash chromatography on silica gel (100% petroleum ether as eluent) reported net product 42 (4,03 g, 88%) in the form of a colorless oil. HPLC tR7,67 minutes.

Example 42 - Synthesis of compound 43 (S)-2-phenylethylamine

A mixture of 42 (4.0 g, of 22.8 mmol) and Lindlar catalyst (1.5 g) in EtOAc (50 ml) was stirred at room temperature under H2(40 psi) overnight. The mixture was then filtered through a pad of Celite and the filtrate concentrated under reduced pressure to obtain crude product 43 (3.4 g, 100%) in the form of a light yellow oil. This crude product was used for the reactions conjugate of accession without further purification. MS (ESI) 150 (M+1); VE�X t R1,84 minutes.

Example 43 - Synthesis of compound 44 allyl 2-(methoxy(methyl)amino)-2-oxoethylidene

To Alloc(allyloxycarbonyl)-glycine (1.45 g, 9.1 mmol) in DCM (20 ml) was added THIEF reagent (3.3 g, of 7.46 mmol) and DIPEA (1.5 ml, 10.7 mmol). After stirring at room temperature for 10 minutes was added N,O-dimethylhydroxylamine (0.8 g, 8.2 mmol) and DIPEA (1.5 ml, 10.7 mmol). The reaction was stirred at room temperature overnight. DCM was removed using rotary evaporation and the residue absorbed 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), 1M HCl (3×50 ml), brine (3×50 ml). The organic phase was dried (MgSO4) and EtOAc was removed to obtain an amide Weinrebe 44 in the form of a white solid (0,43 g, 23%).

Alternatively, tert-butyl 2-(methoxy(methyl)amino)-2-oxoethylidene 16 (BOC-Gly amide Weinrebe, 1.4 g, 6.4 mmol) in DCM (5 ml) and TFA (3 ml) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure followed by the addition of DCM (20 ml) and then DIPEA before the main. The solution was cooled to 0°C and added allylcarbamate (1.4 ml, 13.2 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was neutralized with 1M HCl and was extracted with EtOAc. EtOAc was removed using rotary evaporation and �the STATCOM was subjected to column chromatography on silica gel using white spirit:EtOAc (1:1-0:1), providing 44 (0.86 g, 66%).

Example 44 - Synthesis of compound 45 allyl 2-exabot-3-talkabout

To Amida Weinreb 44 (0,43 g, 2.1 mmol) in DCM (5 ml) at 0°C was added vinylmania (10 mmol) in THF (10 ml). The reaction was stirred for 2 hours and checked using 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 1M HCl (2×100 ml) and H2O (3×50 ml). The organic phase was dried (MgSO4) and the volume reduced to 50 ml using rotary evaporation. 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-4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-treatises-19-ene-8-ylcarbamate

To 3.5-dichloraniline (0.49 g, 2.8 mmol) in DCM (5 ml) was added a, (3-unsaturated ketone 45 (2,12 mmol) in DCM (10 ml). After stirring at room temperature for 15 minutes was added Fmoc-diaminobutane acid(BOC)-HE (1.35 g, 3.1 mmol) and DIC (0.5 ml, 3.2 mmol). The reaction was stirred at room temperature overnight. DCM was removed using rotary evaporation and the residue was subjected to column chromatography on silica gel using white spirit:EtOAc (1:1-0:1), providing compound 46 (0,48 g, 22%).

Example 46 - Synthesis of compound 47 (3S,5S)-3-(2-tert-butoxycarbonyl�inatel)-5-(allyloxycarbonyl)-1-(3,5-dichlorobenzyl)-1,4-diazepan-2-one

To compound 46 (0,48 g, to 0.63 mmol) in DCM (3 ml) was added diethylamine (1.5 ml). The reaction was stirred at room temperature for 1 hour. DCM and diethylamine was removed using rotary evaporation. Added DCM (5 ml), triacetoxyborohydride sodium (0.2 g, 0.94 mmol) and the reaction was stirred overnight at room temperature. The organic phase is washed with saturated sodium bicarbonate solution (25 ml), dried (MgSO4) and the DCM removed to obtain cyklinowanie 47 product (0.24 g, 72%).

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

To cyklinowanie 47 product (0.24 g, 0.45 mmol) in DCM (3 ml) was added 1,3-dimethylbarbituric acid (13 mg, 0.08 mmol) and palladium tetranitroaniline (5 mg). The reaction was evacuated and stirred at room temperature for 1 hour. DCM was removed under reduced pressure to obtain crude product 48 (0.15 g, 75%) which was used in subsequent reactions without purification.

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

To Aminu 48 (0.05 mg, 0.11 mmol) in DCM (1 ml) was added DIPEA (0.1 ml, 0.7 mmol), THIEF reagent (0.05 mg, 0.11 mmol) and 2-natoinal acid (0.04 mg, 0,23 mmol). The reaction shuffle�Wali at room temperature for 2 hours. TFA (1 ml) was added and the reaction stirred at room temperature for 2 hours. Rotary evaporation and preparative HPLC received 49 (48 mg, 90%). MS (ESI) 499,3 (M+1); HPLC tR5,77 minutes.

Example 49 -. Synthesis of compound 50 N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthalene-2-sulfonamide

Prepared from allyl 2-exabot-3-talkabout 45, Boc-L-Arg(Fmoc)2-OH and 2,2-diphenylethylamine according to the procedures of Examples 46-48 with following modification: the First group TFA was removed during the method of removing the protective groups/cyclization of Example 47, rather than the use of diethylamine for Fmoc removal. After Alloc removing the protective groups by the method of Example 48 free amine was dissolved in DCM to which was added naphthalene-2-sulphonylchloride (10 mg) and DIPEA (20 μl) and the reaction was stirred for 2 hours at room temperature. Diethylamine (1 ml) was added and stirred overnight to remove the Fmoc protection, and the reaction evaporated to the dry state. Preparative HPLC was obtained the titled compound 50 (13 mg). MS (ESI) 613,5 (M+1); HPLC tR5,89 minutes.

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-trasaction-8-ylcarbamate

To 2-ethylbutylamine (0.15 g, of 1.48 mmol) in DCM (10 ml) was added α,β-nenasi�enny ketone 27 (1,47 mmol) in DCM (30 ml). After stirring at room temperature for 15 minutes was added Fmoc-diaminobutane acid(BOC)-HE (0.95 g, of 2.16 mmol) and DIC (0,34 ml, 2,19 mmol). The reaction was stirred at room temperature overnight. DCM was removed using rotary evaporation and the residue was subjected to column chromatography on silica gel using white spirit:EtOAc (1:1-0:1), providing compound 51 (0.5 g, 46%).

Example 51 - Synthesis of compound 52 (3S,5S)-3-(2-tert-butoxycarbonylamino)-5-(benzyloxycarbonylamino)-1-(2-ethylbutyl)-1,4-diazepan-2-one

To compound 51 (0.5 g, 0.67 mmol) in DCM (3 ml) was added diethylamine (1.5 ml). The reaction was stirred at room temperature for 1 hour. DCM and diethylamine was removed using rotary evaporation. DCM (5 ml) and triacetoxyborohydride sodium (0.2 g, 0.94 mmol) was added and the reaction was stirred overnight at room temperature. The organic phase is washed with saturated sodium bicarbonate solution (25 ml), dried (MgSO4) and DCM was removed to obtain the crude cyklinowanie product 52 (0.4 g).

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

To cyklinowanie product 52 (0.4 g) in methanol (5 ml) was added catalytic Pd/C. the Reaction was stirred under a hydrogen atmosphere all n�never changes. The reaction mixture was filtered through Celite, and the methanol was removed using rotary evaporation to obtain 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-naftalina

To Aminu 53 (0.030 g, 0.08 mmol) in DCM (1 ml) was added DIPEA (0.1 ml, 0.7 mmol), THIEF reagent (0.03 g, 0.07 mmol) and 2-natoinal acid (0.025 g, 0.14 mmol). The reaction was stirred at room temperature for 2 hours. Added TFA (1 ml) and the reaction was stirred at room temperature for 2 hours. Rotary evaporation and preparative HPLC was obtained the compound 54 (23 mg, 68%). MS (ESI) 425,7 (M+1); HPLC tR5,27.

Example 54 - Synthesis of compound 55 (3S,5S)-3-[2-(piperidine-1-yl)ethyl]-5-(benzyloxycarbonylamino)-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), and then the solution was stirred at room temperature for 1 hour. Added DCM (20 ml) and the solution washed with saturated sodium bicarbonate solution (20 ml), dried over MgSO4and was evaporated to obtain the crude amine (0.16 g). To this was added DMF (0.25 ml), potassium carbonate (10 mg) and 1,5-dibromethane (0.35 ml, 2.5 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, then was added DCM (20 ml), organic layer� washed with saturated sodium bicarbonate solution (20 ml) and H 2O (20 ml), dried (MgSO4) and was evaporated to obtain the crude 55, which was used in subsequent reactions without purification.

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

To cyklinowanie 55 product (0.4 g) in methanol (5 ml) was added catalytic Pd/C. the Reaction was stirred under hydrogen atmosphere overnight. The reaction mixture was filtered through Celite and the methanol was removed using rotary evaporation to obtain the amine 56 (0.12 g).

Example 56 - Synthesis of BOC-L-Clu(piperidine) 57 (S)-2-(tert-butoxycarbonylamino)-5-oxo-5-(piperidine-1-yl)pentane 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 minutes, then added piperidine (0.7 ml) and the reaction was stirred overnight at room temperature. The reaction was washed with sodium bicarbonate solution (2×), saturated NH4Cl (2×), brine (2×), dried over MgSO4, filtered and evaporated to obtain 2.9 g of BOC-L-Clu(piperidine)-OBn. Benzyl ester (0.6 g) was dissolved in EtOH (15 ml) with catalytic Pd/C and hydrogenosomal for 1 hour, filtered through Celite and evaporated EUN using rotary evaporation to obtain 0,51 g 57.

Example 57 - Synthesis of compound 58 (3S,5S)-3-(2-tert-butoxide�bonemineral)-5-[benzyloxycarbonyl(methylamino)methyl]-1-(2,2 diphenylether)-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-butoxycarbonylamino)-5-(methylamino)methyl-1-(2,2-diphenylether)of 1.4, diazepan-2-one

Cyklinowanie product 58 (1.9 g) was dissolved in methanol (10 ml) with catalytic Pd/C and hydrogenosomal under a hydrogen atmosphere (40 psi) overnight. The reaction mixture was filtered through Celite and the methanol was removed using rotary evaporation to obtain the amine 59 (1,86 g, 97%).

Example 59 - Synthesis of compound 60 N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-6-bromo-N-methyl-2-naftalina

Amine 59 was combined with 6-bromo-2-natoinal acid, then removed the protective group with TFA according to Example 31. Rotary evaporation and preparative HPLC gave 60 (7.8 mg). MS (ESI) 629,4 (M+1); HPLC tR6,27 minutes.

Example 60 Synthesis of compound 61 (3S,5S)-3-(tert-butoxycarbonylamino)-5-(6-ROM-2-naftopidil)-1-(2,2-diphenylether)-1,4-diazepan-2-one

Prepared from 2,2-diphenylethylamine, Fmoc-L-Orn(Boc) and 6-bromo-2-natoinal acid according to the procedures of Examples 28 to 31, no stage remove TFA protective group of Example 31.

Example 61 - Synthesis of compound 62 N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-4-�ethyl-2-oxo-1,4-diazepan-5-yl)methyl)-6-bromo-2-naftalina

Compound 61 (20,8 mg) was dissolved in DMF (1 ml) and treated with methyl iodide (6 μl) at room temperature for 1 week. Added additional methyl iodide (0.5 ml) and K2CO3and the reaction left at room temperature for another 2 days. Added TFA (2 ml) and the reaction was stirred at room temperature for 2 hours. Rotary evaporation followed by evaporation under high vacuum and then preparative HPLC gave 62 (8.5 mg). MS (ESI) 629,3 (M+1); HPLC tR6,22 minutes.

Example 62 - Synthesis of compound 63 N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naftalina

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 obtain the free amine. MS(ESI) 535 (M+1); HPLC tR5.78 minutes.

Example 63 - Synthesis of compound 64 N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naftalina

Amine 63 (0,79 g, 1,48 mmol), 1,5-dibromethane (0.2 ml, 1,48 mmol) and K2CO3(0,79 g) in DMF (11 ml) was stirred at room temperature for 4 hours. The resulting mixture was diluted with ethyl acetate (30 ml), washed with H2About (5×30 ml), brine (10 ml) and dried over MgSO4. Purification by preparative CE�X was 64 (0,23 g, 25%) MS(ESI) 603,3 (M+1); HPLC tR6.04 minutes.

Example 64 - Synthesis of compound 65 N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-(isopropylamino)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naftalina

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 triacetoxyborohydride sodium (8.5 mg, 0,04 mmol) at room temperature. Stirring was continued for 2 hours, the mixture was concentrated, re-dissolved in EtOAc (5 ml), washed saturated aqueous solution of NaHCO3(10 ml) and brine (10 ml), dried over MgSO4and concentrated under reduced pressure. Purification by preparative HPLC received 65 (9.5 mg, 80%). MS (ESI) 577,2 (M+1); HPLC tR5.97 minutes.

Example 65 - Synthesis of compound 66 tert-butyl (methylamino)(methylthio)methyltyramine

DIAD (diisopropyl azodicarboxylate) (2.7 ml, of 13.8 mmol) was added to a stirred mixture of topleveldomain (2.0 g, 6.9 mmol), RBS (3.6 g, of 13.8 mmol) and MeOH (0.55 ml, of 13.8 mmol) in dry THF (5 ml) at 0°C under nitrogen. Stirring was continued at 0°C for 3 hours, then at room temperature for 16 hours. The solvent was removed under reduced pressure and the resulting residue re-dissolved in EtOAc, washed with saturated aqueous solution of NaHCO3(20 ml) and brine (20 ml) and dried� over MgSO 4. Purification by silica gel chromatography using 20% EtOAc in petroleum ether as eluent received 66 (1.63 g, 78%) in the form of a colorless oil. MS (ESI) 305 (M+1); HPLC tR7.97 minutes.

Example 66 - Synthesis of compound 67 N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-(3-methylguanine)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naftalina

A mixture of compound 63 (10 mg, is 0.019 mmol), guanylurea substances 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 hours. Added TFA (5 ml) and the resulting mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and crude product purified by preparative HPLC to obtain 67 (0,53 mg, 4.7%) in the form of a white solid. MS (ESI) 591,3 (M+1); HPLC tR5,94 minutes.

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

To a stirred mixture of Fmoc-L-Orn(Cbz)-OH (1.78 g, 3.65 mmol), DIPEA (of 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 was continued for 3 hours, the reaction mixture was washed with a saturated aqueous solution of NaHCO3(20 ml) and brine (20 ml) and dried� over MgSO 4. The solvent was removed under reduced pressure, then the crude 68 was used for subsequent step without further purification. MS (ESI) 853 (M+1); HPLC tR9,90 minutes.

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

A mixture of 68 (136 mg, 0,159 mmol) and Pd/C (20 mg) in ethanol (5 ml) was stirred under N2at 30 psi for 16 hours, then filtered, concentrated under reduced pressure to obtain the crude amine (90 mg, 78%). Amine (90 mg, 0.125 mmol) was treated with excess of a solution of formaldehyde in H2O (37 mmol) in MeOH (5 ml) followed by triacetoxyborohydride sodium (23,5 mg, the 0.375 mmol). After 1 hour the reaction mixture was washed with a saturated aqueous solution of NaHCO3(10 ml) and brine (10 ml), dried over MgSO4, filtered and concentrated. The crude material was used in the next stage without additional purification. MS (ESI) 745 (M+1); HPLC; HPLC tR7,83 minutes.

Example 69 - Synthesis of compound 70 (S)-(9H-fluoren-9-yl)methyl 7-((4-(2-naptime)-3-oxobutyl)(2,2-diphenylether)-carbamoyl)-3-methyl-1,3-diazepan-1-carboxylate

Compound 69 (8 mg, is 0.011 mmol) was treated with a mixture of 1:1 volume/volume of trifluoroacetic acid/DCM (2 ml) for 0 min at room temperature. The mixture was concentrated under reduced pressure, re-dissolved in DCM (5 ml), washed saturated aqueous solution of NaHCO3(5 ml) and brine (5 ml), dried over MgSO4and filtered. The filtrate is then treated with a mixture of 2-natoinal acid (1,8 mg, 0,011 mmol), DIPEA (5,7 µl, 0,033 mmol) and the THIEF (4,8 mg, 0,011 mmol) in DCM (1 ml) with stirring at room temperature. After 3 hours the reaction mixture was washed with a saturated aqueous solution of NaHCO3(10 ml) and brine (10 ml), dried over MgSO4, filtered and concentrated. The crude material was used in the next stage without additional purification. MS (ESI) 799 (M+1); HPLC tR7,90 minutes.

Example 70 Synthesis of compound 71 N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-(methylamino)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naftalina

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 hour, then concentrated under reduced pressure. The residue was re-dissolved in DCM (5 ml), then added triacetoxyborohydride sodium (5 mg, 0,08 mmol) at room temperature. The stirring was continued for 1 hour, the resulting mixture was washed with a saturated aqueous solution of NaHCO3(10 ml) and brine (10 ml), dried over MgSO4, filtered � concentrated. Purification by preparative HPLC was 71 (0.21 mg) in the form of a white solid. MS (ESI) 549,3 (M+1); HPLC tR5.93 minutes.

Example 71 Synthesis of compound 72 (S)-2-(allyloxycarbonyl)-3-(naphthalene-2-yl)propane acid

To a stirred mixture of L-3-(2-naphthyl)allingitalia (5.0 g of 19.8 mmol), Na2CO3(7.3 g, or 69.3 mmol) and 1,4-dioxane (30 ml) in H2O (50 ml) was added allylcarbamate, (2,1 ml of 19.8 mmol) at 0°C. the Resulting mixture was stirred for 16 hours, then concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 ml) and at 0°C was acidified with to pH 2. The aqueous phase was extracted with ethyl acetate (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 obtain 72 in the form of a colorless oil (5.8 g, 97%) which was used for next step without further purification. HPLC (6.60 minutes.

Example 72 Synthesis of compound 73 (S)-allyl 1-(methoxy(methyl)amino)-3-(naphthalene-2-yl)-1-oxoprop-2-ylcarbamate

To a stirred mixture of acid 72 (5,84 g, a 19.5 mmol), DIPEA (3.7 ml, of 2.09 mmol) and the THIEF (8,63 g, a 19.5 mmol) in DCM (10 ml) was added a pre-mixed solution of N,O-dimethylhydroxylamine (1.9 g, 19.5 mmol) and DIPEA (7.3 ml, 41.6 mm�l) in DCM (10 ml) at room temperature. Stirring was continued for 16 hours, the reaction mixture was washed with 1N HCl (3×60 ml), H2O (3×60 ml), a saturated aqueous solution of NaHCO3(3×60 ml) and brine (60 ml), dried over MgSO4. Purification by silica gel chromatography using 20% ethyl acetate in petroleum ether as eluent got 73 (4,83 g, 71%) in the form of a colorless oil. MS (ESI) 343 (M+1); HPLC tR7.07 minutes.

Example 73 Synthesis of compound 74 (S)-allyl 1-(naphthalene-2-yl)-3-oxopent-4-EN-2-ylcarbamate

At 0°C a solution of vinylmania in THF (11.5 ml, 1 M) was added in one portion to Amida Weinreb 73 (1.58 g, 4,62 mmol) under nitrogen with stirring. The resulting mixture was allowed to stir for 2 hours and poured into a mixture of 1N HCl/ice (50 ml). The aqueous mixture was extracted with DCM (3×20 ml), the combined DCM extract was washed with-1N HCl (50 ml), a saturated aqueous solution of NaHCO3(50 ml) and brine (20 ml), dried over MgSO4. The solvent was removed under reduced pressure, obtaining the product 74 (1.14 g, 80%) which was used for next step without further purification. MS (ESI) 310 (M+1); HPLC tR7.51 minutes.

Example 74 Synthesis of compound 75 (S)-allyl 5-(2,2-diphenylethylamine)-1-(naphthalene-2-yl)-3-oxopent-2-ylcarbamate

To a stirred solution of 2,2-diphenylethylamine (0.45 g, 2.3 mmol) in DCM (55 ml added vinylmation 74 (0.71 g, 2,3 mmol) in one portion. Stirring was continued for 2 hours, then the reaction mixture was used for subsequent step without purification. MS (ESI) 507 (M+1); HPLC tR7,22 minutes.

Example 75 Synthesis of compound 76 (S)-allyl 5-(N-(BOC-1-Arg(Cbz)2) 2,2-diphenylethylamine)-1-(naphthalene-2-yl)-3-oxopent-2-ylcarbamate

To a stirred solution of the amine adduct 75 (2,3 mmol) was added to a mixture of BOC-Arg(Cbz)2-OH (1.25 g, 2.3 mmol), DIPEA (0.8 ml, 4.6 mmol) and HATU (of 0.87 g, 2.3 mmol) in DCM (15 ml) at room temperature. Stirring was continued for 16 hours after which the reaction mixture was washed with a saturated aqueous solution of NaHCO3(3×20 ml) and brine (10 ml), then dried over MgSO4. Purification by silica gel chromatography using 20% ethyl acetate in petroleum ether as eluent got 76 in the form of a colorless oil (708 mg, 30% over 3 steps). MS (ESI) 1031 (M+1); HPLC tR10,80 minutes.

Example 76 Synthesis of compound 77 allyl (S)-1-((3S,5RS)-1-(2,2-diphenylether)-3-(bis Cbz 3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalene-2-yl)ethylcarbamate

To a stirred solution of the acyclic intermediate product 76 (0,48 g, 0.47 mmol) in DCM (5 ml) was added TFA (5 ml) at room temperature. Stirring was continued for 30 min, after which the mixture was diluted with DCM (20 ml), then �romali a saturated aqueous solution of NaHCO 3(3×20 ml) and brine (10 ml) and dried over MgSO4. To the resulting solution was added triacetoxyborohydride sodium (0.2 g, 0.94 mmol) with stirring at room temperature, after 30 min the mixture was washed with a saturated aqueous solution of NaHCO3(3×20 ml) and brine (10 ml), then dried over MgSO4. Untreated 77, a mixture of diastereomers in diazepan-2-one C5, was used in the next stage without additional purification. MS (ESI) 915 (M+1)

Example 77 Synthesis of compound 78 bis (Cbz) 1-(3-((2S,7RS)-7-((S)-1-amino-2-(naphthalene-2-yl)ethyl)-4-(2,2-diphenylether)-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 hours. The resulting mixture was used for 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-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalene-2-yl)ethyl)acetamide and N-((S)-1-((3S,5R)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalene"2-yl)ethyl)acetamide

A solution of amine 78 (0,09 mmol) in DCM (5 ml) was treated with acetic anhydride (or 8.6 μl, 0.09 mmol) with stirring at room tempera�ur. After 3 hours the mixture was concentrated, re - dissolved in EtOAc, washed with saturated aqueous solution of NaHCO3(10 ml) and brine (10 ml), dried over MgSO4and then concentrated under reduced pressure. The residue was dissolved in MeOH (10 ml), added Pd/C (5 mg) and the solution was stirred under N2at 20 psi for 16 hours. The reaction was filtered, concentrated and purified by preparative HPLC to obtain the preferred diastereoisomer 79 (3 mg) and the less preferred diastereoisomer 80 (6 mg) in the form of white solids. 79: MS (ESI) 606,4 (M+1); HPLC tRUAH 6,033 minutes 80: MS (ESI) 606,3 in C (M+1); HPLC tR6,046 minutes

Example 79 Synthesis of compounds 81 and 82 (S)-2-acetamido-N-((S)-1-((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalene-2-yl)ethyl)-3-(1H-imidazol-5-yl)propanamide and (S)-2-acetamido-N-((S)-1-((3S,5R)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalene-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 the THIEF (68,8 mg, 0,156 mmol) in DMF (1 ml) was added amine 78 (0,039 mmol) at room temperature. The stirring was continued for 16 hours, then the reaction mixture was diluted with a mixture of DCM/H2O (10 ml, 1:1 volume/volume), and the aqueous phase was extracted with DCM (3×5 ml). United DC extracts were washed with a saturated aqueous solution of NaHCO 3(3×20 ml) and brine (10 ml), dried over MgSO4and concentrated under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and added Pd/C (20 mg). The resulting mixture was stirred under H2at 30 psi for 16 hours, then filtered, concentrated and purified by preparative HPLC to obtain the preferred diastereoisomer 81 (1.9 mg) and the less preferred diastereoisomer 82 (0.9 mg) in the form of white solids.

81: MS (ESI) 743,4 (M+1); HPLC tR5,489 minutes

82: MS (ESI) 743,4 (M+1); HPLC tR5,555 minutes

Example 80 Synthesis of compounds 83 and 84 propyl (S)-1-((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalene-2-yl)ethylcarbamate and propyl (S)-1-((3S,5R)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalene-2-yl)ethylcarbamate

A mixture of 77 (36 mg, 0,039 mmol) and Pd/C (5 mg) in MeOH (5 ml) was stirred under N2at 20 psi for 16 hours, then filtered, concentrated and purified by preparative HPLC to obtain the preferred diastereoisomer 83 (0.07 mg) and the less preferred diastereoisomer 84 (2.7 mg) in the form of white solids.

83: MS (ESI) 650,3 (M+1); HPLC tR6,52 minutes

84: MS (ESI) 650,2 (M+1); HPLC tR6,64 minutes

Example 81 Synthesis of compounds 85-87 1-(3-((2S,7S)-7-(N-R1 (R)-1-amino-2-(�Talin-2-yl)ethyl)-4-(2,2-diphenylether)-3-oxo-1,4-diazepan-2-yl)propyl)guanidine

Compounds 85-87 were prepared in the same manner as the preferred diastereomers of compounds 79, 81 and 83 by means of techniques described in the Examples 72-81 D-(2-naphthyl)lininginterior as source material.

ConnectionR1groupMS (M+1)tR(min)
85Ac606,26,01
86Ac-His743,55,41
87Propylenecarbonate650,4Is 6.42

Examples 82-90: Synthesis via scheme 2: Preparation of all four diastereomers of N-((1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naftalina 88

Example 82 Synthesis of compound 89 2,2-dimethyl-10-(2,2-diphenylether)-4,7,11-trioxo-3,12-dioxa-5,10-disapinted-14-Jena

2,2-diphenylethylamine (3 g) was added to BOC-venicethe 16 (2.8 g) as in Example 17. To uncleaned adduct 17 was added Alloc-Cl (1.6 ml) and the reaction re�estivale as long until TLC (thin layer chromatography) showed the consumption of the secondary amine. The solvent was evaporated and the residue was purified by column chromatography (SiO2gel, pet. ether/EtOAc) to obtain 3.2 g (57%) 89.

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

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) was dissolved in benzene (200 ml) and heated to reflux under conditions of a Dean stark for 5 hours. Most of the solvent is then drove away, the rest were removed under vacuum. The resulting solid was precrystallization from DCM, filtered and dried to obtain 11,19 g (94%) of salt tosylate. To obtain the free amine solid was dissolved in DCM, washed vivid. NaHCO3, the aqueous layer was 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)-Ollila

H-D-Orn(Cbz)-OH (6,66 g, 25 mmol) was turned into 10,93 g (91%) of salt tosylate 91, as in Example 83, then turned into a free amine.

Example 85 Synthesis of compound 92 (2R)-allyl 5-(benzyloxycarbonylamino)-2-(10-(2,2-diphenylether)-2,2-dimethyl-4,11-diokso-3,12-dioxa-5,10-disapinted-14-ene-7-ylamino)PE�of tenuate

Zaseyany aminoketone 89 (746 mg, 1.6 mmol), D-Orn(Cbz)-Ollil 91 (538 mg, of 1.76 mmol) and NaBH(SLA)3(678 mg, 3.2 mmol) in a minimal volume of DCM was stirred for 24 hours. Added a drop of Acoh immediately before working out, this level was added saturated NaHCO3, extracted with DCM (3×) and the organic extracts were combined and washed with saturated NaHCO3and H2O, dried over MgSO4and evaporated to dryness. The product was purified by column chromatography (SiO2gel, pet. ether/EtOAc) to obtain 890 mg (74%) of 92 as a mixture of diastereomers.

Example 86 Synthesis of compound 93 (28)-allyl 5-(benzyloxycarbonylamino)-2-(10-(2,2-diphenylether)-2,2-dimethyl-4,11-diokso-3,12-dioxa-5,10-disapinted-14-ene-7-ylamino)pentanoate

L-Orn(Cbz)-Ollil 90 (592 mg, of 1.93 mmol) was turned into a mixture of various 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-diphenylether)-1,4-diazepan-2-one and (3R,5R)-5-(N-Boc aminomethyl)-3-(N-Cbz 3-aminopropyl)-1-(2,2-diphenylether)-1,4-diazepan-2-one

Alloc/allyl-protected derivative 92 (840 mg, 1,11 mmol) was dissolved in minimum amount of DCM. Added 1,3-dimethylbarbituric acid (346 mg, 2.22 mmol) and kata�political RA(RRPs)4, and the reaction degassed under vacuum, sealed and stirred overnight. The reaction was diluted to 50 ml DCM was added DIPEA (430 mg of 3.33 mmol) and the THIEF (540 mg, 1,22 mmol) and the reaction was stirred for 30 minutes. DCM was removed under vacuum and the residue absorbed in EtOAc, washed (saturated NaHCOa, HsO, saturated NaCl), dried (MgSO4) and evaporated to dryness (TLC: EtOAc, 2 spots, Rf of 0.33 and 0.57). Two diastereomeric product was separated by column chromatography (SiO2gel, pet. ether/EtOAc) to obtain 362 mg earlier-eluted (3R,5S) isomer 94, and 342 mg later-eluted (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-diphenylether)-1,4-diazepan-2-one and (3S,5S)-5-(N-Boc aminomethyl)-3-(N-Cbz 3-aminopropyl)-1-(2,2-diphenylether)-1,4-diazepan-2-one

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

Example 89 Synthesis of compounds 98-101 5-(N-Boc aminomethyl)-3-(N,N'-Cbz 3-guanidinopropionic)-1-(2,2-diphenylether)-1,4-diazepan-2-one

Orn Cbz group 94 was removed by hydrogenation (H2, 30 psi) over catalytic Pd/C in methanol overnight. The solution was filtered through Celite and was evaporated to obtain a solid substance. A solution of the resulting amine (187 mg, 0,39 mmol) in DCM was mixed with p�the target guanylurea reagent CbzNHC(=NCbz)NHTf (196 mg, 0,43 mmol) in DCM. Added TEA (43 mg, 0.43 mmol) and the reaction was stirred overnight. The solution was diluted with DCM, washed (KHSO4, rich. NaHCO3, brine), dried (MgSO4) and was evaporated to dryness, then purified using flash chromatography on SiO2using hexane/EtOAc as eluent to obtain (3R,5S) 98 (182 mg, 59%). Other isomers 95-97 turned in a similar manner to obtain:

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

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

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

Example 90 Synthesis of compounds 102-105

102 N-(((3R,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

103 N-(((3R,5R)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

104 N-(((3S,5R)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

105 N-(((3S,5S)-1 -(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

The first derivative 99 (180 mg) in DCM (1 ml) was treated with TFA (1 ml) in 20 ml. of Solvent was removed by evaporation, was added a solution of NaHCO3and was extracted with 3× DCM. The dichloromethane solution was dried over MgSO4, filtered and evaporated to dryness. Portion (56 mg, 0,086 mmol) of crude amine with removed protective groups in DCM PE�amichevoli 2 natoinal acid (16 mg), DIPEA (60 μl) and a THIEF (42 mg) for 30 min. was Added MeOH and the reaction was stirred overnight. The reaction was filtered, then purified using flash chromatography on SiO2using petroleum ether/EtOAc as eluent to obtain (3R,5R) isomer (43 mg, 94%). Other isomers were transformed in a similar way to obtain: (3R,5S): 41 mg (85%) of 60 mg 98, (3S,5R): 27 mg (70%) of 40 mg 101, and (3S,5S): 13 mg (74%) of 20 mg 100.

Each compound was dissolved in dioxane:MeOH and gidrirovanie over catalytic Pd/C at 30 psi H2 overnight. The solution was filtered through Celite and was evaporated to obtain a solid substance. 102 (3R,5S): 27 mg (96%) of 41 mg, 103 (3R,5R): 25 mg (85%) of 43 mg, 104 (3S,5R): 11 mg (quantitative) of 13 and 105 mg (3S,5S): 3 mg (73%) of 6 mg.

ConnectionstereochemistryMS (M+1)tR(min)
102(3R,5S)577,45,775
103(3R,5R)577,55,750
104(3S,5R)577,55,783
105(3S,5S)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-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

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

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

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

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

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

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

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

Connection 425, 565 and 580-585 prepared by following similar methods as used to prepare compounds 102-104 (scheme 2). Moreover, compound 425, 565, 580 and 585 was prepared according to the route of scheme 1; detailed methods� for the preparation of compound 425 contained in the Examples 92-99.

ConnectionstereochemistryMS (M+1)tR(min)
425(3S,5S,2'S)575,36,269
565(3S,5S,2'S)574,86,265
580(3R,5R,2'S)575,46,404
581(3S,5R,2'S)575,26,262
582(3R,5S,2'S)575,26,110
583(3S,5R,2'S)575,16,211
584(3R,5S,2'S)575,26,253
585(3R,5R,2'S)575,46,274

Example 92 Synthesis of compounds 586 (S)-N-(2-oxo-4-(2-phenylethylamine)butyl)-3-phenylpropanamide

To a solution of (S)-phenylethylamine (8.5 g, 57,07 mmol) in DCM (100 ml) was added a solution of α,β-unsaturated ketone 27 (12.5 g, of 57.1 mmol) in DCM (100 ml) at room temperature for one portion. The resulting mixture was stirred until then, until all of the α,β-unsaturated ketones has not used up (within one hour), then the conjugate adduct accession 586 was used directly in subsequent reactions.

HPLC tR5.71 minutes

MS (ESI) 369,3 (M+1)

Example 93 Synthesis of compounds 587 (S)-9-fluorenylmethyl 10-[(S)-2-phenylbutyl]-2,2-dimethyl-18-phenyl-4,9,13,1 6 tetraoxo-3,17-dioxa-5,10,15-trasaction-8-ylcarbamate

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

TLC rf of 0.23 (50% EtOAc/white spirit)

HPLC tR10,03 minutes

MS (ESI) 791,2 (M+1)

Example 94 - Synthesis of compound 588 (S)-10-[(S)-2-phenylbutyl]-2,2-dimethyl-8-amino-18-phenyl-4,9,13,16-t�trioxo-3,17-dioxa-5,10,15-trasaction

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 minutes. The solvent and diethylamine was removed under reduced pressure to obtain the target product 588. It was used in the next stage without additional purification.

HPLC tR6.85 per minute

MS (ESI) 569,3 (M+1)

Example 95 Synthesis of compounds 589 (3S,5S)-3-(2-tert-butoxycarbonylamino)-5-(benzyloxycarbonylamino)-1-[(5)-2-phenylbutyl]-1,4-diazepan-2-one

To a solution of crude Fmoc material with removed protective groups 588 in DCM (50 ml) was added Acoh (15 ml) then NaBH(SLA)3(Of 5.34 g of 25.2 mmol) in one portion at room temperature. The resulting mixture was stirred for 30 minutes, then washed with saturated solution of NaHCO3(water.) (80 ml × 3), brine (80 ml) and dried over MgSO4. Filtering and concentrating the organic phase under reduced pressure was obtained the crude product, which was purified using silica-gel column chromatography using 50-100% EtOAc/white spirit, then 20% MeCN/EtOAc to obtain the product 589 (12.3 g, 88% over two steps).

TLC rf of 0.19 (70% EtOAc/white spirit)

HPLC tR7,06 minutes

MS (ESI) 553,3 (M+1)

Example 96 - Synthesis of compound 590 tert-butyl 2-{(2S,7S)--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 stirred at room temperature under hydrogen at atmospheric pressure for one hour. The mixture was then filtered through a pad of celite may® and the filtrate concentrated under reduced pressure to obtain the crude amine 590. The crude material was used in the next stage without additional purification. HPLC tR5,77 minutes, MS (ESI) 419,3 (M+1)

Example 97 Synthesis of compounds 591 tert-butyl 2-((2S,7S)-7-((6-chloro-2-naptime)methyl)T3-oxo-4-((S)-2-phenylbutyl)-1,4-diazepan-2-yl)ethylcarbamate

To a solution of the free amine 590 and 6-chloro-2-natoinal acid (4,58 g of 22.3 mmol) in DCM (125 ml) was added diisopropylethylamine (7,74 ml of 44.5 mmol) and the THIEF (9,84 g of 22.3 mmol) at room temperature. The resulting mixture was stirred for 16 hours, then DCM was removed under reduced pressure. The residue is absorbed in EtOAc (80 ml), then washed with saturated NaHCO3(water.) (100 ml × 5), brine (100 ml) and dried over MgSO4. Filtration and concentration of organic phase was obtained the crude material which was purified using silica-gel column chromatography using 80-100% EtOAc/white spirit as eluent to obtain the product 591 (10.7 g, 79%).

TLC rf 0,31 (80% EtOAc/white spirit)

HPLC tR 7,66 minutes

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-naftalina

To the New protected material 591 (10.7 g, a 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 absorbed in EtOAc (30 ml), washed with saturated NaHCO3(water.) (30 ml × 3), brine (30 ml) and dried over MgSO4. Filtering and concentrating the organic phase under reduced pressure was obtained the crude amine 465, which was used for next step without further purification.

HPLC tR5,98 minutes

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-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naftalina

To a mixture of crude amine 465 in CH3CN (800 ml) was added 1,5-dibromethane (23,9 ml 175,7 mmol), then K2CO3(48,6 g, 351,4 mmol). The resulting mixture was stirred at room temperature for 44 hours, was observed using HPLC for conversion of sm (6,0 min) in the product (6,4 min), avoiding extended reaction times, leading to parallelomania for education braintraining byproduct (7,1 min). In �burden allocation, avoid excessive heat/concentration of the crude solution prior to removal of excess dibromopropane avoid parallelomania piperidino ring. K2CO3removed by filtration through a pad celite may® and the filtrate was washed with white spirit (800 ml × 2). Phase MeCN concentrated under reduced pressure to 400 ml and washed with white spirit (400 ml × 2). MeCN has additionally concentrated under reduced pressure to 200 ml and washed with white spirit (200 ml × 2). Evaporation of the final rinse white spirit showed was extracted with 1.5-dibromethane, so that the phase of MeCN was concentrated under reduced pressure.

Aminopropyl-functionalized TLC rf 0.05 to 0.47 inch (80% EtOAc/white spirit)

Analytical HPLC tR6,41 minutes

MS (ESI) 575,2 (M+1).

The crude product is purified using a combination of flash column chromatography using aminopropyl-functionalized silica gel and/or recrystallization from acetonitrile.

Flash column: In the column, filled aminopropyltriethoxysilane silica gel (154 g) in 20% ethyl acetate/white spirit, loaded crude free base oil (7.2 g). The column was suirable 20% ethyl acetate/white spirit (150 ml) followed by 50% ethyl acetate/white spirit (150 ml), 80% ethyl acetate/white spirit (150 ml × 2), 100% ethyl acetate (150 ml) and, in the end�th account 100% acetonitrile (150 ml). Fractions containing 425, were combined and evaporated to dryness to obtain a white crystalline solid.

Crystallization: a White crystalline solid (2,87 g) obtained by column purification, was dissolved in boiling acetonitrile (50 ml) of 85°C. Activated carbon (Darco® G-60, -100 mesh, Sigma-Aldrich) (200 mg) was added to remove colored impurities. Added additional portion of acetonitrile (50 ml) and the resulting mixture was heated to boiling for 5 minutes. The charcoal was filtered while the solution was hot, filter paper and charcoal soaked in hot acetonitrile (25 ml). A pure solution of acetonitrile was reduced to 50 ml and left to stand to cool to room temperature for 16 hours. The white crystals were filtered and dried by suction to obtain 2.22 g (99,0% purity by HPLC analysis). Additional 117,2 mg (93,3% purity) received an additional crystallization from the filtrate.

The transformation in Cl salt: the Free base (2,4229 g, 42.1 mmol) was suspended in 1:1 mixture of acetonitrile and milliQ H2O (10 ml). A solution of 1 M HCl in the water.) added until then, until you dissolve all solids (approximately 5 ml). An additional amount of milliQ H2O then added (20 ml) and the resulting solution was frozen and liofilizirovanny all night, getting b�white powder (2,61 g, 95.6% yield).

HPLC tR6,27 minutes

MS (ESI) 575,1 (M+1).

1H NMR (600 MHz, CDCl3): δ of 0.75 (t, 3H, J=7,2 Hz), of 1.40 (m, 1H), of 1.56 (m, 1H), 1,65 (m, 1H), 1,76-1,90 (m, 4H), 1,90-of 2.06 (m, 2H), 2,13 (m, 1H), 2,30 (br, 1H), of 2.57 (m, 1H), 2,64-2,86 (m, 4H), 2,90-3,10 (m, 2H), 3,25 (dd, 1H, J=15,2, of 10.4 Hz), 3,53 (m, 2H), 3,70-of 3.85 (m, 3H), of 4.00 (m, 2H), 4,10 (dd, 1H, J=13,6, 5,6 Hz), of 4.45 (m, 1H), 7,10 (d, 2 H, J=7,2 Hz), 7,18 (t, 1H, J=7,2 Hz), 7,26 (t, 1H, J=7,2 Hz), value of 7, 37 (dd, 1H, J=9,0, 1,8 Hz), 7,71 (d, 1H, J=8,4 Hz), of 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-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)[2H2]methyl)-2-naftalina

Compound 579 was synthesized according to the procedures in Examples 92-99, except that the steps of removing the Fmoc protective groups/the reductive amination of Examples 94 and 95 were replaced by the following techniques for the introduction of 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-trasaction-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 D2O (of 99.96 atom. % deuterium, 3.0 ml, 168 mmol). This mixture of paramashiva�and under nitrogen at room temperature for 16 hours with application of the reaction mixture in the next stage without isolation.

MS (ESI) 573,0 (M+1).

tR6.95 minutes.

To the crude reaction mixture of materialmen added NaBD3CN (152 mg, 2,31 mmol) in one portion, the reaction was stirred at room temperature for 24 hours. Added additional portion NaBD3CN (182,4 mg, or 3.28 mmol) and stirring was continued at room temperature for 24 hours. The reaction is rapidly cooled by addition of a saturated NaHCO3(water.) and water mixture, extracted EtOAc (3 × 10 ml × 3). The combined organic extracts were washed with brine (15 ml), dried over MgSO4and concentrated in vacuum. Flash chromatography (60% EtOAc/white spirit) gave the product (175,8 mg, 67%).

TLC Rf0,32 (70% EtOAc/white spirit)

Analytical HPLC tR7,06 min; MS (ESI) m/z 558,0 (M+1), 559,0, 557,0, 560,0.

Example 101 Synthesis of compounds 106-579.

Connection 106-579, with alternates, as identified in table 1, were obtained as in previous examples, according to the ways identified in schemes 1-5, as summarized in table 2, with the experimental properties are summarized in table 4.

Table 1:
The identity of connections
Vos. R1XR2R3YRW
142-naphtolNNCH2(CH2)3NHC(=NH)NH23.5-dichlorobenzyl
256-fluoro-2-naphtolNNCH2(CH2)2N(CH2CH3)22,2-diphenylether
316-fluoro-2-naphtolNNCH2(CH2)2NH22,2-diphenylether
334-chlorocinnamicNNCH2(CN2)2(1-piperidinyl)2,2-diffenret�l
372-naphtolNNCH2(CH2)2NH22-phenylbutyl
382-naphtolNNCH2(CH2)2(1-piperidinyl)(S)-2-phenylbutyl
392-naphtolNNCH2(CH2)2(1-piperidinyl)(R)-2-phenylbutyl
492-naphtolNNCH2(CH2)2NH23.5-dichlorobenzyl
502-naphthylmethylNNCH2(CHsub> 2)2NHC(=NH)NH22,2-diphenylether
542-naphtolNNCH2(CH2)2NH22-ethylbutyl
606-bromo-2-naphtolMeNCH2(CH2)3NH22,2-diphenylether
626-bromo-2-naphtolNMeCH2(CH2)3NH22,2-diphenylether
632-naphtolNNCH2(CH2)3NH22,2-diphenylether
642-naphtolNN CH2(CH2)3(1-piperidinyl)2,2-diphenylether
652-naphtolNNCH2(CH2)3NHCH(CH3)22,2-diphenylether
672-naphtolNNCH2(CH2)3NHC(=NH)NHMe2,2-diphenylether
712-naphtolNNCH2(CH2)3NHMe2,2-diphenylether
79acetylNN(S)-SNSN2-(2-naphthyl)(CH2)3NHC(=NH)NH22,2-diphenylether
81Ac-L-His NN(S)-SNSN2-(2-naphthyl)(CH2)3NHC(=NH)NH22,2-diphenylether
83propylenecarbonateNN(S)-SNSN2-(2-naphthyl)(CH2)3NHC(=NH)NH22,2-diphenylether
85acetylNN(R)-SNSN2-(2-naphthyl)(CH2)3NHC(=NH)NH22,2-diphenylether
86Ac-L-HisNN(R)-CHCH2-(2-naphthyl)(CH2)3NHC(=NH)NH22,2-diphenylether
87propylenecarbonateNN(R)-SNSN2-(2-naphthyl)(CH2 )3NHC(=NH)NH22,2-diphenylether
1052-naphtolNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1064-biphenylcarboxylicNNCH2(CH2)3NH22,2-diphenylether
107indole-2-carbonylNNCH2(CH2)3NH22,2-diphenylether
1084-biphenylcarboxylicHHCH2(CH2)3NHC(=NH)NH22,2-diphenylether

td align="center"> CH2
Vos.R1/sup> XR2R3YRW
109indole-2-carbonylHHCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1102-naphthylacetylHHCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1111,2,3,4-tetrahydro-2-naphtolHHCH2(CH2)3NHC(=NH)NH22,2-diphenylether
112the quinoline-3-carbonylHHCH2(CH2)3NHC(=NH)NH22,2-diphenylether
113hee�oksalin-2-carbonyl HHCH2(CH2)3NHC(=NH)NH22,2-diphenylether
114isoquinoline-3-carbonylHHCH2(CH2)3NHC(=NH)NH22,2-diphenylether
115benzoylHHCH2(CH2)3NHC(=NH)NH22,2-diphenylether
116ginaldiHHCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1172-naphtolHHCH2(CH2)4NH21-naphthylmethyl
118 HHCH2(CH2)4NH21-naphthylmethyl
1191-naphtolHHCH2(CH2)4NH21-naphthylmethyl
120indole-3-acetylHHCH2(CH2)4NH21-naphthylmethyl
1214-biphenylaceticHHCH2(CH2)4NH22-naphthylmethyl
1222-naphtolHHCH2(CH2)4NH22-naphthylmethyl
1232-naphthylacetyl HHCH2(CH2)4NH22-naphthylmethyl
1241-naphtolHHCH2(CH2)4NH22-naphthylmethyl
1251-naphthylacetylHHCH2(CH2)4NH22-naphthylmethyl
1262-naphtolHHCH2(CH2)4NH22,2-diphenylether
127S-TicHHCH2(CH2)4NH22,2-diphenylether
128R-TicHH(CH2)4NH22,2-diphenylether
1292-benzofuranylHHCH2(CH2)4NH22,2-diphenylether
130R-TicHHCH2(CH2)3NHC(=NH)NHMe2,2-diphenylether
131S-TicHHCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1322-benzofuranylHHCH2(CH2)3NHC(=NH)NH22,2-diphenylether
133indane-2-carbonylNNCH2 (CH2)3NHC(=NH)NH22,2-diphenylether
134R-TicNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
135benzothiophen-2-carbonylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1362,4-dichlorobenzoylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1372,5-dichlorobenzoylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
138benzoylNN CH2(CH2)3NHC(=NH)NH22,2-diphenylether
139cyclohexanolNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1403-phenoxybenzoylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1414-phenoxybenzoylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
142indole-2-carbonylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1433-phenyl-propanolN NCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1443,4-dimethylbenzoylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1454-tert-butylbenzoylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1462,4-dimethoxybenzoylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
147cyclohexylethylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
148piperonylic NNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
149benzimidazol-5-carbonylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
150the benzotriazole-5-carbonylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
151CyclopentanolNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether

3-methyl-2-phenyl-pyrazole-4-carbonyl
Vos.R1XR2R3YRW
152 3,4-dichlorobenzoylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
153TRANS-cinnamoylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1543.5-dichlorobenzoylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1552,4-dichloro-phenylacetylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1561-methoxy-2-naphtolNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1573,4-dichloro-phenylacetylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1586-methoxy-2-naphtolNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1592-naphtolHHCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1602,4-dichloro-cinnamoylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
161adamantane-1-carbonylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
162phenoxyacetylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1633-methoxy-2-naphtolNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1644-bromobenzoylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
165S-benzodioxan-2-carbonylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1664-chlorocinnamicNNCH2(CH2)3NHC(=NH)NH2 2,2-diphenylether
1673-(2-thienyl)acryloylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
168R-benzodioxan-2-carbonylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1694-hydroxycinnamicNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1702-methoxycinnamylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1714-methylcinnamicNNCH2 (CH2)3NHC(=NH)NH22,2-diphenylether
1722-trifluoromethyl-cinnamoylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1733-forcenavyNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
174alpha-methyl cinnamoylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
175TRANS-2-phenylcyclopropane-1-carbonylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1762,4-dichloro-PHENOXYACETIC NNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1773-chlorocinnamicNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1781,3-benzothiazol-6-carbonylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1795-phenyl-2-furoylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1803-methoxycinnamate lNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
181NNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1822-naphtolNNCH2(CH2)3NHC(=NH)NH2phenetyl
1832-naphtolNNCH2(CH2)3NHC(=NH)NH23,4-dichlorophenacyl
1842-naphtolNNCH2(CH2)3NHC(=NH)NH22,4-dichlorophenacyl
185benzothiophen-5-carbonylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
186NNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1874-methoxycinnamylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1886-fluoro-2-naphtolNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1892-chlorocinnamicNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1902-hydroxycinnamicNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether/td>

N
Vos.R1XR2R3YRW
1913-methylcinnamicNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1923-triftormetilfullerenovNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1933-hydroxycinnamicNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1942-forcenavyHHCH2(CH2)3NHC(=NH)NH2 2,2-diphenylether
1952-methylcinnamicHHCH2(CH2)3NHC(=NH)NH22,2-diphenylether
196alpha forcenavyNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
1972-naphtolNNCH24-piperidinyl2,2-diphenylether
1982-naphtolNNCH2CH2(4-piperidinyl)2,2-diphenylether
1994-forcenavyNNCH2(CH2)3NHC(=NH)NH2 2,2-diphenylether
2004-trifluoromethyl-cinnamoylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
2012-naphtolNNCH2(CH2)3NHC(=NH)NH22,2-diphenylpropyl
2022-naphtolNNCH2(CH2)3NHC(=NH)NH2cyclohexylmethyl
2032-naphtolNNCH2(CH2)3NHC(=NH)NH21-adamantane-methyl
2042-naphtolNNCH2(CH2)3NHC(=NH)NH2 (S)-1,1-diphenyl-2-propyl
2052-naphtolNNCH2(CH2)3NHC(=NH)NH2(R)-1,1-diphenyl-2-propyl
2062-naphtolNNCH2(CH2)3NHC(=NH)NH2cyclohexyl
2072-naphtolNNCH2(CH2)3NHC(=NH)NH2(R)-1,1-diphenyl-1-fluoro-2-propyl
2082,6-divertinglyNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
2092-chloro-6-forcenavyNNCH2 (CH2)3NHC(=NH)NH22,2-diphenylether
2104-bromocinnamicNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
2114-ethoxycinnamicNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
2126-brominatorNNCH2(CH2)3NH22,2-diphenylether
213TRANS-cinnamoylNNCH2(CH2)3NH22,2-diphenylether
2144-chlorocinnamicNNCH2 (CH2)3NH22,2-diphenylether
2151,4-dimethoxy-2-naphtolNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
2162-naphtolNNCH2(CH2)3NHC(=NH)N(Me)22,2-diphenylether
2176-hydroxy-2-naphtolNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
2186-amino-2-naphtolNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
2194-IU cinnamoylN NCH2(CH2)3NH22,2-diphenylether
2204-fluoro, cinnamoylNNCH2(CH2)3NH22,2-diphenylether
221b-fluoro-2-naphtolNNCH2(CH2)3NH22,2-diphenylether
2222-ethylhexanoylNNCH2(CH2)3NH22,2-diphenylether
2233,4-dimethylbenzoylNNCH2(CH2)3NH22,2-diphenylether
2243,4-dimethylbenzoylNCH2(CH2)3NH22,2-diphenylether
2252-ethylhexanoylNNCH2(CH2)3NHC(=NH)NH22,2-diphenylether
2262-naphtolNNCH2(CH2)3NH(cyclohexyl)2,2-diphenylether
2272-naphtolNNCH2(CH2)3NHC(=NH)NH22-naphthyl
2282-naphtolNNCH2(CH2)3NHC(=NH)NH2(9-fluorenyl)methyl
2292-naphtolN NCH2CH2(3-pyridinyl)2,2-diphenylether
2302-naftomarNNCH2CH2(4-pyridinyl)2,2-diphenylether
2314-forcenavyNNCH2(CH2)3NH(cyclohexyl)2,2-diphenylether

H
Vos.R1XR2R3YRW
2322-naphtolHHCH2(CH2)4NHCH(CH3)22,2-diphenylether
2332,4-divertinglyHCH2(CH2)3NH22,2-diphenylether
2344-cyanocinnamicHHCH2(CH2)3NH22,2-diphenylether
2353-(2-naphthyl)acryloylNNCH2(CH2)3NH22,2-diphenylether
2364-fluoro-PHENOXYACETICNNCH2(CH2)3NH22,2-diphenylether
2375-(4-chlorophenyl)-2-furoylNNCH2(CH2)3NH22,2-diphenylether
2384-(pyrrol-1-yl)-benzoylNCH2(CH2)3NH22,2-diphenylether
2392-oxo-1-phenyl-pyrrolidin-3-carbonylNNCH2(CH2)3NH22,2-diphenylether
2405-(4-chlorophenyl)-isoxazol-3-carbonylNNCH2(CH2)3NH22,2-diphenylether
2415-(2-furyl)-isoxazol-3-carbonylNNCH2(CH2)3NH22,2-diphenylether
2422-phenyl-4-diazocarbonylNNCH2(CH2)3NH22,2-diphenylether
2434-(3,5-dimethyl-1H-pyrazol-1-yl)benzoylNNCH2(CH2)3NH22,2-diphenylether
2443-methyl-2-phenyl-pyrazole-4-carbonylNNCH2(CH2)3NH22,2-diphenylether
2452-naphtolNNCH2(CH2)3NHC(=NH)NH2cyclohexanediol
2462-naphtolNNCH2(CH2)3NHC(=NH)NH22-norbornanyl
2472-naphtolNNCH2(CH2)3NHC(=NH)NH2 2,2-bis(4-methoxyphenyl)ethyl
2482-naphtolNNCH2(CH2)4NHCH2Ph2,2-diphenylether
2492-naphtolNNCH2(CH2)4NH(cyclopentyl)2,2-diphenylether
2502-naphtolNNCH2(CH2)4NH(cyclobutyl)2,2-diphenylether
2512-naphtolNNCH2(CH2)4N(cyclobutyl)22,2-diphenylether
2522-naphtolNNCH2(CH2)3NHC(=NH)NH2 benzyl
2532-naphtolNNCH2(CH2)3NHC(=NH)NH22,2-bis(4-fluorophenyl)ethyl
2542-naphtolNNCH2(CH2)3NHC(=NH)NH22-naphthalenethiol
2553-(5-methyl-2-thienyl)-acryloylNNCH2(CH2)3NH22,2-diphenylether
2565-phenyl-pyrazole-3-carbonylNNCH2(CH2)3NH22,2-diphenylether
2574-forcenavyMeNCH2 (CH2)3NH22,2-diphenylether
2584-forcenavyNMeCH2(CH2)3NH22,2-diphenylether
2594-(3-methyl-5-oxo-2-pyrazolin-1-yl)benzoylNNCH2(CH2)3NH22,2-diphenylether
2604-bromocinnamicNNCH2(CH2)3NH22,2-diphenylether
2614-chlorocinnamicNNCH2(CH2)3(1-pyrrolidinyl)2,2-diphenylether
2624-chlorocinnamicNN(CH2)3(1-piperidinyl)2,2-diphenylether
2632-naphtolNNCH2CH2CH2NH22,2-diphenylether
2642-naphtolNNCH2(CH2)3(1-pyrrolidinyl)2,2-diphenylether
2652-naphtolNNCH2(CH2)2(1-azetidine)2,2-diphenylether
2662-naphtolNNCH2(CH2)3NHC(=NH)NH21-naphthalenethiol
2672-naphtolNN CH2(CH2)3NHC(=NH)NH22-(2-naphthyl)ethyl
2682-naphtolNNCH2(CH2)3NHC(=NH)NH2(S)-CH2CH(Ph)NHCOMe

N
SdnR1XR2R3YRW
269TRANS-cinnamoylNNCH2(CH2)3(1-piperidinyl)2,2-diphenylether
2703,4-dimethylbenzoylNNCH2(CH2)3(1-piperidinyl)2,2-diphenylether
2713,4-dichlorobenzoylN NCH2CH2)3(1-piperidinyl)2,2-diphenylether
2722-naphtolNNCH2(CH2)3N(=NH)NH2(S)-CH2CH(Ph)-NHCOcBu
2732-naphtolNNCH2(CH2)3NHC(=NH)NH2(S)-CH2CH(Ph)-NHCOcHex
2742-naphtolNNCH2CH2NH22,2-diphenylether
2754-chlorocinnamicNNCH2CH2NH22,2-diphenylether
2764-forcenavy NNCH2(CH2)2NH22,2-diphenylether
2774-methylcinnamicNNCH2(CH2)2NH22,2-diphenylether
2782-naphtolNNCH2CH2(1-piperidinyl)2,2-diphenylether
2794-chlorocinnamicNNCH2CH2(1-piperidinyl)2,2-diphenylether
2803,4-dichlorobenzoylNNCH2(CH2)2NH22,2-diphenylether
2813,4-dimethylbenzoyl NNCH2(CH2)2NH22,2-diphenylether
282TRANS-cinnamoylNNCH2(CH2)2NH22,2-diphenylether
2834-chlorocinnamicNNCH2(CH2)MN2,2-diphenylether
2843,4-dichlorobenzoylNNCH2(CH2)2(1-piperidinyl)2,2-diphenylether
2853,4-dimethylbenzoylNNCH2(CH2)2(1-piperidinyl)2,2-diphenylether
286TRANS-cinnamoylNCH2(CH2)2(1-piperidinyl)2,2-diphenylether
2874-forcenavyNNCH2(CH2)2(1-piperidinyl)2,2-diphenylether
2884-methylcinnamicNNCH2(CH2)2(1-piperidinyl)2,2-diphenylether
2892-naphtolNNCH2(CH2)3N(=NH)NH23.5-dimethylbenzyl
2902-naphtolNNCH2(CH2)3NHC(=NH)NH2(S)-CH2CH(Ph)NHCOPh
291 2-naphtolNNCH2(CH2)3NHC(=NH)NH2(R)-CH2CH(Ph)NHCOPh
2922-naphtolNNCH2(CH2)3N(=NH)NH2CH2CH(Ph)OMe
2932-naphtolNNCH2(CH2)3NHC(=NH)NH2CH2CH(Ph)OnPr
2942-naphtolNNCH2(CH2)3N(=NH)NH2CH2CH(Ph)OBn
2952-naphtolNNCH2(CH2)3NHC(=NH)NH2CH2CH(PH)Ollil
296 2-naphtolNNCH2(CH2)3CH32,2-diphenylether
2974-chlorocinnamicNNCH2(CH2)3CH32,2-diphenylether
2984-chlorocinnamicNNCH2(CH2)2CONH22,2-diphenylether
2992-naphtolNNCH2(CH2)2CONH22,2-diphenylether
3004-methylcinnamicNNCH2(CH2)3The N32,2-diphenylether
3014-methylcinnamicNNCH2(CH2)3The N(cyclohexyl)2,2-diphenylether
3022-naphtolNNCH2(CH2)3NHC(=NH)NH2CH2CH(Ph)OPh
3032-naphtolNNCH2(CH2)3NHC(=NH)NH2CH2CH(Ph)CO2Et
3042-naphtolNNCH2(CH2)3N(=NH)NH22-ethylbutyl
3052-naphtolNNCH2(CH2)3NHC(=NH)NH23,5-dimethyl-cyclo�exility
3064-chlorocinnamicNNCH2(CH2)2The N(cyclohexyl)2,2-diphenylether
3074-chlorocinnamicNNCH2(CH2)2The N2(cyclohexyl)2,2-diphenylether
308benzoylNN(CH2)2(CH2)2NH22,2-diphenylether
3093,4-dichlorobenzoylNN(CH2)2(CH2)2NH22,2-diphenylether
3102-naphtolNN(CH2)2(CH2 )2NH22,2-diphenylether
311benzoylNN(CH2)2(CH2)2(1-piperidinyl)2,2-diphenylether

CH2 CH2Ph
SdnR1XR2R3YRW
3123,4-dichlorobenzoylNN(CH2)2(CH2)2(1-piperidinyl)2,2-diphenylether
3132-naphtolNN(CH2)2(CH2)2(1-piperidinyl)2,2-diphenylether
3142-naphtolNN CH2(CH2)3NHC(=NH)NH2CH2CH(Ph)CONMe2
3152-naphtolNNCH2CH2cyclohexyl2,2-diphenylether
3164-chlorocinnamicNNCH2CH2cyclohexyl2,2-diphenylether
3172-naphtolNNCH2(CH2)2WITH(1-piperidinyl)2,2-diphenylether
3184-chlorocinnamicNNCH2(CH2)2WITH(1-piperidinyl)2,2-diphenylether
3192-naphtolNNCH2CH2Ph2,2-diphenylether
3204-chlorocinnamicNNCH2CH2CH2Ph2,2-diphenylether
3212-naphtolNNCH2(CH2)2cyclohexyl2,2-diphenylether
3224-chlorocinnamicNNCH2(CH2)2cyclohexyl2,2-diphenylether
3232-naphtolNNCH2CH2Ph2,2-diphenylether
3244-chlorocinnamicNNCH22,2-diphenylether
3253,4-dichlorobenzoylNNCH2(CH2)2NH23.5-dichlorobenzyl
3264-chlorocinnamicNNCH2(CH2)2NH23.5-dichlorobenzyl
3272-naphtolNNCH2(CH2)3N(=NH)NH23-chloro-5-tormentil
3282-naphtolNNCH2(CH2)3NHC(=NH)NH23.5-differentil
3292-naphtolNNCH2 (CH2)3NH23-chloro-5-tormentil
3302-naphtolNNCH2(CH2)3NH23.5-differentil
3312-naphtolNNCH2(CH2)3NH22,5-dichlorobenzyl
3322-naphtolNNCH2(CH2)3NH22,6-dichlorobenzyl
3332-naphtolNNCH2(CH2)3NH23.5-dimethoxybenzyl
3342-naphtolNNCH2 (CH2)3NH22-chlorbenzyl
3352-naphtolNNCH2(CH2)3NH22,3-dichlorobenzyl
3362-naphtolNNCH2(CH2)3NH22,4-dichlorobenzyl
3372-naphtolNNCH2(CH2)3NH23,4-dichlorobenzyl
3382-naphtolNNCH2(CH2)3NH23-fluoro-5-methylbenzyl
3392-naphtolNNCH23-fluoro-5-(trifluoromethyl)-benzyl
3402-naphtolNNCH2(CH2)3NH24-chlorbenzyl
3412-naphtolNNCH2(CH2)3NH22-phenylbutyl
3422-naphtolNNCH2(CH2)3NH21-(1-phenyl-cyclohexyl)-methyl
3433,4-dichlorobenzoylNNCH2(CH2)2(1-piperidinyl))3.5-dichlorobenzyl
3442-naphtolNNCH2/sub> (CH2)2(1-piperidinyl)3.5-dichlorobenzyl
3454-chlorocinnamicNNCH2(CH2)2(1-piperidinyl)3.5-dichlorobenzyl
3463,4-dichlorobenzoylNNCH2(CH2)2NH22-ethylbutyl
3474-chlorocinnamicNNCH2(CH2)2NH22-Stivali
3484-chlorocinnamicNNCH2(CH2)2(1-piperidinyl)2-ethylbutyl
3493,4-dichlorobenzoylNN CH2(CH2)2(1-piperidinyl)2-ethylbutyl
3502-naphtolNNCH2(CH2)2(1-piperidinyl)2-ethylbutyl
3514-chloro-3-fluoro-benzoylNNCH2(CH2)2NH22-ethylbutyl
3524-chloro-3-methyl-benzoylNNCH2(CH2)2NH22-ethylbutyl
3533-chloro-4-fluoro-benzoylNNCH2(CH2)2NH22-ethylbutyl

Sdn R1XR2R3YRW
3543-chloro-4-methyl-benzoylNNCH2(CH2)2NH22-ethylbutyl
3554-chlorocinnamicNNCH2CH2(1-piperidinyl)2-ethylbutyl
3562-naphtolNN(CH2)2CH2CH2(1-pyrrolidinyl)2,2-diphenylether
3572-naphtolNNCH2(CH2)3NH23,5-bis(trifluoromethyl)-benzyl
3582-n�ftail NNCH2(CH2)3NH23-chlorbenzyl
3592-naphtolNNCH2(CH2)3(1-piperidinyl)2-phenylbutyl (mixture of isomers)
3602-naphtolNNCH2(CH2)3N(=NH)NH2CH2CH(Ph)CON[-(CH2)5]
3612-naphtolNNCH2(CH2)3NHC(=NH)NH2CH2CH(Ph)CONHPh
3623,4-dichlorobenzoylNN(CH2)2(CH2)2N(CH3)22,2-diphenylether
3633,4-dichlorobenzoylNN(CH2)2(CH2)2N(CH(CH3)2)22,2-diphenylether
3643,4-dichlorobenzoylNNCH2CH2NH23.5-dichlorobenzyl
3652-naphtolNNCH2CH2NH23.5-dichlorobenzyl
3664-chlorocinnamicNNCH2CH2NH23.5-dichlorobenzyl
3673,4-dichlorobenzoylNNCH2CH2(1-piperidinyl) 3.5-dichlorobenzyl
3684-chlorocinnamicNNCH2CH2(1-piperidinyl)3.5-dichlorobenzyl
3693,4-dichlorobenzoylNNCH2(CH2)2NH22-phenylbutyl
3704-chlorocinnamicNNCH2(CH2)2NH22-phenylbutyl
3713,4-dichlorobenzoylNNCH2CH2(1-pyrrolidinyl)3.5-dichlorobenzyl
3722-naphtolNNCH2CH2(1-pyrrolidinyl) 3.5-dichlorobenzyl
3732-naphtolNNCH2(CH2)3NH2(S)-(3-methylphenethyl
3742-naphtolNNCH2(CH2)2CH2NH2(R)-(3-methylphenethyl
3752-naphtolNNCH2(CH2)2N(CH3)22,2-diphenylether
3766-fluoro-2-naphtolNNCH2(CH2)3(1-piperidinyl)2,2-diphenylether
3772-naphtolNNCH2(CH2)3NH2 3.5-diethenylbenzene
3784-chlorocinnamicNNCH2(CH2)2N(CH2CH3)22,2-diphenylether
3792-naphtolNNCH2(CH2)2N(CH2CH3)22,2-diphenylether
3803,4-dichlorobenzoylNNCH2(CH2)2(1-piperidinyl)(R)-2-phenylbutyl
3814-chlorocinnamicNNCH2(CH2)2(1-piperidinyl)(R)-2-phenylbutyl
3824-chlorocinnamicNN CH2(CH2)2(1-piperidinyl)(S)-2-phenylbutyl
3836-chloro-2-naphtolNNCH2(CH2)2NH22,2-diphenylether
3842-naphtolNNCH2(CH2)2(1-pyrrolidinyl)2,2-diphenylether
3852-naphtolNNCH2(CH2)2(1-piperidinyl)2,2-diphenylether
3866-fluoro-2-naphtolNNCH2(CH2)2NH22-ethylbutyl
3876-chloro-2-naphtolN CH2(CH2)2NH22-ethylbutyl
3886-bromo-2-naphtolNNCH2(CH2)2NH22-ethylbutyl
3896-fluoro-2-naphtolNNCH2(CH2)2(1-piperidinyl)2-ethylbutyl
3906-chloro-2-naphtolNNCH2(CH2)2(1-piperidinyl)2-ethylbutyl
3916-bromo-2-naphtolNNCH2(CH2)2(1-piperidinyl)2-ethylbutyl
3923,4-dichlorobenzoylN NCH2(CH2)2NH23,5-dimethyl-cyclohexyl
3932-naphtolNNCH2(CH2)2NH23,5-dimethyl-cyclohexyl
3944-chlorocinnamicNNCH2(CH2)2NH23,5-dimethyl-cyclohexyl

SdnR1XR2R3YRW
3956-chloro-2-naphtolNNCH2(CH2)2(1-piperidinyl)2,2-diphenylether
3966-fluoro-2-�toil NNCH2(CH2)2(1-piperidinyl)2,2-diphenylether
3974-chlorocinnamicNNCH2(CH2)2(1-pyrrolidinyl)2,2-diphenylether
3984-chlorocinnamicNNCH2(CH2)2N(CH3)22,2-diphenylether
3992-naphtolNNCH2(CH2)2N(CH3)22,2-diphenylether
4003,4-dichlorobenzoylNNCH2(CH2)2N(CH3)22,2-diphenylether
4012-naphtolNNCH2(CH2)3NH22,6-dimethyl-cyclohexylmethyl
4022-naphtolNNCH2(CH2)3NH2(S)-2-phenylbutyl
4033,4-dichlorobenzoylNNCH2(CH2)2(1-piperidinyl)3,5-dimethyl-cyclohexylmethyl
4043,4-dichlorobenzoylNNCH2CH2CH2N(CH3)23,5-dimethyl-cyclohexylmethyl
4052-naphtolNNCH2(CH2 2NH23-methyl-2-phenylbutyl
4062-naphtolNNCH2(CH2)2NH2(3)-2-phenylbutyl
4072-naphtolNNCH2(CH2)2NH2(K)-2-phenylbutyl
4084-chlorocinnamicNNCH2CH2(imidazol-3-yl)2,2-diphenylether
4093-(4-chlorophenyl)-propanolNNCH2(CH2)2(1-piperidinyl)2,2-diphenylether
4103-(4-chlorophenyl)-propanolNNCH2 (CH2)2NH22,2-diphenylether
4114-chlorocinnamicNNCH2CH2The N(2-pyridyl)2,2-diphenylether
4124-chlorocinnamicNNCH2CH2(2-pyridinyl)2,2-diphenylether
4132-naphtolNNCH2(CH2)2(1-piperidinyl)(R)-3-methyl-2-phenylbutyl
4142-naphtolNNCH2(CH2)2(1-piperidinyl)(S)-3-methyl-2-phenylbutyl
4154-isopropylphenolNNCH 2(CH2)2(1-piperidinyl)2,2-diphenylether
4164-isopropylphenolNNCH2(CH2)2NH22,2-diphenylether
4172,4-dimethylcinnamicNNCH2(CH2)2(1-piperidinyl)2,2-diphenylether
4182,4-dimethylcinnamicNNCH2(CH2)2NH22,2-diphenylether
4192,4-divertinglyNNCH2(CH2)21-piperidinyl)2,2-diphenylether
4202,4-divertingly NCH2(CH2)2NH22,2-diphenylether
4214-chlorocinnamicNNCH2CH2The N(cyclohexyl)2,2-diphenylether
4224-chlorocinnamicNNCH2(CH2)2(4-morpholinyl)2,2-diphenylether
4234-chlorocinnamicNNCH2CH2CH2N[-C(IU)=SNSN=C(Me)-]2,2-diphenylether
4244-chlorocinnamicNNCH2CH2CH2(2,5-dimethyl-2-pyrrolidin-1-yl)2,2-diphenylether
425 6-chloro-2-naphtolNNCH2(CH2)2(1-piperidinyl)(S)-2-phenylbutyl
4264-chlorocinnamicNNCH2(CH2)2(1-pyrrolidinyl)(S)-2-phenylbutyl
4274-chlorocinnamicNNCH2(CH2)2NHCH(CH3)2(S)-2-phenylbutyl
4286-chloro-2-naphtolNNCH2CH2CH2(1-pyrrolidinyl)(S)-2-phenylbutyl
4293,4-dichlorobenzoylNNCH2(CH2)2(1-piperidinyl)(S)-2-phenylbutyl
4303,4-dichlorobenzoylNNCH2(CH2)21-pyrrolidinyl)(S)-2-phenylbutyl
431CbzNNCH2(CN2)2(1-piperidinyl)2,2-diphenylether
4324-bromocinnamicNNCH2(CH2)2(1-piperidinyl)2,2-diphenylether

SdnR1XR2R3YRW
4335-(4-chlorophenyl)-isoxazol-3-carbonylNNCH2(CH2) 2(1-piperidinyl)2,2-diphenylether
4344-chlorocinnamicNNCH2CH2N(2-pyridyl)2,2-diphenylether
4354-chlorocinnamicNNCH2CH2WITH(1-piperidinyl)2,2-diphenylether
4366-chloro-2-naphtolNNCH2(CH2)2WITH(1-piperidinyl)(S)-2-phenylbutyl
4373,4-dichlorobenzoylNNCH2(CH2)2WITH(1-piperidinyl)(S)-2-phenylbutyl
4386-chloro-2-naphtolNNCH2 CH2(1-piperidinyl)(S)-2-phenylbutyl
4393,4-dichlorobenzoylNNCH2CH2(1-piperidinyl)(S)-2-phenylbutyl
4406-chloro-2-naphtolNNCH2(CH2)3(1-piperidinyl)(S)-2-phenylbutyl
4413,4-dichlorobenzoylNNCH2(CH2)3(1-piperidinyl)(S)-2-phenylbutyl
4424-chlorocinnamicNNWith(IU)2CH2CH2NH22,2-diphenylether
4434-chlorocinnamicNN With(IU)2(CH2)2(1-piperidinyl)2,2-diphenylether
4442-naphtolNNCH2(CH2)2NH2(R)-2-(4-chloro-phenyl) - propyl
4452-naphtolNNCH2(CH2)2NH22-(4-chloro-phenyl) - propyl
4462-naphtolNNCH2(CH2)2(1-piperidinyl)(R)-2-(4-chloro-phenyl) - propyl
4472-naphtolNNCH2(CH2)2(1-piperidinyl)(8)-2-(4-chloro-phenyl) - propyl
4483,4-dichlorobenzoylNN CH2(CH2)2N(phenyl)CH3(S)-2-phenylbutyl
4493,4-dichlorobenzoylNNCH2(CH2)2N(CH2CH3)2(S)-2-phenylbutyl
4503,4-dichlorobenzoylNNCH2(CH2)2(4-morpholinyl)(S)-2-phenylbutyl
4513,4-dichlorobenzoylNNCH2(CH2)2NH(phenyl)(S)-2-phenylbutyl
4523,4-dichlorobenzoylNNCH2(CH2)2NH(benzyl)(S)-2-phenylbutyl
4534-chlorocinnamic/td> NNCH2CH2(2-NH2-Ph)2,2-diphenylether
4543,4-dichlorobenzoylNNCH2(CH2)2N(CH3)3(S)-2-phenylbutyl
4553,4-dichlorobenzoylNNCH2(CH2)2(4-CH3-piperazine-1-yl)(S)-2-phenylbutyl
4562-naphtolNNCH2(CH2)2(1-piperidinyl)(R)-2-phenylpentyl
4572-naphtolNNCH2(CH2)2(1-piperidinyl)(S)-2-phenylpentyl
458 p-trifluoromethyl-benzoylNNCH2(CH2)2(1-piperidinyl)2,2-diphenylether
459p-trifluoromethyl-benzoylNNCH2(CH2)2NH22,2-diphenylether
460m-trifluoromethyl-benzoylNNCH2(CH2)2(1-piperidinyl)2,2-diphenylether
461m-trifluoromethyl-benzoylNNCH2(CH2)2NH22,2-diphenylether
4626-chloro-2-naphtolNNCH2(CH2)2N(CH3)2 3.5-dichlorobenzyl
4633,4-dichlorobenzoylNNCH2(CH2)2NHCH(CH3)23.5-dichlorobenzyl
4646-chloro-2-naphtolNNCH2(CH2)2N(CH3)2(S)-2-phenylbutyl
4656-chloro-2-naphtolNNCH2(CH2)2NH2(S)-2-phenylbutyl
4662-naphtolNNCH2CH2(2-NH2-Ph)2,2-diphenylether
4673,4-dichlorobenzoylNNCH2 (CH2)2N(benzyl)SN3(S)-2-phenylbutyl
4683,4-dichlorobenzoylNNCH2(CH2)2(piperazine-1-yl)(S)-2-phenylbutyl
4693,4-dichlorobenzoylNNCH2(CH2)2N(n-pentyl)CH3(S)-2-phenylbutyl
4703,4-dichlorobenzoylNNCH2(CH2)2N[(CH(CH3)2]2(S)-2-phenylbutyl
4713,4-dichlorobenzoylNNCH2(CH2)2(4-CH3-piperidine-1-yl)(S)-2-phenylbutyl
4726-chloro-2-naphtol NNCH24-piperidinyl(S)-2-phenylbutyl
4736-chloro-2-naphtolNNCH21-isopentyl-4-piperidinyl(S)-2-phenylbutyl

SdnR1XR2R3YRW
4746-chloro-2-naphtolNNCH2(CH2)3CHW(S)-2-phenylbutyl
4756-chloro-2-naphtolNNCH2CH2CH2RG(S)-2-phenylbutyl
4763,4-dichlorobenzoyl NNCH2(CH2)2(3,5-Me2-piperidine-1-yl)(S)-2-phenylbutyl
4773,4-dichlorobenzoylNNCH2(CH2)2(4-IT-piperidine-1-yl)(S)-2-phenylbutyl
4783,4-dichlorobenzoylNNCH2(CH2)2(4-CO2N-piperidine-1-yl)(S)-2-phenylbutyl
4793,4-dichlorobenzoylNNCH2(CH2)2NH[-(CH2)6-](S)-2-phenylbutyl
4803,4-dichlorobenzoylNNCH2(CH2)2[(S)-2-Me-piperidine-1-yl](S)-2-phenylbutyl
4813,4-dichlorobenzoylNNCH2(CH2)2N(tu)CH3(S)-2-phenylbutyl
4822-naphtolNNCH2CH2(2-(piperidine-1-yl)phenyl)-2,2-diphenylether
4832-naphtolNNCH2(CH2)2CON(Me)nBu(S)-2-phenylbutyl
4842-naphtolNNCH2(CH2)2CONHcHex(S)-2-phenylbutyl
4856-chloro-2-naphtolNNCH21-ethyl-piperidine-4-yl(S)-2-phenylbutyl
4863,4-dichlorobenzylNNCH2(CH2)2(1-piperidinyl)2,2-diphenylether
4876-chloro-2-naphtolNNCH2(CH2)2NHC(=NH)NH2(S)-2-phenylbutyl
4886-chloro-2-naphtolNNCH2(CH2)2NHC(=NH)NHMe(S)-2-phenylbutyl
4893,4-dichlorobenzoylNNCH2(CH2)2NH2(R)-2-isopropylbenzyl
4903,4-dichlorobenzoylNNCH2(CH2)2NH24913,4-dichlorobenzoylNNCH2(CH2)2(1-piperidinyl)(R)-2-isopropylbenzyl
4923,4-dichlorobenzoylNNCH2(CH2)2(1-piperidinyl)(S)-2-isopropylbenzyl
4936-chloro-2-naphtolNNCH2S-CH2C(Me2NH2(S)-2-phenylbutyl
4946-chloro-2-naphtolNNCH2R-CH2C(Me2NH2(S)-2-phenylbutyl
4953,4-dichlorobenzoylNNCH2 (CH2)2NH2(S)-2-phenylbutyl
4963,4-dichlorobenzoylNNCH2(CH2)2N(CH3)2(S)-2-phenylbutyl
4976-chloro-2-naphtolNNCH2(CH2)2NH23.5-dichlorobenzyl
4986-chloro-2-naphtolNNCH2(CH2)2(1-piperidinyl)3.5-dichlorobenzyl
4996-chloro-2-naphtolNNCH2S-CH2With(Me2)(1-piperidinyl)(S)-2-phenylbutyl
5006-chloro-2-naphtolNN CH2R-CH2C(Me2)(1-piperidinyl)(S)-2-phenylbutyl
5016-chloro-2-naphtolNNCH2(CH2)2NH2(R)-2-isopropylbenzyl
5026-chloro-2-naphtolNNCH2(CH2)2NH2(S)-2-isopropylbenzyl
5036-chloro-2-naphtolNNCH2(CH2)2(1-piperidinyl)(R)-2-isopropylbenzyl
5046-chloro-2-naphtolNNCH2(CH2)2(1-piperidinyl)(S)-2-isopropylbenzyl
5056-chloro-2-naphtol NNCH2(CH2)2If they fixed(S)-2-phenylbutyl

(CH2)2N[-CO(CH2)2CO-]
SdnR1XR2R3YRW
5066-chloro-2-naphtolNNCH2pneh(S)-2-phenylbutyl
5076-carocci-2-naphtolNNCH2CH2)2(1-piperidinyl)2,2-diphenylether
5086-chloro-2-naphtolNNCH2(CH2)2NHC(=NH)NH-CH(CH3)2(S)-2-phenylbutyl
5096-chloro-2-n�ftail NNCH2(CH2)4HE(S)-2-phenylbutyl
5106-chloro-2-naphtolNNCH2(CH2)2OMe(S)-2-phenylbutyl
5116-chloro-2-naphtolNNCH2(CH2)2AFP(S)-2-phenylbutyl
5126-chloro-2-naphtolNNCH2iBu(S)-2-phenylbutyl
5133,4-dichlorobenzoylNNCH2(CH2)2NH22-ethyl-3-methyl-but-3-enyl
5143,4-dichlorobenzoylNCH2(CH2)2(1-piperidinyl)2-ethyl-3-methyl-but-3-enyl
5156-chloro-2-naphtolNNCH2(CH2)2NH22-ethyl-3-methyl-but-3-enyl
5166-chloro-2-naphtolNNCH2(CH2)2(1-piperidinyl)(R)-2-ethyl-3-methyl-but-3-enyl
5176-chloro-2-naphtolNNCH2(CH2)2(1-piperidinyl)(S)-2-ethyl-3-methyl-but-3-enyl
5184-biphenylcarboxylicNNCH2(CH2)3N(=NH)NH2cyclohexylmethyl
519indole-3-acetylNNCH2(CH2)3N(=NH)NH2cyclohexylmethyl
5203-chinainternationalNNCH2(CH2)3NHC(=NH)NH2cyclohexylmethyl
5213,4-dichlorobenzoylNNCH2(CH2)2(4,4-debtor-1-piperidinyl)(S)-2-phenylbutyl
5223,4-dichlorobenzoylNNCH2(CH2)2HE(S)-2-phenylbutyl
5233,4-dichlorobenzoylNNCH2(CH2)2(3,3-debtor-1-piperidinyl) (S)-2-phenylbutyl
5243,4-dichlorobenzylNNCH2(CH2)2(1-piperidinyl)(S)-2-phenylbutyl
5253,4-dichlorobenzoylNNCH2(CH2)2(1-piperidinyl)2-cyclopropylmethyl
5266-chloro-2-naphtolNNCH2(CH2)2NH22-cyclopropylmethyl
5276-chloro-2-naphtolNNCH2(CH2)2(1-piperidinyl)2-cyclopropylmethyl
5283,4-dichlorobenzoylNNCH2(S)-2-phenylbutyl
5296-chloro-2-naphtolNNCH2(CH2)3NN2(S)-2-phenylbutyl
5303,4-dichlorobenzoylNNCH2(CH2)2N(IU)CF3(S)-2-phenylbutyl
5313,4-dichlorobenzoylNNCH2CH2CH2N[-SOS(IU)2CH2CO-](S)-2-phenylbutyl
5326-chloro-2-naphtolNNCH2(CH2)2N[-(CH2)6-](S)-2-phenylbutyl
5336-chloro-2-naphtolN NCH2(CH2)2NHCONHiPr(S)-2-phenylbutyl
5344-biphenylcarboxylicNNCH2(CH2)2(1-piperidinyl)(S)-2-phenylbutyl
5352-phenylthiazol-4-carbonylNNCH2(CH2)2(1-piperidinyl)(S)-2-phenylbutyl
5364-chloro-biphenyl-2-carbonylNNCH2(CH2)2(1-piperidinyl)(S)-2-phenylbutyl

SdnR1XR2R3YRW
537 6-chloro-2-naphtolNNCH2(CH2)2N(Ac)iPr(S)-2-phenylbutyl
5386-chloro-2-naphtolNNCH2CH2NHiPr(S)-2-phenylbutyl
5396-chloro-2-naphtolNNCH2CH2NC(=NH)NH2(S)-2-phenylbutyl
5402,4-dichlorophenacylNNCH2(CH2)2(1-piperidinyl)(S)-2-phenylbutyl
5413,4-dichlorobenzoylNNCH2(CH2)2NH22,4-dichlorobenzyl
542 3,4-dichlorobenzoylNNCH2(CH2)2(1-piperidinyl)2,4-dichlorobenzyl
5433,4-dichlorobenzoylNNCH2(CH2)2NHSO2Me2,4-dichlorobenzyl
5443,4-dichlorobenzoylNNCH2(CH2)2NHSO2(4-Me-Ph)2,4-dichlorobenzyl
5453,4-dichlorobenzoylNNCH2(S)-(CH2)2NHCO-CH(iPr)NH22,4-dichlorobenzyl
5466-chloro-2-naphtolNNCH2(CH2)2NH22,4-dichlorobenzyl
5476-chloro-2-naphtolNNCH2(CH2)2(1-piperidinyl)2,4-dichlorobenzyl
5486-chloro-2-naphtolNNCH2(CH2)2NH22-(3-thienyl)butyl
5496-chloro-2-naphtolNNCH2(CH2)2(1-piperidinyl)(R)-2-(3-thienyl)butyl
5506-chloro-2-naphtolNNCH2(CH2)2(1-piperidinyl)(S)-2-(3-thienyl)butyl
5516-chloro-2-naphtolNNCH2(CH2)2NH2Etil-2-methylbutyl
5526-chloro-2-naphtolNNCH2(CH2)2(1-piperidinyl)2-ethyl-2-methylbutyl
5536-chloro-2-naphtolNNCH2(CH2)2(4-morpholinyl)2,2-diphenylether
5546-chloro-2-naphtolNNCH2(CH2)2(4-morpholinyl)(S)-2-phenylbutyl
5556-chloro-2-naphtolNNCH2(CH2)2(4-morpholinyl)3.5-dichlorobenzyl
5563,4-dichlorobenzoylNNCH2(CH2)2(4-mo�folini) 3.5-dichlorobenzyl
557(4-chloro-benzyl)NNNCH2(CH2)2(1-piperidinyl)(S)-2-phenylbutyl
5583,4-dichlorobenzyl + MesoACNCH2(CH2)2(1-piperidinyl)(S)-2-phenylbutyl
5593,4-dichlorobenzoylNNCH2(CH2)2NH22-ethyl-2-methylbutyl
5603,4-dichlorobenzoylNNCH2(CH2)2(1-piperidinyl)2-ethyl-2-methylbutyl
5616-chloro-2-naphtolNNCH (CH2)2(1-piperidinyl)2,3,5-trichlorobenzoyl
5626-chloro-2-naphtolNNCH2(CH2)2NHSO2iPr(S)-2-phenylbutyl
5636-chloro-2-naphtolNNCH2(CH2)2NHCO2nBu(S)-2-phenylbutyl
5646-chloro-2-naphtolNNCH21-iPr-4-piperidinyl(S)-2-phenylbutyl
5656-chloro-2-naphtolNNCH2(CH2)2(1-piperidinyl)(R)-2-phenylbutyl
5665-(4-chlorophenyl)-isoxazol-3-carbonylN NCH2(CH2)2(1-piperidinyl)3.5-dichlorobenzyl
5672,4-dichlorobenzoylNNCH2(CH2)2(1-piperidinyl)3.5-dichlorobenzyl

td align="center" namest="c8" nameend="c10"> (CH2)2(1-piperidinyl)
SdnR1XR2R3YRW
5686-methoxy-2-naphtolNNCH2(CH2)2(1-piperidinyl)3.5-dichlorobenzyl
5696-chloro-2-naphtolNNCH2 (CH2)2(1-piperidinyl)(S)-2-phenylbutyl
5701-methoxy-2-naphtolNNCH2(CH2)2(1-piperidinyl)3.5-dichlorobenzyl
5714-(trifter-methoxy)cinnamoylNNCH2(CH2)2(1-piperidinyl)3.5-dichlorobenzyl
5725-(4-chlorophenyl)-isoxazol-3-carbonylNNCH2(CH2)2(1-piperidinyl)(S)-2-phenylbutyl
5732,4-dichlorobenzoylNNCH2(S)-2-phenylbutyl
5744,5-dichlorophenolR1NCH2(CH2)2(1-piperidinyl)3.5-dichlorobenzyl
5753-fluoro-4-(trifter-methoxy)cinnamoylNNCH2(CH2)2(1-piperidinyl)3.5-dichlorobenzyl
576b-methoxy-2-naphtolNNCH2(CH2)2(1-piperidinyl)(S)-2-phenylbutyl
5771-methoxy-2-naphtolNNCH2 (CH2)2(1-piperidinyl)(S)-2-phenylbutyl
5783-fluoro-4-(trifter-methoxy)cinnamoylNNCH2(CH2)2(1-piperidinyl)(S)-2-phenylbutyl
579b-chloro-2-naphtolNNCH2(CH2)2(1-piperidinyl)(S)-2-phenylbutyl
Table 2:
The synthesis of compounds
Vos.The path AndScheme 1: VN(R2)-Y-CO2HP1NH-CH(U)-CO2HThe transformation in the productmodification U
14Scheme 12-�attoiney-Gly-OH Fmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
25Scheme 1Boc-Gly-OHCbz-L-Asp - [(NMe)OMe-OHScheme 4recovery to acetaldehyde, then reductive amination of
31Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
33Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
37Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4withdrawal W�protective group P3
38Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
38Scheme 12-naftaly-Gly-OHFmoc-L-Dab(Boc)-OHScheme 3the removal of the protective group P3, then dialkylamino alkylamino
39Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
49Scheme 1Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
50Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
54Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3

108
Vos.The path AndScheme 1: VN(R2)-Y-CO2HP1NH-CH(U)-CO2HThe transformation in the productmodification U
60Scheme 1Cbz-SarFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3
62Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 3to remove the P1 protecting groups, R1 to allievate, ring metilirovanie, remove P3 protective group
63Scheme 2 Boc-Gly-OHH-L-Orn(Cbz)-OllilScheme 4the removal of the protective group P3
63Scheme 12-naftaly-Gly-OHFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3
64Scheme 12-naftaly-Gly-OHFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3, then dialkylamino alkylamino
65Scheme 12-naftaly-Gly-OHFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3, reductive alkylation
67Scheme 12-naftaly-Gly-OHFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3, guanylurea
79Scheme 1Alloc-β-(2-naphthyl)-L-AlaBoc-L-Arg-(Cbz)2-OHCX�mA 4 the removal of the protective group P3
81Scheme 1Alloc-β-(2-naphthyl)-L-AlaBoc-L-Arg-(Cbz)2-OHScheme 4the removal of the protective group P3
83Scheme 1Alloc-β-(2-naphthyl)-L-AlaBoc-L-Arg-(Cbz)2-OHScheme 4the removal of the protective group P3
85Scheme 1Altoc-β-(2-naphthyl)-L-AlaBoc-L-Arg-(Cbz)2-OHScheme 4the removal of the protective group P3
86Scheme 1Alloc-β-(2-naphthyl)-L-AlaBoc-L-Arg-(Cbz)2-OHScheme 4the removal of the protective group P3
87Scheme 1Alloc-β-(2-naphthyl)-L-AlaBoc-L-Arg-(Cbz)2-OHScheme 4the removal of the protective group P3
105Scheme 2 Boc-Gly-OHH-L-Orn(Cbz)-OllilScheme 5the removal of the protective group P3, guanidinylation, removing the protective groups
105Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
105Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
105Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
106Scheme 2Boc-Gly-OHH-L-Orn(Cbz)-OllilScheme 4the removal of the protective group P3
107Scheme 2Boc-Gly-OHH-L-Orn(Cbz)-OllilScheme 4the removal of the protective group P3
Scheme 2Boc-Gly-OHH-L-Orn(Cbz)-OllilScheme 5the removal of the protective group P3, guanidinylation, removing the protective groups
109Scheme 2Boc-Gly-OHH-L-Orn(Cbz)-OllilScheme 5the removal of the protective group P3, guanidinylation, removing the protective groups

Vos.The path AndScheme 1: VN(R2)-Y-CO2HP1NH-CH(U)-CO2HThe transformation in the productmodification U
110Scheme 2Boc-Gly-OHH-L-Orn(Cbz)-OllilScheme 5the removal of the protective group P3, guanidinylation, removing the protective groups
111Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4 the removal of the protective group P3
112Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
113Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
114Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
115Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
116Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
117Scheme 2 Boc-Gly-OHBoc-L-Lys(Cbz)-OHScheme 4the removal of the protective group P3
118Scheme 2Boc-Gly-OHBoc-L-Lys(Cbz)-OHScheme 4the removal of the protective group P3
119Scheme 2Boc-Gly-OHBoc-L-Lys(Cbz)-OHScheme 4the removal of the protective group P3
120Scheme 2Boc-Gly-OHBoc-L-Lys(Cbz)-OHScheme 4the removal of the protective group P3
121Scheme 2Boc-Gly-OHBoc-L-Lys(Cbz)-OHScheme 4the removal of the protective group P3
122Scheme 2Boc-Gly-OHBoc-L-Lys(Cbz)-OHScheme 4removing protective �the group P3
123Scheme 2Boc-Gly-OHBoc-L-Lys(Cbz)-OHScheme 4the removal of the protective group P3
124Scheme 2Boc-Gly-OHBoc-L-Lys(Cbz)-OHScheme 4the removal of the protective group P3
125Scheme 2Boc-Gly-OHBoc-L-Lys(Cbz)-OHScheme 4the removal of the protective group P3
126Scheme 2Boc-Gly-OHBoc-L-Lys(Cbz)-OHScheme 4the removal of the protective group P3
127Scheme 2Boc-Gly-OHBoc-L-Lys(Cbz)-OHScheme 4the removal of the protective group P3
128Scheme 2Boc-Gly-OHBoc-L-Lys(Cbz)-OH Scheme 4the removal of the protective group P3
129Scheme 2Boc-Gly-OHBoc-L-Lys(Cbz)-OHScheme 4the removal of the protective group P3
130Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
131Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
132Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
133Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
134 Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
135Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
136Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
137Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
138Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
139Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-�allyl Scheme 4the removal of the protective group P3

Vos.The path AndScheme 1: VN(R2)-Y-CO2HP1NH-CH(U)-CO2HThe transformation in the productmodification U
140Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
141Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
142Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
143Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group�s P3
144Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
145Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
146Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
147Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
148Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
149Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-Ollilthe removal of the protective group P3
150Scheme 2Boc-Gly-OHH-L-Arg(Cbz)2-OllilScheme 4the removal of the protective group P3
151Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
152Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
153Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
154Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
155Scheme 1Alloc-Gly-OH Boc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
156Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
157Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
158Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
159Scheme 1Alloc-Gly-OHBoc-L-canavanine(Fmoc)-OHScheme 4the removal of the protective group P3
160Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
161Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
162Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
163Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
164Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
165Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
166Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
167 Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
168Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
169Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
170Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3

Scheme 4 Scheme 4
Vos.The path AndScheme 1: VN(R2)-Y-CO2HP1NH-CH(U)-CO2HThe transformation in the productmodification U
171Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHthe removal of the protective group P3
172Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
173Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
174Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
175Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
176Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
177Scheme 1Alloc-Gly-OH Boc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
178Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
179Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
180Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
181Scheme 1Alloc-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
182Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
183Scheme 1 2-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
184Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 4the removal of the protective group P3
185Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
186Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
187Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
188Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
189 Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
190Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
191Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
192Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
193Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
194Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
195Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
196Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
197Scheme 12-naftaly-Gly-OHFmoc-α-(1-Boc-4-piperidinyl)-DL-Gly-OHScheme 3the removal of the protective group P3
198Scheme 12-naftaly-Gly-OHFmoc-β-(1-Boc-4-piperidinyl)-DL-Ala-OHScheme 3the removal of the protective group P3
199Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
200Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHthe removal of the protective group P3

Scheme 3
Vos.The path AndScheme 1: VN(R2)-Y-CO2HP1NH-CH(U)-CO2HThe transformation in the productmodification U
201Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
202Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
203Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
204Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
205Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
206Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
207Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
208Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
209Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
210Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4starred in his�their protective group P3
211Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
212Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3
213Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3
214Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3
215Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
216Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3with�Yachiyo protective group P3
217Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
218Scheme 1Alloc-Gly-OHBoc-L-Arg(Fmoc)2-OHScheme 4the removal of the protective group P3
219Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3
220Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3
221Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3
222Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4removing sett�a combined group P3
223Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3
224Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3, guanidinylation
225Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3, reductive alkylation
226Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
227Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
228Scheme 12-naftaly-Gly-OHFmoc-L-Orn(Boc)-OHthe removal of the protective group P3, reductive alkylation
229Scheme 12-naftaly-Gly-OHFmoc-L-3-Ala-OHScheme 3no

Vos.The path AndScheme 1: VN(R2)-Y-CO2NR2NH-CH(U)-CO2NThe transformation in the productmodification U
230Scheme 12-naftaly-Gly-ITFmoc-L-4-peredelau-HEScheme 3no
231Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3, reductive alkylation
232Scheme 12-naftaly-Gly-ITFmoc-L-Lys(i-Pr)Fmoc-OHScheme 3the removal of protective�th group P3
233Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3
234Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3
235Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3
236Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3
237Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3
238Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3
239Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3
240Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3
241Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3
242Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3
243Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3
244Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3
245Scheme 12-naftaly-Gly-ITFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
246Scheme 12-naftaly-Gly-ITFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
247Scheme 12-naftaly-Gly-ITFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
248Scheme 12-naftaly-Gly-ITFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3, reductive alkylation
249Scheme 12-naftaly-Gly-ITFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3, reductive alkylation
250Scheme 12-naftaly-Gly-IT Fmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3, reductive alkylation
251Scheme 12-naftaly-Gly-ITFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3, reductive alkylation
252Scheme 12-naftaly-Gly-ITFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
253Scheme 12-naftaly-Gly-ITFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
254Scheme 12-naftaly-Gly-ITFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
255Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3

Vos.The path AndScheme 1: VN(R2)-Y-CO2HP1NH-CH(U)-CO2HThe transformation in the productmodification U256Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3257Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3258Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4to remove the P1 protecting groups, R1 to allievate, ring metilirovanie, remove P3 protective group259Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3260Scheme 1Cbz-Gly-OHScheme 4the removal of the protective group P3261Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3,then dialkylamino alkylamino262Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino262Scheme 1Boc-Gly-OHFmoc-L-Orn(Cbz)-OHScheme 5the removal of the protective group P3, dialkylamino263Scheme 12-naftaly-Gly-OHFmoc-L-Dab(Boc)-OHScheme 3the removal of the protective group P3263Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3 264Scheme 12-naftaly-Gly-OHFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3,then dialkylamino alkylamino265Scheme 12-naftaly-Gly-OHFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3, then dialkylamino alkylamino266Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3267Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3268Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3269Scheme 1Cbz-Gly-OHFmocL-Orn(Boc)-OH Scheme 4the removal of the protective group P3, then dialkylamino alkylamino270Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino271Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino272Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3273Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3274Scheme 1Cbz-Gly-OHFmoc-L-Dap(Boc)-OHScheme 4the removal of the protective group P3 275Scheme 1Cbz-Gly-OHFmoc-L-Dap(Boc)-OHScheme 4the removal of the protective group P3

Vos.The path AndScheme 1: VN(R2)-Y-CO2NP2NH-CH(U)-CO2HThe transformation in the productmodification U
276Scheme 1Cbz-Gly-OHBoc-L-Dab(Fmoc)-OHScheme 4the removal of the protective group P3
276Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
277Scheme 1Cbz-Gly-OHBoc-L-Dab(Fmoc)-OHScheme 4the removal of the protective group P3
277Scheme 1Cbz-Gly-OHFmocL-Dab(Boc)-OH Scheme 4the removal of the protective group P3
278Scheme 1Cbz-Gly-OHFmoc-L-Dap(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
279Scheme 1Cbz-Gly-OHFmoc-L-Dap(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
279Scheme 1Cbz-Gly-OHFmoc-L-Dap(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
280Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
281Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
282Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
283Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
284Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
285Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
286Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
287Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc-OH Scheme 4the removal of the protective group P3, then dialkylamino alkylamino
288Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
289Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
290Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
291Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
292Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
293Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
294Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
295Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
296Scheme 1Cbz-Gly-OHBoc-L-Nle-OHScheme 4no

Scheme 4
Vos.The path AndScheme 1: VN(R2)-Y-CO2HP2NH-CH(U)CO2HThe transformation in the productmodification U
297Scheme 1Cbz-Gly-OHBoc-L-Nle-OH Scheme 4no
298Scheme 1Cbz-Gly-OHBoc-L-Gln-OHScheme 4no
299Scheme 1Cbz-Gly-OHBoc-L-Gln-OHScheme 4no
300Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3, then acylation
301Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3, then acylation
302Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
303Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3 the removal of the protective group P3
304Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
305Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
306Scheme 1Gbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then acylation
307Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3,then acylation
308Scheme 1Cbz-β-AlaFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
309Scheme 1Cbz-β-AlaFmoc-L-Dab(Boc)-OHthe removal of the protective group P3
310Scheme 1Cbz-β-AlaFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
311Scheme 1Cbz-β-AlaFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
312Scheme 1Cbz-β-AlaFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
313Scheme 1Cbz-β-AlaFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
314Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group R5 and the amidation, and then removing the protective�a combined group P3
315Scheme 1Cbz-Gly-OHBoc-L-Cha-OHScheme 4no
316Scheme 1Cbz-Gly-OHBoc-L-Cha-OHScheme 4no
317Scheme 1Cbz-Gly-OHBoc-L-Glu(1-piperidinyl)Scheme 4no
318Scheme 1Cbz-Gly-OHBoc-L-Glu(1-piperidinyl)Scheme 4no
319Scheme 1Cbz-Gly-OHBoc-L-Hfe-OHScheme 4no
320Scheme 1Cbz-Gly-OHBoc-L-Hfe-OHScheme 4no
321Scheme 1Cbz-Gly-OHScheme 4no
322Scheme 1Cbz-Gly-OHBoc-L-hCha-OHScheme 4no
323Scheme 1Cbz-Gly-OHBoc-L-Phe-OHScheme 4no
324Scheme 1Cbz-Gly-OHBoc-L-Phe-OHScheme 4no

Vos.The path AndScheme 1: VN(R2)-Y-CO2HP2NH-CH(U)-CO2HThe transformation in the productmodification U
325Scheme 1Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
326Scheme 1Alloc-Gly-OHFmocL-Dab(Boc)-OH Scheme 4the removal of the protective group P3
327Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
328Scheme 12-naftaly-Gly-ITFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group P3
329Scheme 12-naftaly-Gly-ITFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3
330Scheme 12-naftaly-Gly-ITFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3
331Scheme 12-naftaly-Gly-ITFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3
332Scheme 1 2-naftaly-Gly-ITFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3
333Scheme 12-naftaly-Gly-ITFmoc-L-Om(Boc)-OHScheme 3the removal of the protective group P3
334Scheme 12-naftaly-Gly-ITFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3
335Scheme 12-naftaly-Gly-ITFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3
336Scheme 12-naftaly-Gly-ITFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3
337Scheme 12-naftaly-Gly-ITFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3
338 Scheme 12-naftaly-Gly-ITFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3
339Scheme 12-naftaly-Gly-ITFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3
340Scheme 12-naftaly-Gly-ITFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3
341Scheme 12-naftaly-Gly-ITFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3
342Scheme 12-naftaly-Gly-ITFmoc-L-Om(Boc)-OHScheme 3the removal of the protective group P3
343Scheme 1Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of protections�th group P3, then dialkylamino alkylamino
344Scheme 1Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
345Scheme 1Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
346Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
347Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
348Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
348Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino

td align="left"> Scheme 1
Vos.The path AndScheme 1: VN(R2)-Y-CO2NP2NH-CH(U)-CO2HThe transformation in the productmodification U
349Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
350Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
351Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
352CX�mA 1 Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
353Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
354Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
355Scheme 1Cbz-Gly-OHFmoc-L-Dap(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
356Scheme 1Cbz-Gly-OHFmoc-L-Dap(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
357Scheme 12-naftaly-Gly-OHFmoc-L-Orn(Boc)-OHScheme 3removing �protective group P3
358Scheme 12-naftaly-Gly-OHFmoc-l-Orn(Boc)-OHScheme 3the removal of the protective group P3
359Scheme 12-naftaly-Gly-OHFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3, then dialkylamino alkylamino
360Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group R5 and the amidation, and then removing the protective group P3
361Scheme 12-naftaly-Gly-OHFmoc-L-Arg(Pbf)-OHScheme 3the removal of the protective group R5 and the amidation, and then removing the protective group P3
362Scheme 1Cbz-Gly-OHFmoc-L-Dap(Boc)-OHScheme 4the removal of the protective group P3, alkylation
363Cbz-Gly-OHFmoc-L-Dap(Boc)-OHScheme 4the removal of the protective group P3, dialkylamino
364Scheme 1Alloc-Gly-OHFmoc-L-Dap(Boc)-OHScheme 4the removal of the protective group P3
365Scheme 1Alloc-Gly-OHFmoc-L-Dap(Boc)-OHScheme 4the removal of the protective group P3
366Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
367Scheme 1Cbz-Gly-OHFmoc-L-Dap(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
367Scheme 1Cbz-Gly-OHFmoc-L-Dap(Boc)-OHScheme 4the removal of the protective group P3,�eat dialkylamino alkylamino

Vos.The path AndScheme 1: VN(R2)-Y-CO2NP2NH-CH(U)-CO2HThe transformation in the productmodification U
368Scheme 1Cbz-Gly-OHFmoc-L-Dap(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
369Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
370Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
371Scheme 1Alloc-Gly-OHFmoc-L-Dap(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
372 Scheme 1Alloc-Gly-OHFmoc-L-Dap(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
373Scheme 12-naftaly-Gly-OHFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3
374Scheme 12-naftaly-Gly-OHFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3
375Scheme 12-naftaly-Gly-OHCbz-L-Asp[N(Me)OMe]-OHScheme 3the transformation of P3 in the aldehyde then reductive amination of
376Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
377Scheme 12-naftaly-Gly-IT Fmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3
378Scheme 1Boc-Gly-OHCbz-L-Asp[N(Me)OMe]-OHScheme 4the transformation of P3 in the aldehyde then reductive amination of
379Scheme 1Boc-Gly-OHCbz-L-Asp[N(Me)OMe]-OHScheme 4the transformation of P3 in the aldehyde then reductive amination of
380Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
381Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
382Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4 the removal of the protective group P3, then dialkylamino alkylamino
383Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
384Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
385Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
386Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3

Vos.The path AndScheme 1: VN(R2)-Y-CO2HP2NH-CH(U)-CO2HThe transformation in the product modification U
387Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
388Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
389Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
390Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
391Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
392Scheme 1 Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
393Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
394Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
395Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
396Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
397Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkyl�El of alkyldiphenyl
398Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, alkylation
399Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, alkylation
400Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, alkylation
401Scheme 12-naftaly-Gly-OHFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3
402Scheme 12-naftaly-Gly-OHFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3
403Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OH the removal of the protective group P3, then dialkylamino alkylamino
404Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, alkylation
405Scheme 12-naftaly-Gly-OHFmoc-L-Dab(Boc)-OHScheme 3the removal of the protective group P3
406Scheme 12-naftaly-Gly-OHFmoc-L-Dab(Boc)-OHScheme 3the removal of the protective group P3
407Scheme 12-naftaly-Gly-OHFmoc-L-Orn(Boc)-OHScheme 3the removal of the protective group P3
408Scheme 1Cbz-Gly-OHFmoc-L-His(Boc)-OHScheme 4the removal of the protective group P3

The path And
Vos.Scheme 1: VN(R2)-Y-CO2HP2NH-CH(U)-CO2HThe transformation in the productmodification U
409Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
410Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
411Scheme 1Cbz-Gly-OHFmoc-L-Dap(Boc)-OHScheme 4the removal of the protective group P3, acylation
412Scheme 2Cbz-Gly-OHN-p-(2-pyridyl)-1-Ala-OllilScheme 4no
413Scheme 12-naftaly-Gly-OHFmoc-L-Dab(Boc)-OHScheme 3 the removal of the protective group P3, then dialkylamino alkylamino
414Scheme 12-naftaly-o-OHFmoc-L-Dab(Boc)-OHScheme 3the removal of the protective group P3, then dialkylamino alkylamino
415Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
416Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
417Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
418Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
419Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
420Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
421Scheme 1Cbz-Gly-OHFmoc-L-Dap(Boc)-OHScheme 4the removal of the protective group P3, acylation
422Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
423Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, condensation
424Scheme 1Cbz-Gly-OHPmoc-L-Dab(Boc)-OH Scheme 4the removal of the protective group P3, condensation, recovery
425Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
426Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
427Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino

Vos.The path AndScheme 1: VN(R2)-Y-CO2HP2NH-CH(U)-CO2HThe transformation in the productmodification U
428Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 4the removal of the protective group P3, then dialkylamino alkylamino
429Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
430Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
431Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 3the removal of the protective group P3, then dialkylamino alkylamino
432Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
433Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 5the removal of the protective group P3, then dialkylamino alkylamino
434Scheme 1Cbz-Gly-OHFmoc-L-Asp(OtBu)-OHScheme 4the removal of the protective group P3, the amidation
435Scheme 1Cbz-Gly-OHFmoc-L-Asp(OtBu)-OHScheme 4the removal of the protective group P3, the amidation
436Scheme 1Cbz-Gly-OHBoc-L-Gln(piperidyl)Scheme 4no
437Scheme 1Cbz-Gly-OHBoc-L-Gln(piperidyl)Scheme 4no
438Scheme 1Cbz-Gly-OHFmoc-L-Dap(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
439Scheme 1 Cbz-Gly-OHFmoc-L-Dap(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
440Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
441Scheme 1Cbz-Gly-OHFmoc-L-Orn(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
442Scheme 1Boc-AibFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
443Scheme 1Boc-AibFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
444Scheme 12-naftaly-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 3the removal of the protective group P3
445Scheme 12-naftaly-Gly-OHFmoc-L-Dab(Boc)-OHScheme 3the removal of the protective group P3

Vos.The path AndScheme 1: VN(R2)-Y-CO2HP2NH-CH(U)-CO2HThe transformation in the productmodification U
446Scheme 12-naftaly-Gly-OHFmoc-L-Dab(Boc)-OHScheme 3the removal of the protective group P3, then dialkylamino alkylamino
447Scheme 12-naftaly-Gly-ITFmoc-L-Dab(Boc)-OHScheme 3the removal of the protective group P3, then dialkylamino alkylamino
448Scheme 1Cbz-Gly-OHFmoc-L-Asp[N(Me)OMe]-OHScheme 4 the transformation of P3 in the aldehyde then reductive amination of
449Scheme 1Cbz-Gly-OHFmoc-L-Asp[N(Me)OMe]-OHScheme 4the transformation of P3 in the aldehyde then reductive amination of
450Scheme 1Cbz-Gly-OHFmoc-L-Asp[N(Me)OMe]-OHScheme 4the transformation of P3 in the aldehyde then reductive amination of
451Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the transformation of P3 in the aldehyde then reductive amination of
452Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the transformation of P3 in the aldehyde then reductive amination of
453Scheme 1Fmoc-Gly-OHBoc-L-(2-NO2)-Phe-OHScheme 5Hidirova�their nitrogen
454Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the transformation of P3 in the aldehyde then reductive amination of
455Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the transformation of P3 in the aldehyde then reductive amination of
456Scheme 12-naftaly-Gly-OHFmoc-L-Dab(Boc)-OHScheme 3the removal of the protective group P3, then dialkylamino alkylamino
457Scheme 12-naftaly-Gly-OHFmoc-L-Dab(Boc)-OHScheme 3the removal of the protective group P3, then dialkylamino alkylamino
458Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
459Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4no
460Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
461Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4no
462Scheme 1Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, reductive alkylation

Vos.The path AndScheme 1: VN(R2)-Y-CO2HP2NH-CH(U)-CO2HThe transformation in the productmodification U
463Scheme 1Alloc-Gly-OH Fmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, reductive alkylation
464Scheme 1Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, reductive alkylation
465Scheme 1Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 3the removal of the protective group P3
466Scheme 1Fmoc-Gly-OHBoc-L-(2-N02)-Phe-OHScheme 4hydrogenation of nitrogen
467Scheme 1Cbz-Gly-OHFmoc-L-Asp[N(Me)OMe]-OHScheme 4the transformation of P3 in the aldehyde then reductive amination of
468Scheme 1Cbz-Gly-OHFmoc-L-Asp[N(Me)OMe]-OHScheme 4the transformation in P3 and�edege, then reductive amination of
469Scheme 1Cbz-Gly-OHFmoc-L-Asp[N(Me)OMe]-OHScheme 4the transformation of P3 in the aldehyde then reductive amination of
470Scheme 1Cbz-Gly-OHFmoc-L-Asp[N(Me)OMe]-OHScheme 4the transformation of P3 in the aldehyde then reductive amination of
471Scheme 1Cbz-Gly-OHFmoc-L-Asp[N(Me)OMe]-OHScheme 4the transformation of P3 in the aldehyde then reductive amination of
472Scheme 1Cbz-Gly-OHN-Fmoc-1(1-Boc-piperidine-yl)-D,L-Gly-OHScheme 4the removal of the protective group P3
473Scheme 1Cbz-Gly-OHN-Fmoc-1(1-Boc-piperidine-yl)-D,L-Gly-OHScheme 4the removal of the protective group P3, restorative �alkilirovanny
474Scheme 1Cbz-Gly-OHBoc-L-Nle-OHScheme 4no
475Scheme 1Cbz-Gly-OHFmoc-L-HoLeu-OHScheme 4no
476Scheme 1Cbz-Gly-OHFmoc-L-Asp[N(Me)OMe]-OHScheme 4the transformation of P3 in the aldehyde then reductive amination of
477Scheme 1Cbz-Gly-OHFmoc-L-Asp[N(Me)OMe]-OHScheme 4the transformation of P3 in the aldehyde then reductive amination of
478Scheme 1Cbz-Gly-OHFmoc-L-Asp[N(Me)OMe]-OHScheme 4the transformation of P3 in the aldehyde then reductive amination of
479Scheme 1Cbz-Gly-OHFmoc-L-Asp[N(Me)OMe]-OH Scheme 4the transformation of P3 in the aldehyde then reductive amination of
480Scheme 1Cbz-Gly-OHFmoc-L-Asp[N(Me)OMe]-OHScheme 4the transformation of P3 in the aldehyde then reductive amination of

Vos.The path AndScheme 1: VN(R2)-Y-CO2HP2NH-CH(U)-CO2HThe transformation in the productmodification U
481Scheme 1Cbz-Gly-OHFmoc-L-Asp[N(Me)OMe]-OHScheme 4the transformation of P3 in the aldehyde then reductive amination of
482Scheme 1Fmoc-Gly-OHBoc-L-(2-N02)-Phe-OHScheme 5hydrogenation of nitrogen then dialkylamino alkylamino
483Scheme 12-naftaly-Gly-OH Boc-L-Gln(Me, nBu)-OHScheme 4no
484Scheme 12-naftaly-Gly-ITBoc-L-Gln(chex)-OHScheme 4no
485Scheme 1Cbz-Gly-OHN-Fmoc-1-(1-Boc-piperidine-4-yl)-D,L-Gly-OHScheme 4the removal of the protective group P3, reductive alkylation
486Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, alkylation
487Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, alkylation
488Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, alkylation
489 Boc-Gly-OHCbz-DL-γ-nitro-Leu-OHScheme 4restore P3 to amine
490Scheme 1Boc-Gly-OHCbz-DL-γ-nitro-Leu-OHScheme 4restore P3 to amine
491Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
492Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
493Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, dialkylamino alkylamino
494Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, dialkylamino ALCALDIA�house
495Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
496Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then reductive alkylation
497Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
498Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino
499Scheme 1Boc-Gly-OHCbz-DL-γ-nitro-Leu-OHScheme 4restoring P3 at Amin then dialkylamino alkylamino
500Scheme 1Boc-Gly-OHScheme 4restoring P3 at Amin then dialkylamino alkylamino
501Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3

Vos.The path AndScheme 1: VN(R2)-Y-CO2HR2N-SN(U)-CO2NThe transformation in the productmodification U
502Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
503Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, dialkylamino alkylamino
504Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4 the removal of the protective group P3, dialkylamino alkylamino
505Scheme 1Cbz-Gly-OHFmoc-L-HoCha-OHScheme 4no
506Scheme 1Cbz-Gly-OHFmoc-L-2-aminooctanoic acidScheme 4no
507Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, alkylation
508Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, alkylation
509Scheme 1Cbz-Gly-OHBoc-L-5-HO-Nle-OHScheme 4no
510Scheme 1Cbz-Gly-OHFmoc-L-HoSer(Me)-OH Scheme 4no
511Scheme 1Alloc-Gly-OHBoc-L-HoSer(Bzl)-OHScheme 4no
512Scheme 1Cbz-Gly-OHBoc-L-Leu-OHScheme 4no
513Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
514Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, dialkylamino alkylamino
515Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
516Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4with�Yachiyo protective group P3, dialkylamino alkylamino
517Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, dialkylamino alkylamino
518Scheme 2Boc-Gly-OHBoc-L-Arg(Cbz)z-OHScheme 4the removal of the protective group P3
519Scheme 2Boc-Gly-OHBoc-L-Arg(Cbz)2-OHScheme 4the removal of the protective group P3
520Scheme 2Boc-Gly-OHBoc-L-Arg(Cbz)2-OHScheme 4the removal of the protective group P3
521Scheme 1Boc-Gly-OHCbz-L-Asp[N(Me)OMe]Scheme 4the transformation of P3 in the aldehyde then reductive amination of
522Scheme 1Boc-Gly-OH Cbz-L-Asp[N(Me)OMe]Scheme 4the transformation of P3 to the aldehyde, then recovery
523Scheme 1Boc-Gly-OHCbz-L-Asp[N(Me)OMe]Scheme 4the transformation of P3 in the aldehyde then reductive amination of

/tr>
Vos.The path AndScheme 1: VN(R2)-Y-CO2HP2NH-CH(U)-CO2HThe transformation in the productmodification U
524Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5; reductive alkylation for R1Xthe removal of the protective group P3, then dialkylamino alkylamino
525Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
526 Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
527Scheme 1Gbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
528Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)Scheme 4the removal of the protective group P3, diallylamine anhydride
529Scheme 1Cbz-Gly-OHBoc-L-citrulline-OHScheme 4no
530Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)Scheme 4the removal of the protective group P3, reductive alkylation
531Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)Scheme 4removing sett�a combined group P3, Vallirana anhydride
532Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)Scheme 4the removal of the protective group P3, then dialkylamino alkylamino
533Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)Scheme 4the removal of the protective group P3, then the acylation of the isocyanate
534Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
535Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
536Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
537Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then reductive alkylation, then acetylation
538Scheme 1Cbz-Gly-OHFmoc-L-Dap(Boc)-OHScheme 4the removal of the protective group P3, then reductive alkylation
539Scheme 1Cbz-Gly-OHFmoc-L-Dap(Boc)-OHScheme 4the removal of the protective group P3, then guanylurea

Vos.The path AndScheme 1: VN(R2)-Y-CO2HP2NH-CH(U)-CO2HThe transformation in the productmodification U
540Scheme 1Cbz-Gly-OHFrnoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, Guan�generirovanie, the removal of the protective groups
541Scheme 1Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
542Scheme 1Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
543Scheme 1Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then sulfonylamine
544Scheme 1Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then sulfonylamine
545Scheme 1Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, acylation, removal of protective groups
546Schemes� 1 Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
547Scheme 1Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
548Scheme 1N-(6-Cl-2-naftaly)-Gly-OHFmoc-L-Dab(Boc)-OHScheme 3the removal of the protective group P3
549Scheme 1N-(6-CL-2-naftaly)-Gly-ITFmoc-L-Dab(Boc)-OHScheme 3the removal of the protective group P3, then dialkylamino alkylamino
550Scheme 1N-(6-CL-2-naftaly)-Gly-ITFmoc-L-Dab(Boc)-OHScheme 3the removal of the protective group P3, then dialkylamino alkylamino
551Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
552Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
553Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
554Scheme 1Gbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
555Scheme 1Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
556Scheme 1Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4 the removal of the protective group P3, then dialkylamino alkylamino

Vos.The path AndScheme 1: VN(R2)-Y-CO2HR2NH-CH(U)-CO2NThe transformation in the productmodification U
557Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5, the use of isocyanate for R1Xthe removal of the protective group P3, then dialkylamino alkylamino
558Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5; reductive alkylation, then acetylation for R1X and R2the removal of the protective group P3, then dialkylamino alkylamino
559Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3
560Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
561Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
562Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then sulfonylamine
563Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then acylation with CHLOROFORMATES
564Scheme 1Cbz-Gly-OHFmoc-DL-2-(1-Boc-4-piperidyl)-Gly-ITScheme 4the removal of the protective group P3, then reductive alkylation with ketone
565Scheme 1Cbz-Gly-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
566Scheme 1Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
567Scheme 1Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
568Scheme 1Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
569Scheme 1Cbz-[15N,1,2-13C2]Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then reductive alkylation, then acetylation
570Scheme 1 Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
571Scheme 1Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino

Vos.The path AndScheme 1: VN(R2)-Y-CO2HP2NH-CH(U)-CO2HThe transformation in the productmodification U
572Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
573Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
574Scheme 1Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
575Scheme 1Alloc-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
576Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
577Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino alkylamino
578Scheme 1Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 5the removal of the protective group P3, then dialkylamino�e alkylamino
579Scheme 1 exchange with D2O during removal of the protective Fmoc group and restore NaBD3CNCbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then reductive alkylation, then acetylation
580Scheme 1Cbz-Gly-OHFmoc-D-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
581Scheme 2Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
582Scheme 2Cbz-Gly-OHFmoc-D-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
583Schema Cbz-Gly-OHFmoc-L-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
584Scheme 2Cbz-Gly-OHFmoc-D-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino
585Scheme 1Cbz-Gly-OHFmoc-D-Dab(Boc)-OHScheme 4the removal of the protective group P3, then dialkylamino alkylamino

Example 102 - test radioligands linking human MC5R

Assessment of binding of compounds to human MC5R (hMC5R) by moving125I-labeled NDP-MSH receptor ligand peptide was carried out mainly as described in the specifications, manufactured by Perkin Elmer to accompany them frozen hMC5R membranes (Perkin Elmer catalog number RBXMC5M400UA).

[125I] NDP-MSH: labeled radioactive label of its own production and purified by HPLC:

Na125I (0.5 MCI, of 17.4 CI/mg) added to 50 µl phosphate� sodium (50 mm, pH 7.4) in Eppendorf tube, pre-coated with IODOGEN. After incubation for 10 minutes in phosphate buffer containing iodine, added to NDP-MSH (10 μl at 1 mg/ml) in a separate Eppendorf tube. It was incubated for another 10 min Iodized NDP-MSH was purified by HPLC on a Zorbax SB-300 column with solvent A: 0.05% of TFA and solvent B: 90% acetonitrile to 0.045% TFA with a linear gradient, 0-67% within 60 minutes.125I NDP-MSH was elyuirovaniya in 52 minutes after unlabeled starting material (48 minutes) and has been calculated and stored in the freezer. It was used not later than 48 hours as radioactive decay and decomposition of the ligand, resulting in significantly reduced specific binding observed after 72 hours.

Reagents:

The incubation buffer; 25 mm HEPES(N-2-hydroxyethylpiperazine-N-2-econsultancy acid)-KOH (pH 7.0), 1.5 mm CaCl2, 1 mm MgSO4, 0.1 M NaCl, 1 mm 1,10-phenanthroline and 1 tablet proteasome inhibitor Complete™/100 ml (Roche, catalog number 1873580) frozen membranes PMS Perkin Elmer: catalog number RBXMC5M400UA, 0.4 ml/vial; 400 microspine/vial, 0,78 mg/ml protein concentration Vials of frozen membranes were rapidly thawed immediately before use, diluted with binding buffer and shook. Kept resuspendable membrane on ice until then, until they added in �unki tablet.

Protocol binding for 400 microspine on the tube:

The tests were carried out in polypropylene 96 tablets. Membrane (0,78 mcg ál 1:40 dilution in incubation buffer) was added to [125I] NDP-MSH (0,84 nm; 2200 CI/mmol) and test compounds in a total volume of 140 μl. They were incubated for 1 hour at 37°C. Nonspecific binding was determined using a 3 mm NDP-MSH. The plates were filtered using a Tomtec harvester cells with GF/A filters (Wallac) (pre-soaked in 0.6% polyethyleneimine and washed three times with 1.0 ml of ice promising buffer (above incubation buffer without 1,10-phenanthroline and tablets proteasome inhibitor Complete™). The filters were dried in a 37°C oven, was placed in a bag for samples and added 5 ml Betaplatescint (Wallac). Received the filters counted in cassettes in a Microbeta Trilux (Wallac) for 1 min, Nonspecific binding only at 5%. Data analysis was performed using GraphPad Prism 4 through a competitive single-site binding model and the constant hill coefficient. Used the following equation: Y=Bottom + (Upper value - Lower value)/1/10^(X-logEC50), where X = log (concentration) and Y = the binding to match the data.

Example 103 - Identification of the preferred diastereoisomer for binding to MC5R

Four diastereoisomer one kit will replace�LEU tested for binding in the test hMC5R, as in Examples 102, as listed in Table 3.

Table 3:
Activity four diastereomers
Vos.stereochemistryHuman MC5R IC50(nm)
102(3R,5S)3500
103(3R,5R)500
104(3S,5R)1500
105(3S,5S)56

As you can see 3S, 5S isomer is almost ten times more active than the next most active isomer and substantially more active than the other two possible isomers. This unexpected high level of differential activity and, hence, specificity (S,S) diastereomers was unexpected and not predictable from knowledge hMC5R or previously known ligands.

Example 104 - Activity of selected compounds: linking hMC5R

Typical compounds of this invention were tested for binding in the test hMC5R as in Example 102, as listed in Table 4. �couplers have been tested as their triptorelin or hydrochloride salt, or the free base.

Table 4:
The properties of connections

x=<10 μm; XX=<1 μm, xxx=<100 nm xxxx=<10 nm

Vos.MS (M+1)tR(minutes)MC5R radioligand IC50
14556,25,74XXX
25595,36,22XXX
31To 539.35,92XX
33599,46,31XXXX
37473,45,59XXX
38541,35.78% was establishedXXX
39541,3 5,67XXX
49499,35,77XX
50613,5To 5.89X
54425,75,27XX
60629,46,27X
62629,36,22XX
63To 535.35,76XX
64603,36,04XXX
65577,25,97XXX
67591,35,94XXXX
71549,35,93XX
79 606,4UAH 6,033X
81743,45,489XX
83650,36,524XX
85606,26,008X
86743,55,410XX
87650,46,424X
102577,45,775X
103577,55,750XX
104577,55,783X
105577,35,79XXX
106561,46,05XX
107524,35,63XX
108603,36,11XXX
109566,25,65XX
110591,25,82XX
111581,35,95XXX
112578,35,26XXX
113579,35,52XX
114578,3Of 5.72XX
115527,35,41XX
116578,35.78% was establishedXX
117509,25,51118523,3The 5.56X
119To 523.25,51X
120512,35,10X
121549,45,96XX
122509,2The 5.56XX
123523,45,63X
124509,25,41X

Vos.MS (M+1)tR(minutes)MC5R radioligand IC50
125523,3Of 5.68X
126549,35,79 XX
127554,25,87X
128554,25,87XX
129539,1Is 5.58X
130596,55,87X
131582,45,88X
132567,4To 5.62X
133567,4To 5.62X
134582,45,88XX
135583.4 kilograms5,86XX
136595,45,31XXX
137595,4 5,87XX
138527,2Is 5.33XX
139533,35,54X
140620,2USD 6.16XXX
141620,26,21XX
142566,35,70XXX
143555,25,55XX
144555,25,74XXX
145583.4 kilograms6,21XX
146587,24,90X
147547,45.78% was establishedXX
148 571,25,34XX
149567,14,48X
150568,14,87X
151519,55,23X
152595,45,92XXX
153553,5Is 5.58XXX
154595,45,95XX
155609,45,88XX
156607,55,96XXX
157609,4-X
158607,45,88XXX
159579,3Of 5.83XX
160621,36,22XXX
161585,66,00X
162557,45,50X
163607,55,94XX
164607,25,69XX
165585,45,64XX
166557,36,06XXX
167559,55,47XXX
168585,5Is 5.58XX
169569,5Of 5.17 XX
170583,65,70XX
171567,65,79XXX

Vos.MS (M+1)tR(minutes)MC5R radioligand IC50
172To 621.46,01XX
173571,55,65XXX
174567,55,50XX
175567,5Levels lower than the 5.37XX
176Of 625.5Of 5.81XXX
177For 587.45,65XXX
178584,54,84 XX
179593,45,60XX
180583,65,41XX
181655,25,97XXXX
182501,45,20XX
183570,25,64X
184570,25,66XX
185583,55,43XXX
186607,35,28XXX
187583.4 kilogramsLevels lower than the 5.37XXX
188595,65,64XXX
189For 587.4 5.78% was establishedXX
190569,55,23XX
191567,75,92XXX
192To 621.46,19XX
193569,65,23XX
194571,55,69XXX
195567,55,98XXX
196571,56,00XX
197561,35,84XX
198575,45,98XX
199571,15,69XXX
200 621,36,19XXX
201591,2Of 6.02XX
202493,35,41XX
203Of 545.25,91XX
204591,35,88XXX
205591,35,90XX
206479,45,09XX
207609,46,13XX
208589,35,69XXX
209605,35,85XXX
210631,46,09XXXX
211597,4To 5.89XXX
212615,36,20XXX
213511,35,63XX
214545,45,92XXX
215637,66,15XX
216605,55,94XXX
217553,35,88XXX
218592,44,99X

Vos.MS (M+1)tR(minutes)MC5R radioligand IC50
219525,35,79XXX
220529,55,59XXX
221553,55,87XXX
222507,25,64X
223513,5Of 5.68XX
224553,3To 5.89XXX
225549,75,87XX
226617,46,21XXX
227523,35,49X
228575,5Of 5.72X
229569,25,87XX
230569,2Of 5.83 X
231611,26,20XXXX
232591,46,03XXX
233547,55,70XXX
234To 536.55,47XX
235561,76,11XX
236533,55,53XX
237585,56,23XXX
238550,5Of 5.81XXX
239568,5The 5.45X
240586,56.18 ofXXX
241To 542.5 5,57XX
242568,45,91XX
243579,75,60XX
244565,55,42X
245506,45,73XX
246519,35.78% was establishedXX
247637,55,84X
248624,36,28XXX
249603,26,14XXX
250589,46,04XXX
251543,36,30XXX
252 487,25,13X
253613,56,06XXX
254537,45,66X
255531,65,65XX
256551,55,47XX
257EUR 543.55,77X
258EUR 543.55,66XX
259581,55,10XX
260591,45,94XXX
261599,45,99XXX
262613,56,08XXX
263521,45,85XX
264589,3Of 5.81XXX
265575,55,79XXX

Vos.MS (M+1)tR(minutes)MC5R radioligand IC50
266537,25,61X
267551,45,70X
268558,4With 4.86X
269579,65,73XXX
270581,45,84XXX
271621,26,07XXX
272598,65,27XX
273626,75,64X
274507,36.35 mmXX
275517,4Is 6.51XXX
276515,35,18XXX
277511,4Of 5.81XXX
278575,36,71XXX
279585,46,83XXXX
280To 539.35,87XX
281499,5To 5.62XX
282497,6Is 5.58 XX
283531,4To 5.89XXX
284607,36,29XXXX
285567,35,99XXX
286565,45,93XXX
287583,5Of 6.02XXXX
288579,66.18 ofXXX
289515,3Is 5.58XX
290620,55,44XX
291620,55,38X
292531,55,22XX
293559,5 5,74XX
294607,46,06XX
295557,45,61XX
296534,47,27XX
297544,5Of 7.42XX
298559,46,59XX
299549,4Is 6.42XX
300567,3Of 6.52XX
301635,57,34XX
302593,5Of 6.02XXX
303573,45,47XX
304 481,45,47XX
305521,56,10XXX
306641,47,38XX
307655,3Members, 7.59XX
308485,3Of 5.17X
309553,35,82XX
310To 535.3Of 5.72XX
311553,55,39X
312621,26,06XX

Vos.MS (M+1)tR(minutes)MC5R radioligand IC50
313 603,45,94XX
314572,3Of 4.91X
315574,57,69XX
316584,57,83XX
317617,7To 7.04XX
318To € 627.57,11XXX
319582,37,44XX
320592,4To 7.55XX
321588,48,00XX
322598,48,15XX
323568,1To 7.28XX
324578,37,45XX
325519,25,93XX
326511,25,94XXX
327540,35,61XX
328To 523.2Levels lower than the 5.37XX
329498,45,49XX
330481,55,27X
331514,35,52X
332514,25,42X
333505,45,27X
334480,3Is 5.33 X
335514,45,65X
336514,4To 5.62XX
337514,35,63X
338477,35,35X
339531,55,65X
340480,45,38X
341487,25,55XX
342527,35,96XX
343587,26,33XXX
344567,36,12XXX
345577,2 6,31XXXX
346443,25,43XX
347435,35,46XX
348503,1Is 5.58XX
349511,45,73XXX
350493,75,71XXX
351427,35,04X
352Of 423.45,28X
353427,35,13X
354423,3Of 5.32X
355489,4Is 6.42XX
356 589,45,92XX
357581,36,03X
358480,4Is 5.33X
359555,4Of 5.81XXX

Vos.MS (M+1)tR(minutes)MC5R radioligand IC50
360612,65,49X
361620,5-X
362595,46,12XX
363637,26,30X
364505,1Of 6.46XX
365 485,26,26XX
366To 491.25,69XX
367573,16,07XX
368565,2To 6.88XXX
369To 491.25,69XX
370483,45,77XXX
371559,16,12XX
372539,25,84XX
373473,3Of 5.29XX
374473,25,21X
375549,46,03XX
376To 621.46,13XXX
377493,3Of 5.32XX
378587,26,17XXX
379577,46,04XXX
380559,36,01XXX
381551,35,99XXX
382551,46,04XXXX
383555,36,19XXX
384575,46,11XXX
385589,36,06XXX
386443,6Of 5.36 XX
387Which is 459, 95,66XX
388503,25,74XX
389511,45,65XXX
390527,35,95XXX
391573,26,07XXX
392483,35,97XX
393465,4Of 5.81XX
394To 475.35,98XX
395623,26,41XXXX
396607,46,17XXXX
397585,4 6,12XXX
398573,26,12XXX
399563,45,95XX
400581,36,12XX
401479,1Of 5.68X
402487,4The 5.45XX
403551,5Is 6.42XXX
404525,36,31XX
405487,35,69X
406473,45,51XX

Vos.MS (M+1)tR(minutes) MC5R radioligand IC50
407487,45,40X
408568,15,91X
409601,36,08XXX
410533,35,82X
411622,36,90X
412579,36,60X
413555,46,00XX
414555,46,10XXX
415607,56,60XXX
416539,46.32 perXX
417 593,56,26XXX
418525,36,03XX
419601,36,09XXX
420533,2Of 5.81XX
421627,47,20X
422601,36,10XXX
423609,4Of 7.64XX
424613,46,31XXX
425575,36,26XXXX
426537,45,98XXX
427RUB 525.15,96XXX
428561,46,26XXXX
429559,16,11XXX
430545,16,01XXX
431569,35,92XX
432645,36,28XXXX
433640,26,70XXX
434622,36,49XX
435613,4Of 7.03XX
436603,27.23 percentXXX
437587,27,01X
438561,4To 6.88 XXX
439545,16,68XX
440589,4For 6.24XXX
441573,15,95XXX
442559,15,90XX
443627,46,56XX
444493,2Of 5.68X
445493,25,71X
446561,45,93X
447561,46,09XX
448581,36,93XX
449547,3 6,00XXX
450561,25,92XXX
451567,26,94XX
452581,26,45XXX
453593,36,56XX

Vos.MS (M+1)tR(minutes)MC5R radioligand IC50
454547,26,12XXX
455574,35,67XXX
456555,36,15XXX
457555,3The 6.25XXX
458607,2 6,20XXX
459539,25,90X
460607,36,11XX
461539,15,94X
462577,16,37XXXX
463561,16,17XXX
464549,26,28XXXX
465507,26,00XXX
466583,36,38XX
467595,26,50XXXX
468560,35,64XXX
469 575,2To 6.62XXX
470575,26,27XXXX
471573,26,28XXXX
472547,25,96XXX
473617,2Of 6.52XXX
474520,27,40XX
475USD 534.3With 7.66XXX
476For 587.46,55XXX
477575,25,82XXX
478603,45,98XXX
479573,16.32 perXXX
480573,16.18 ofXXXX
481561,26,21XXX
482651,3Of 6.85X
483571,17,11XX
484583,36,98XX
485575,26,06XXX
486593,46,01XXX
487549,25,87XXX
488Weighed 563.36,05XXX
489457,25,64X
490457,25.78% was established X
491525,26,05XXX
492525,36,13XXX
493535,26,33XX
494535,26,50X
495491,35,63XX
496533,25,94XXX
497533,16,44XXX
498603,36,44XXX
499603,27,15XXX
500603,26,96XXX

Vos.MS (M+1)tR(minutes)MC5R radioligand IC50
501To 473.15,99XX
502473,26,09XX
503541,2System 6.34XXX
504541,16,43XXX
505574,28,16X
506548,37,86XXX
507633,45,66XX
508591,16,36XXXX
509536,26,57XXX
510522,4 6,72XXX
511598,27,49X
512520,1Of 7.36X
513455,25,16X
514523,36,09XX
515Of 471.15,53XXXX
516To 539.36,11XXX
517539,26,19XXXX
518- 519,3Of 5.72XX
519496,3Of 4.91XXX
520494,44,65XX
521 595,36,30XXX
522492,2USD 6.16X
523595,36,39XX
524Of 545.25,91XXX
525523,05,88XX
526Of 471.15,79XX
527To 539.36,14XXX
528573,16,50X
529564,56,60XX
530587,26,61XX
531601,3Of 7.03X
532589,36,59XXX
533592,37,08XX
534567,3System 6.34XXX
535574,26,14XXX
536601,36,69XXX
537591,37,24XX
538To 535.36,94XXX
539To 535.36,37XXX
540573,16,13XX
541519,25,98XX
542587,1System 6.34 XX
543597,16,61X
544673,07,50X
545618,4-X
546533,16,20XXX
547603,16,57XXX

Vos.MS (M+1)tR(minutes)MC5R radioligand IC50
548513,36,00XXX
549581,26,22XXX
550581,06,33XXXX
551473,36,03 XX
552541,16,36XXX
553625,46,57XXX
554577,26,30XXX
555603,16,45XXX
556Of 589.16,23XXX
557554,3Of 6.02XX
558587,16,50X
559457,05,73X
560525,26,20XXX
561637,0The 6.75XXX
562613,3 Of 7.03XXX
563607,2-XX
564589,56,19XXX
565574,86,27XXXX
566618,96,74XXX
567587,76,19XXXX
568596,96,20XXX
569578,06,38XXXX
570597,0Is 6.42XXX
571626,96,70XXXX
572591,96,61XXXX
573 559,06,03XXXX
574612,8To 7.04XX
575644,9Of 6.79XXX
576570,96,04XXX
577570,86,21XXX
578Of 618.86,61XXXX
579Kostroma 579.96,39XXXX
580575,46,40XX
581575,26,26XXX
582575,26,11XXX
583575,16,21XX
584575,2The 6.25XX
585575,46,27X

Example 105 - Test radioligand binding MC5R using MC receptors from other species

Radioligands linking and testing camp was also conducted using membranes and cells expressing MC5R cloned from other species (mouse MC5R membrane was obtained from Euroscreen; MC5 receptors dog, macaque-rhesus, cynomolgus macaque and Guinea pigs have been cloned and expressed from cDNA libraries and temporarily transfected by, as described in Examples 107 and 109. The plasma membrane of the cells tested in radioligand the same test as in Example 102.

Example 106 - Activity of selected compounds: MC5R other types

Typical compounds of this invention were tested for binding to MC5R from other species, as described in Example 105, the results are listed in Table 5.

Table 5:
Associate the selected connection with MC5R from different types
Vos.human MC5R (membrane) IC50(nm) human MC5R (whole cells) IC50(nm)mouse MC5R (membrane) IC50(nm)canine MC5R (whole cells) IC50(nm)rhesus MC5R (membrane) IC50(nm)rhesus MC5R (whole cells) IC50(nm)
105572194000640060273000
6430127-130007307>5000

These results demonstrate the selectivity of the compounds of this invention for human MC5R compared to MC5R in other species. Although there is activity in other species, it is significantly reduced compared to human MC5R, which shouldn " t be expected, taking into account the high receptor homology between species.

Example 107 - Test radioligand binding MC1R, MC3R and MC4R person

Test radioligand binding was performed using the commercially available or prepared by development hMC1R, DMC3R and DMC4R membranes and [125I] NDP-MSH, with�publicly hMC5R the method in Example 102.

The plasma membrane of own development prepared from transfected mammalian cells (prepared as in Example 109, using plasmid DNA containing human MC1R, MC3R or MC4R gene or another gene of interest in a plasmid vector with a replication origin of a mammal):

Sessile cells were washed with warm buffer salt solution Hank (HBSS). 1 ml of cold HBSS was added to each vessel and the cells were scraped with a rubber scraper. Erased cells are added in 50 ml tube on ice. The tablet then washed twice with 5 ml of cold HBSS, and it also added to the test tube. The cells are centrifuged at 1000×g for 5 minutes in a tabletop centrifuge and the supernatant was decanted. The remaining cell precipitate was resuspended in 0.25 M sucrose. The cell suspension was again centrifuged as before, and the precipitate was resuspended in 5 ml of 0.25 M sucrose containing protease inhibitors. The cells are homogenized by 10 seconds surge Ika disperser, followed 30 seconds on ice. Homogenization and ice-cold incubation was repeated three times. The mixture was then centrifuged at 1260×g for 5 min. Supernatant was decanted into another centrifuge tube, to which was added a buffer containing 50 mm Tris (Tris(gidroximetil)aminomethane), pH 7.4, 12.5 mm MgCl2, 5 mm EGTA(etilenvinilatsetata acid) and protease inhibitors to get the volume to 30 ml. It was centrifuged at 30,000×g for 90 min at 4°C. the Resulting precipitate was resuspended in 1 ml of the above buffer, which also contained 10% glycerol. Took aliquots of membranes in cryovials, which were quickly frozen in a bath of dry ice/ethanol before storage at -80°C until then, until required for use.

Example 108 - selectivity of selected compounds: linking hMCR

Typical compounds of this invention were tested for binding in the test hMC1R, DMC3R, hMC4R and hMC5R, as shown in Examples 102 and 107, as listed in Table 6.

Table 6:
The selectivity of binding of hMCR chosen connections
Vos.human MC5R IC50(nm)human MC1R IC50(nm)human MC3R IC50(nm)human MC4R IC50(nm)
10557666017503280
643192202240339285015006060
34815020000183020000

These results demonstrate the selectivity of the compounds of this invention for human MC5R compared to other receptor subtypes of the human melanocortin receptor family..

Example 109 - inhibition or stimulation of camp signal in the cells, 30 expressing MC5R person

Temporary transfection of cell lines mammals:

Cell line of mammalian cells human embryonic kidney (HEK 293), contained in modified according to the method of Dulbecco environment Needle (DMEM) with 5% embryonic bovine serum, L-glutamine, high glucose, and antibiotics/antimycotic. A day before transfection, cells were reseeded using trypsin/EDTA and seeded in 75 cm2the vessels so that they were approximately 90% confluent the next day. The next day, the cell medium was replaced with fresh antibiotic/antifungal-containing DMEM. Approximately 100 µl transfection lipid Turbofectin 8.0 (Origene Technologies, MD, USA) diluted� in 1.0 ml of serum and does not contain an antibiotic/antifungal OptiMEM in a sterile 15 ml test tube and incubated for 5 min at room temperature. After incubation, approximately 10-20 μg of plasmid DNA for expressing a gene (for example: pCMV6-XL4:Homo sapiens melanocortin 5 receptor (Origene Technologies, MD, USA) diluted in transfection mixture and incubated for another 30 min at room temperature. A solution of DNA/lipid is then added dropwise to the medium covering the cells under gentle rocking of the vessel. 24 hours after transfection, cells were reseeded and planted directly in two 75 cm2vessels and left for allocation. 48 hours after transfection cells were collected for use in the test solution for cellular dissociation.

Test of stimulation of cyclic-adenosine monophosphate [camp]:

Cells HEK 293, temporarily expressing melanocortin MC receptor were suspended in a stimulating buffer (buffer solely solution Khanka (HBSS), and 0.1% bovine serum albumin, protease inhibitors and 0.5 mm 3-isobutyl-1-methylxanthine), with 4×106cells/ml 5 ál of cells, plus compounds/peptides, as described below, was added to the wells of 384-well plates, as soon as possible after resuspension.

For the detection of antagonistic activity of the diluted test compounds at varying concentrations in stimulating the buffer to four times the concentrate and added to 2.5 μl into the wells containing the cells. 2,5 µl fourfold �rebamol concentrations of NDP-MSH or alpha-MSH was added to all wells, containing compounds. The negative control wells contained dwukrotnie concentrated NDP-MSH or alpha-MSH separately without connection.

For the detection of antagonistic activity, diluted test compounds at varying concentrations in stimulating the buffer of twice the concentrate and added 5 μl into the wells containing the cells. The positive control wells contained only NDP-MSH or alpha-MSH (without connections) in the twofold concentrate

The wells of the control basal level (camp) contained only stimulating buffer (no agonist or connections). On the tablet were included with known concentrations of camp (standards) in stimulating the buffer, but the cells in these wells was added. The tablet then incubated for 30 minutes at 37°C with mild shaking. After incubation added 10 µl of lysing buffer (10% tween 20, 1 M HEPES, 0.1% of BSA (bovine serum albumin), protease inhibitors, ddH2O (double distilled water)) in all measured wells. Detection of camp is then completed with a set of Alphascreen cAMP (Perkin Elmer, USA), as briefly described below. The dilution of 10 μl acceptor pellets/ml lysing buffer prepared in low light conditions. 5 µl of the diluted granules acceptor added to each measured the hole, and then the plate was incubated for 30 min at room temperature, in those�note, with a weak shaking. In low light conditions, the pellets donor were diluted in 10 µl/ml of lysing buffer to which was added 0,75 µl biotinylated camp/ml of lysing buffer. This mixture was allowed to inkubirovanija for 30 min at room temperature (in the dark) before you continue the test. After incubation, 5 µl/ml of a mixture biotinylating camp/donor bead added per well in low light conditions, and the plate incubated in the dark at room temperature for an additional hour. Plates were read on a tablet reader Envision (Perkin Elmer) after 1 hour and about 16 hours of incubation. The concentration of camp in the cells was determined with the use of a 'standard curve', formed from the results of known concentrations of cyclic amp, as described below.

Each analytical tablet contained a standard curve of known concentrations of camp, 10-fold dilutions. It is an essential part of the analysis, as there is a high inter-tablet variability. The plates were read on megamarketinccom tablet reader Envision, equipped with Alphascreen technology, and raw data were imported into the software GraphPad Prism 4 (GraphPad, USA) for analysis. The curve was adjusted to a known concentration using a nonlinear regression, especially with the help of sigmoidal equations "dose - resp�Naya response (Y = Bottom + (Lower + (Upper value - The lower value)/1+10logEC50-X), where the equation shows the response as a function of the logarithm of concentration. X represents the logarithm of the concentration of peptide/compound, and Y represents the response. Also considered in this equation are lower plateau upper plateau of the curve and EC50(effective concentration, 50%)

Example 110 - Activity of selected compounds: hMC5R

Typical compounds of this invention were tested for agonism or antagonism hMC5R as in Example 109, the results are listed in Table 7.

Table 7:
Agonism and antagonism hMC5 selected connections
Vos.human MC5R EC50(camp, agonism) (nm)human MC5R IC50(camp, antagonism 10-6M alpha-MSH) (nm)
105>10000400
64>1000070
33>10000190
348>1000094

<> Links

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Details of specific embodiments described in the present invention should not be construed as limitations. Various equivalents and modifications can be made without deviation from the essence and scope of this invention and it is understood that such equivalent embodiments of are part of this invention.

1. Method of lowering the activity of MC5R in which MC5R is subjected to impact by introducing inhibitory amount of a compound selected from the group consisting of the following compounds:
- N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(3-guanidine�propyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-3-(2-(diethylamino)ethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-methyl)-6-fluoro-2-naptime
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naptime
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)-ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
- N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-(2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(2-aminoethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)naphthalene-2-sulfonamide
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-6-bromo-N-methyl-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-4-methyl-2-oxo-1,4-diazepan-5-yl)methyl)-6-bromo-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-(isopropylamino)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-(3-methylguanine)propyl)-2-oxo-1,4-Diaz�pan-5-yl)methyl)-2-naptime
- (E)-N-(((3S,5S)-3-butyl-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
- N-((S)-1-((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalene-2-yl)ethyl)acetamide
- (S)-2-acetamido-N-((S)-1-((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalene-2-yl)ethyl)-3-(1H-imidazol-5-yl)propanamide
- propyl ether (S)-1-((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalene-2-yl)ethylcarbamate acid
- N-((R)-1-((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalene-2-yl)ethyl)acetamide
- (S)-2-acetamido-N-((R)-1-((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalene-2-yl)ethyl)-3-(1H-imidazol-4-yl)propanamide
- propyl ether (R)-1-((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalene-2-yl)ethylcarbamate acid
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-biphenyl-4-carboxamide
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-1H-indole-2-carboxamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl) - biphenyl-4-carboxamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-1H-indole-2-carboxamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-3- guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-(naphthalene-2-yl)acetamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-1,2,3,4-tetrahydronaphthalen-2-carboxamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)quinoline-3-carboxamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)quinoxaline-2-carboxamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)isoquinoline-3-carboxamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl) - benzamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)quinoline-2-carboxamide
- N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalene-1-ylmethyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalene-1-ylmethyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-(naphthalene-2-yl)acetamide
- N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalene-1-yl methyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-1-naptime
- N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalene-1-ylmethyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-(1H-indol-3-yl)acetamide
- N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalene-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-(biphenyl-4-yl)acetamide
- N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalene-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalene-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-(naphthalene-2-yl)acetamide
- N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalene-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)-methyl-1-naptime
- N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalene-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-(naphthalene-1-yl)acetamide
- N-(((3S,5S)-3-(4-aminobutyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)2-naptime
- (S)-N-(((3S,5S)-3-(4-aminobutyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-methyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
- (R)-N-(((3S,5S)-3-(4-aminobutyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-methyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
- N-(((3S,5S)-3-(4-aminobutyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)benzofuran-2-carboxamide
- (R)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-(3-methylguanine)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
- (S)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)benzofuran-2-carboxamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-2,3-dihydro-1H-indene-2-carboxamide
- (R)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)benzo[b]thiophene-2-carboxamide
- 2,4-dichloro-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
- 2,5-dichloro-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanido�propyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl) - benzamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)cyclohexanecarboxylic
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-3-phenoxybenzamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-4-phenoxybenzamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-1H-indole-2-carboxamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-3-phenylpropanamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-3,4-dimethylbenzamide
- 4-tert-butyl-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-2,4-dimethoxybenzamide
- 2-cyclohexyl-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)acetamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)benzo[d][1,3]dioxol-5-carboxamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-1H-benzo[d]imidazole-5-carboxamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-1H-benzo[d][1,2,3]triazole-5-carboxamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-goinig�npropyl)-2-oxo-1,4-diazepan-5-yl)-methyl)cyclopentanecarboxylic
- 3,4-dichloro-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)cinnamamide
- 3,5-dichloro-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
- 2-(2,4-dichlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)acetamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-1-methoxy-2-naptime
- 2-(3,4-dichlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)acetamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-6-methoxy-2-naptime
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(2-(guanidinium)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
(E)-3-(2,4-dichlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-adamantane-1-carboxamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-phenoxyacetamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-3-methoxy-2-naptime
- 4-bromo-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
- (S)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)m�Teal)-2,3-dihydrobenzo[b][1,4]dioxine-2-carboxamide
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
- (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(thiophene-2-yl)acrylamide
- (R)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxine-2-carboxamide
- (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-hydroxyphenyl)acrylamide
- (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2-methoxyphenyl)acrylamide
- (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-p-tolylacetic
- (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2-(trifluoromethyl)phenyl)acrylamide
- (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(3-fluorophenyl)acrylamide
- (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-methyl-3-phenylacrylate
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-phenylcyclopropanecarboxylic
- 2-(2,4-dichlorophenoxy)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)acetamide
(E)-3-(3-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-Diaz�pan-5-yl)-methyl)benzo[d]thiazole-6-carboxamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-5-phenylfuro-2-carboxamide
- (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(3-methoxyphenyl)acrylamide
- 6-bromo-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-guanidinopropionic)-2-oxo-1-phenethyl-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(3,4-dichlorophenacyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(2,4-dichlorophenacyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)benzo[b]thiophene-5-carboxamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide
- (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-methoxyphenyl)acrylamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-6-fluoro-2-naptime
(E)-3-(2-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
- (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2-hydroxyphenyl)acrylamide
- (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-m-tolylacetic
- (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidino�sawdust)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(3-(trifluoromethyl)phenyl)acrylamide
- (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(3-hydroxyphenyl)acrylamide
- (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2-fluorophenyl)acrylamide
- (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-o-tolylacetic
- (Z)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-fluoro-3-phenylacrylate
- N-((1-(2,2-diphenylether)-2-oxo-3-(piperidine-4-yl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-((1-(2,2-diphenylether)-2-oxo-3-(piperidine-4-ylmethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide
- (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-(trifluoromethyl)phenyl)acrylamide
- N-(((3S,5S)-1-(2,2-diphenylpropyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(cyclohexylmethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(1-adamantylamine)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-((S)-1,1-diphenylpropane-2-yl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-((R)-1,1-diphenylpropane-2-yl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-cyclohexyl-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-((R)-1-fluoro-1,1-diphenylpropane-2-yl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
(E)-3-(2,6-differenl)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
(E)-3-(2-chloro-6-fluorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
(E)-3-(4-bromophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
- (E)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-ethoxyphenyl)acrylamide
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)6-bromo-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)cinnamamide
- (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-methyl)-3-(4-chlorophenyl)acrylamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-1,4-dimethoxy-2-naptime
- N-(((3S,5S)-3-(3-(3,3-dimethylguanidine)propyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-6-hydroxy-2-naptime
- 6-amino-N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-methyl)-3-p-tolylacetic
- (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-methyl)-3-(4-fluorophenyl)acrylamide
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-dia�epan-5-yl)methyl)6-fluoro-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)2-ethylhexanate
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)3,4-dimethylbenzamide
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)3,4-dichlorobenzamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-ethylhexanate
- N-(((3S,5S)-3-(3-(cyclohexylamino)propyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-guanidinopropionic)-1-(naphthalene-2-yl)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-1-((9H-fluoren-9-yl)methyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(pyridin-3-ylmethyl)-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(pyridin-4-ylmethyl)-1,4-diazepan-5-yl)-methyl)-2-naptime
- (E)-N-(((3S,5S)-3-(3-(cyclohexylamino)propyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(4-(isopropylamino)butyl)-2-oxo-1,4-diazepan-5 yl)methyl)-2-naptime
- (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-methyl)-3-(2,4-differenl)acrylamide
- (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-methyl)-3-(4-cyanophenyl)acrylamide
- (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-methyl)-3-(naphthalene-2-yl)acrylamide
- N-(((3S,5S)-3-(3-�aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)2-(4-pertenece)acetamide
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)5-(4-chlorophenyl)furan-2-carboxamide
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)4-(1H-pyrrol-1-yl)benzamide
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)2-oxo-1-phenylpyrrolidine-3-carboxamide
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)5-(4-chlorophenyl isoxazol-3-carboxamide
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)5-(furan-2-yl isoxazol-3-carboxamide
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)2-phenylthiazol-4-carboxamide
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)4-(3,5-dimethyl-1H-pyrazol-1-yl)benzamide
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide
- N-(((3S,5S)-1-(2-cyclohexylethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-1-(2-(bicyclo[2.2.1]heptane-2-yl)ethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(2,2-bis(4-methoxyphenyl)ethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-(benzylamino)propyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-(cyclopentylamine)propyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-3-(cyclobutylamine)propyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-(bicyclobutane)propyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-benzyl-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(2,2-bis(4-fluorophenyl)ethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-guanidinopropionic)-1-(naphthalene-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-methyl)-3-(5-methylthiophene-2-yl)acrylamide
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-phenyl-1H-pyrazole-5-carboxamide
- (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-methyl)-3-(4-fluorophenyl)-N-methylacrylamide
- (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-4-methyl-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)4-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzamide
- (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-methyl)-3-(4-bromophenyl)acrylamide
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-defenilty)-2-oxo-3-(3-(pyrrolidin-1-yl)-propyl)-1,4-diazepan-5-yl)methyl)acrylamide
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(3-(piperidine-1-yl)-propyl)-1,4-diazepan-5-yl)methyl)acrylamide
- N-(((3S,5S)-3-(2-aminopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(2,2-diphenylether)-2-�CSR-3-(3-(pyrrolidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-(azetidin-1-yl)propyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-guanidinopropionic)-1-(naphthalene-1-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-guanidinopropionic)-1-(2-(naphthalene-2-yl)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-((S)-2-acetamido-2-phenylethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)cinnamamide
- N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-3,4-dimethylbenzamide
- 3,4-dichloro-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)benzamide
- N-(((3S,5S)-1-((S)-2-(cyclobutanecarboxylic)-2-phenylethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-((S)-2-(cyclohexanecarboxylate)-2-phenylethyl)-3-(3-guanidino-propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(aminomethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- (E)-N-(((3S,5S)-3-(aminomethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-methyl)-3-(4-chlorophenyl)acrylamide
- (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-methyl)-3-(4-fluorophenyl)acrylamide
- (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-methyl)-3-p-tolylacetic
- N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(piperidine-1-ylmethyl)-1,4-diazepan-5-yl)meth�l)-2-naptime
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(piperidine-1-yl-methyl)-1,4-diazepan-5-yl)methyl)acrylamide
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dimethylbenzamide
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-cinnamamide
- (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-methyl)-3-(4-chlorophenyl)acrylamide
- 3,4-dichloro-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
- N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3,4-dimethylbenzamide
- N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)cinnamamide
- (E)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide
- (E)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-p-tolylacetic
- N-(((3S,5S)-1-(3,5-dimethylbenzyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-1-((S)-2-benzamido-2-phenylethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-((R)-2-benzamido-2-phenylethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-guanidinopropionic)-1-(2-methoxy-2-phenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(2-(benzyloxy)-2-phenylethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(2-(allyloxy)-2-phenylethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-butyl-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- (E)-N-(((3S,5S)-3-butyl-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
- (E)-N-(((3S,5S)-3-(3-amino-3-oxopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
- N-(((3S,5S)-3-(3-amino-3-oxopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- (E)-N-(((3S,5S)-3-(3-acetamidophenyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-p-tolylacetic
- N-(3-((2S,7S)-4-(2,2-diphenylether)-3-oxo-7-(((E)-3-p-tolylamino)methyl)-1,4-diazepan-2-yl)propyl)cyclohexanecarboxylic
- N-(((3S,5S)-3-(3-guanidinopropionic)-2-oxo-1-(2-phenoxy-2-phenylethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- ethyl 3-((3S,5S)-5-((2-naphthalide)methyl)-3-(3-guanidinopropionic)-2-oxo-1,4 diazepan-1-yl)-2-phenylpropenoic acid
- N-(((3S,5S)-1-(2-ethylbutyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-((3,5-dimethylcyclohexyl)methyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(2-((2S,7S)-7-((E)-3-(4-chlorophenyl)acrylamido)methyl)-4-(2,2-diphenylether)-3-oxo-1,4-diazepan-2-yl)ethyl)cyclohexanecarboxylic
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-3-(2-(2-cyclohexylamino)ethyl)-1-(,2-diphenyl-ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
- N-(2-((3S,5R)-1-(2,2-diphenylether)-2-oxo-3-(2-aminoethyl)-1,4-diazepan-5-yl)ethyl)-benzamide
- 3,4-dichloro-N-(2-((3S,5R)-1-(2,2-diphenylether)-2-oxo-3-(2-aminoethyl)-1,4-diazepan-5-yl)ethyl)benzamide
- N-(2-((3S,5R)-1-(2,2-diphenylether)-2-oxo-3-(2-aminoethyl)-1,4-diazepan-5-yl)ethyl)-2-naptime
- N-(2-((3S,5R)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)ethyl)benzamide
- 3,4-dichloro-N-(2-((3S,5R)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)ethyl)benzamide
- N-(2-((3S,5R)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)ethyl)-2-naptime
- N-(((3S,5S)-1-(3-(dimethylamino)-3-oxo-2-phenylpropyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(cyclohexylmethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-3-(2-aminoethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(3-oxo-3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naptime
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(3-oxo-3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)acrylamide
- N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-phenethyl-1,4-diazepan-5-yl)methyl)-2-naptime
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-phenethyl-1,4-diazepan-5-yl)methyl)acrylamide
- N-(((3S,5S)-3-(2-cyclohexylethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-3-(2-cyclohexylethyl)-1-(2,2-diphenylether)2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
- N-(((3S,5S)-3-benzyl-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- (E)-N-(((3S,5S)-3-benzyl-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
- N-(((3S,5S)-3-(2-aminoethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
- (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-3-(4-chlorophenyl)acrylamide
- N-(((3S,5S)-1-(3-chloro-5-terbisil)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(3,5-diferensial)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-1-(3-chloro-5-terbisil)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-1-(3,5-diferensial)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,6-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-1-(3,5-dimethoxybenzyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2-chlorbenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,3-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-1-(2,4-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-1-(3,4-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-1-(3-fluoro-5-methyl�benzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-1-(3-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-1-(4-chlorbenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-(2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-((1-phenylcyclohexyl)methyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- 3,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
- N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)-ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
- (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
- (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
- 3,4-dichloro-N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
- N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-4-chloro-3-perbenzoic
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-4-chloro-
3 - methylbenzamide
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo,4-diazepan-5-yl)methyl)-3-chloro-
4 - perbenzoic
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-chloro-
4 - methylbenzamide
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(piperidine-1-ylmethyl)-1,4-diazepan-5-yl)methyl)acrylamide
- N-(2-((3S,5R)-1-(2,2-diphenylether)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)-1,4-diazepan-
5 - yl)ethyl)-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-1-(3,5-bis(trifluoromethyl)benzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-1-(3-chlorbenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-2-oxo-1-(2-phenylbutyl)-3-(3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-guanidinopropionic)-2-oxo-1-(3-oxo-2-phenyl-3-(piperidine-1-yl)-propyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-guanidinopropionic)-2-oxo-1-(3-oxo-2-phenyl-3-(phenylamino)propyl)1,4-diazepan-5-yl)methyl)-2-naptime
- 3,4-dichloro-N-(2-((3S,5R)-1-(2,2-diphenylether)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)ethyl)benzamide
- 3,4-dichloro-N-(2-((3S,5R)-3-(2-(diisopropylaminoethyl)ethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)ethyl)benzamide
- N-(((3S,5S)-3-(aminomethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
- N-(((3S,5S)-3-(aminomethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- (E)-N-(((3S,5S)-3-(aminomethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-3-(4-chlorophenyl)acrylamide
- 3,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(piperidine-1-ylmethyl)-1,4-diazepa�-5-yl)methyl)benzamide
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(piperidine-1-yl-methyl)-1,4-diazepan-5-yl)methyl)acrylamide
- N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-(2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
- (E)-N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-(2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
- 3,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(pyrrolidin-1-ylmethyl)-1,4-diazepan-5-yl)methyl)benzamide
- N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(pyrrolidin-1-ylmethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-((S)-2-phenylpropyl)-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-((R)-2-phenylpropyl)-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-3-(2-(dimethylamino)ethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-1-(3,5-diethylphenyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-3-(2-(diethylamino)ethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
- N-(((3S,5S)-3-(2-(diethylamino)ethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime
- 3,4-dichloro-N-(((3S,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidine-1-yl)-ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
(E)-3-(4-chlorphen�l)-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)-ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naptime
- N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro 2-naptime
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naptime
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-bromo 2-naptime
- N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)-methyl)-6-fluoro-2-naptime
- 6-chloro-N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5 yl)methyl)-2-naptime
- 6-bromo-N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(2-aminoethyl)-1-((3,5-dimethylcyclohexyl)methyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
- N-(((3S,5S)-3-(2-aminoethyl)-1-((3,5-dimethylcyclohexyl)methyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-((3,5-dimethylcyclohexyl)methyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
- 6-chloro-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naptime
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-define�ethyl)-2-oxo-3-(2-(pyrrolidin-1-yl)-ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
- N-(((3S,5S)-1-(2,2-diphenylether)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- 3,4-dichloro-N-(((3S,5S)-1-(2,2-diphenylether)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
- N-(((3S,5S)-3-(3-aminopropyl)-1-((2,6-dimethylcyclohexyl)methyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)-methyl)-2-naptime
- 3,4-dichloro-N-(((3S,5S)-1-((3,5-dimethylcyclohexyl)methyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
- 3,4-dichloro-N-(((3S,5S)-1-((3,5-dimethylcyclohexyl)methyl)-3-(2-(isopropylamino)-ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
- N-(((3S,5S)-3-(2-aminoethyl)-1-(3-methyl-2-phenylbutyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-((R)-2-phenylbutyl)-1,4-diazepan-5-yl)-methyl)-2-naptime
- (E)-N-(((3S,5S)-3-((1H-imidazol-4-yl)methyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide
- 3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)propanamide
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)propanamide
- N-(((2S,7S)-7-(((E)-3-(4-chlorophenyl)acrylamido)methyl)-4-(2,2-diphenylether)-3-oxo-1,4-d�azepin-2-yl)methyl)picolinate
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(pyridin-2-ylmethyl)-1,4-diazepan-5-yl)methyl)acrylamide
- N-(((3S,5S)-1-((R)-3-methyl-2-phenylbutyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-((S)-3-methyl-2-phenylbutyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- (E)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-(4-isopropylphenyl)acrylamide
- (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-methyl)-3-(4-isopropylphenyl)acrylamide
(E)-3-(2,4-dimethylphenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
- (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-methyl)-3-(2,4-dimethylphenyl)acrylamide
(E)-3-(2,4-differenl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
- (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-methyl)-3-(2,4-differenl)acrylamide
- N-(((2S,7S)-7-(((E)-3-(4-chlorophenyl)acrylamido)methyl)-4-(2,2-diphenylether)-3-oxo-1,4-diazepan-2-yl)methyl)cyclohexanecarboxylic
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-3-(2-morpholinoethyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-3-(2-(2,5-dimethyl-1H-pyrrol-1-yl)ethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-3-(2-(2,5-dimethylpyrrole-1-yl)ethyl)-1-(2,2-dif�retil)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide
- 6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
(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
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-3-(2-(isopropylamino)ethyl)-2-oxo-1-((S)-2-phenyl-butyl)-1,4-diazepan-5-yl)methyl)acrylamide
- 6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(pyrrolidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- 3,4-dichloro-N-(((3S,5S)-2-oxo-1-(S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
- 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
- benzyl ester ((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methylcarbamate acid
(E)-3-(4-bromophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)-ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
- 5-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)1,4-diazepan-5-yl)methyl isoxazol-3-carboxamide
- (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-oxo-2-(pyridin-2-ylamino)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-oxo-2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide
- 6-chloro-N-(((3S,5S)-2-oxo-3-(3-oxo-3-(piperidine-1-yl)propyl)-1-((S)-2-phenylbutyl)1,4-diazepan-5-yl)methyl)-2-naptime
- 3,4-dichloro-N-(((3S,5S)-2-oxo-3-(3-oxo-3-(piperidine-1-yl)propyl)-1-((S-2-phenyl-butyl)-1,4-diazepan-5-yl)methyl)benzamide
- 6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(piperidine-1-ylmethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- 3,4-Dior-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(piperidine-1-ylmethyl)-1,4-diazepan-5-yl)methyl)benzamide
- 6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- 3,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)benzamide
- (E)-N-(2-((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)-propan-2-yl)-3-(4-chlorophenyl)acrylamide
(E)-3-(4-chlorophenyl)-N-(2-((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)propan-2-yl)acrylamide
- N-(((3S,5S)-3-(2-aminoethyl)-1-((R)-2-(4-chlorophenyl)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2-(4-chlorophenyl)propyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-1-((R)-2-(4-chlorophenyl)propyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-((S)-2-(4-chlorophenyl)propyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- 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
- 3,4-dichloro-N-(((3S,5S)-3-(2-(diethylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide
- 3,4-dichloro-N-(((3S,5S)-3-(2-morpholinoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide
- 3,4-dichloro-N-(((3S,5S)-2-oxo-3-(2-(phenylamino)ethyl)-1-((S)-2-phenyl-butyl)-1,4-dia�epan-5-yl)methyl)benzamide
- N-(((3S,5S)-3-(2-(benzylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
- (5S,9aS)-5-(2-aminobenzyl)-2-((E)-3-(4-chlorophenyl)acryloyl)-7-(2,2-diphenylether)-hexahydro-1H-imidazo[1,5-d][1,4]diazepin-6(5H)-he
- N-(((3S,5S)-3-(2-(tert-butylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
- 3,4-dichloro-N-(((3S,5S)-3-(2-(4-methylpiperazin-1-yl)ethyl)-2-oxo-1-((S)-2-phenyl-butyl)-1,4-diazepan-5-yl)methyl)benzamide
- N-(((3S,5S)-2-oxo-1-((R)-2-phenylpentyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-2-oxo-1-((S)-2-phenylpentyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-4-(trifluoromethyl)benzamide
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-4-(trifluoromethyl)benzamide
- N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-(trifluoromethyl)benzamide
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(trifluoromethyl)benzamide
- 6-chloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime
- 3,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide
- 6-chloro-N-(((3S,5S)-3-(2-(isopropylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-((S)-2-fenil�Teal)-1,4-diazepan-5-yl)methyl)-6 chloro-2-naptime
- N-(((3S,5S)-3-(2-aminobenzyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)2-naptime
- N-(((3S,5S)-3-(2-(benzyl(methyl)amino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
- 3,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperazine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide
- 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
- 3,4-dichloro-N-(((3S,5S)-3-(2-(diisopropylaminoethyl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide
- 3,4-dichloro-N-(((3S,5S)-3-(2-(4-demerol-1-yl)ethyl)-2-oxo-1-((S)-2-phenyl-butyl)-1,4-diazepan-5-yl)methyl)benzamide
- (S)-6-chloro-N-((2-oxo-1-(2-phenylbutyl)-3-(piperidine-4-yl)-1,4-diazepan-5-yl)-methyl)-2-naptime
- (S)-6-chloro-N-(3-(1-isobutylpyrazine-4-yl)-2-oxo-1-(2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-butyl-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naptime
- 6-chloro-N-(((3S,5S)-3-isopentyl-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)-methyl)-2-naptime
- 3,4-dichloro-N-(((3S,5S)-3-(2-(3,5-dimethylpiperidin-1-yl)ethyl)-2-oxo-1-((S)-2-phenyl-butyl)-1,4-diazepan-5-yl)methyl)benzamide
- 3,4-dichloro-N-(((3S,5S)-3-(2-(4-hydroxypiperidine-1-yl)ethyl)-2-oxo-1-((S)-2-phenyl-butyl)-1,4-diazepan-5-yl)methyl)benzamide
- 1-(2-((2S,7S)-7-((3,4-dichlorobenzamide)methyl)-3-oxo-4-((S)-2-phenylbutyl)-1,4-diazepan-2-yl)ethyl)piperidine-4-carboxylic acid
- N-(((3S,5S)-3-(2-(azepin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-yl)-methyl)-3,4-dichlorobenzamide
- 3,4-dichloro-N-(((3S,5S)-3-(2-((S)-2-demerol-1-yl)ethyl)-2-oxo-1-((S)-2-phenyl-butyl)-1,4-diazepan-5-yl)methyl)benzamide
- 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
- N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)benzyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-(butyl(methyl)amino)-3-oxopropyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(3-(cyclohexylamino)-3-oxopropyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- 6-chloro-N-((3-(1-ethylpiperazin-4-yl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)-methyl)-2-naptime
- (3S,5S)-5-((3,4-dichloraniline)methyl)-1-(2,2-diphenylether)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-2-it
- 6-chloro-N-(((3S,5S)-3-(2-guanidinate)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- 6-chloro-N-(((3S,5S)-3-(2-(3-methylguanine)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(2-aminoethyl)-1-((R)-2-ethyl-3-methylbutyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-3,4-dichlorobenzamide
- N-(((3S,5S)-3-(2-aminoethyl)-1-((S)-2-ethyl-3-methylbutyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-3,4-dichlorobenzamide
- 3,4-dichloro-N-(((3S,5S)-1-((R)-2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidine-1-yl)-ethyl)-1,4-diazepan-5-yl)methyl)benzamide
- 3,4-dichloro-N-(((3S,5S)-1-((S)-2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidine-1-yl)-ethyl)-1,4-diazepan-5-yl)methyl)benzamide
- N-(((3S,5S)-3-(2-amino-2-methylpropyl")-2-oxo-1-((S)-2-FeNi�butyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naptime
- N-(((3R,5R)-3-(2-amino-2-methylpropyl")-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naptime
- N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide
- 3,4-dichloro-N-(((3S,5S)-3-(2-(isopropylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide
- N-(((3S,5S)-3-(2-aminoethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naptime
- (498) 6-chloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- 6-chloro-N-(((3S,5S)-3-(2-methyl-2-(piperidine-1-yl)propyl)-2-oxo-1-((S)-2-phenyl-butyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- 6-chloro-N-(((3R,5R)-3-(2-methyl-2-(piperidine-1-yl)propyl)-2-oxo-1-((S)-2-phenyl-butyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(2-aminoethyl)-1-((R)-2-ethyl-3-methylbutyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-6-chloro-2-naptime
- N-(((3S,5S)-3-(2-aminoethyl)-1-((S)-2-ethyl-3-methylbutyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-6-chloro-2-naptime
- 6-chloro-N-(((3S,5S)-1-((R)-2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- 6-chloro-N-(((3S,5S)-1-((S)-2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- 6-chloro-N-(((3S,5S)-3-(2-cyclohexylethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- 6-chloro-N-(((3S,5S)-3-hexyl-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- 6-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methylcarbamic�yl)-2-naftalina acid
- 6-chloro-N-(((3S,5S)-3-(2-(3-isopropylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- 6-chloro-N-(((3S,5S)-3-(4-hydroxybutyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- 6-chloro-N-(((3S,5S)-3-(2-methoxyethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-3-(2-(benzyloxy)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)-methyl)-6-chloro-2-naptime
- 6-chloro-N-(((3S,5S)-3-isobutyl-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)-methyl)-2-naptime
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethyl-3-methylbut-3-enyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-3,4-dichlorobenzamide
- 3,4-dichloro-N-(((3S,5S)-1-(2-ethyl-3-methylbut-3-enyl)-2-oxo-3-(2-(piperidine-1-yl)-ethyl)-1,4-diazepan-5-yl)methyl)benzamide
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethyl-3-methylbut-3-enyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-6-chloro-2-naptime
- 6-chloro-N-(((3S,5S)-1-((R)-2-ethyl-3-methylbut-3-enyl)-2-oxo-3-(2-(piperidine-1-yl)-ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- 6-chloro-N-(((3S,5S)-1-((S)-2-ethyl-3-methylbut-3-enyl)-2-oxo-3-(2-(piperidine-1-yl)-ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime
- N-(((3S,5S)-1-(cyclohexylmethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl) - biphenyl-4-carboxamide
- N-(((3S,5S)-1-(cyclohexylmethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-(1H-indol-3-yl)acetamide
- N-(((3S,5S)-1-(cyclohexylmethyl)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)quinoline-3-carboxamide;
or its pharmaceutically acceptable salt.

2. SPO�about by p. 1, characterized in that the activity of MC5R at lower mammal

3. A method according to claim 1 or 2, characterized in that the specified connection selected from the group consisting of the following compounds:
- 3,4-dichloro-N-(((3S,5S)-3-(2-(4,4-deformability-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide;
- 3,4-dichloro-N-(((3S,5S)-3-(2-hydroxyethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide;
- 3,4-dichloro-N-(((3S,5S)-3-(2-(3,3-deformability-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide;
- (3S,5S)-5-((3,4-dichloraniline)methyl)-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-2-he;
- 3,4-dichloro-N-(((3S,5S)-1-(2-cyclopropylethyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide;
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2-cyclopropylethyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-6-chloro-2-naptime;
- 6-chloro-N-(((3S,5S)-1-(2-cyclopropylethyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime;
- 3,4-dichloro-N-(((3S,5S)-3-(2-(2,5-dioxopiperidin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide;
- 6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(3-ureidopropionic)-1,4-diazepan-5-yl)methyl l)-2-naphthas ID;
- 3,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(1,1,1-tryptophan-2-yl-amino)ethyl)-1,4-diazepan-5-yl)methyl)benzamide;
- 3,4-dichloro-N-(((3S,5S)-3-(2-(3,3-dimethyl-2,5-dioxopiperidin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide;
- N-(((3S,5S)-3-(2-(�sepan-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naptime;
- 6-chloro-N-(((3S,5S)-3-(2-(3-isopropylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime;
- N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)biphenyl-4-carboxamide;
- N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5 yl)methyl)-2-phenylthiazol-4-carboxamide;
- 4'-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)biphenyl-2-carboxamide;
- 6-chloro-N-(((3S,5S)-3-(2-(N-isopropylacrylamide)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime;
- 6-chloro-N-(((3S,5S)-3-((isopropylamino)methyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime;
- 6-chloro-N-(((3S,5S)-3-(guanidinate)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5 yl)methyl)-2-naptime;
- 2-(2,4-dichlorophenyl)-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acetamide;
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2,4-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide;
- 3,4-dichloro-N-(((3S,5S)-1-(2,4-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide;
- 3,4-dichloro-N-(((3S,5S)-1-(2,4-dichlorobenzyl)-3-(2-(methylsulfonylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide;
- 3,4-dichloro-N-(((3S,5S)-1-(2,4-dichlorobenzyl)-3-(2-(4-methylphenylsulfonyl)-ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide;
- N-(((3S,5S)-3-(2-((S)-2-amino-3-methylbutylamine)ethyl)-1-(2,4-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzo�ID;
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2,4-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naptime;
- 6-chloro-N-(((3S,5S)-1-(2,4-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime;
- N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-(2-(thiophene-3-yl)butyl)-1,4-diazepan-5-yl)-methyl)-6-chloro-2-naptime;
- 6-chloro-N-(((3S,5S)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1-((R)-2-(thiophene-3-yl)butyl)-1,4-diazepan-5-yl)methyl)-2-naptime;
- 6-chloro-N-(((3S,5S)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1-((S)-2-(thiophene-3-yl)butyl)-1,4-diazepan-5-yl)methyl)-2-naptime;
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethyl-2-methylbutyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-6-chloro-2-naptime;
- 6-chloro-N-(((3S,5S)-1-(2-ethyl-2-methylbutyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime;
- 6-chloro-N-(((3S,5S)-1-(2,2-diphenylether)-3-(2-morpholinoethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime;
- 6-chloro-N-(((3S,5S)-3-(2-morpholinoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime;
- 6-chloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(2-morpholinoethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime;
- 3,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(2-morpholinoethyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide;
- N-(3,4-dichlorobenzyl)-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acetamide;
- 1-(4-chlorbenzyl)-3-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)-ethyl)-1,4-diazepan-5-yl)methyl)urea;
- N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethyl-2-methylbutyl)-2-oxo-1,4-diazepan-5-yl)-methyl)-34-dichlorobenzamide;
- 3,4-dichloro-N-(((3S,5S)-1-(2-ethyl-2-methylbutyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide;
- 6-chloro-N-(((3S,5S)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1-(2,3,5-trichlorobenzoyl)-1,4-diazepan-5-yl)methyl)-2-naptime;
- 6-chloro-N-(((3S,5S)-3-(2-(1-methylethylacetate)ethyl)-2-oxo-1-((S)-2-phenyl-butyl)-1,4-diazepan-5-yl)methyl)-2-naptime;
- butyl ether 2-((2S,7S)-7-((6-chloro-2-naphthalide)methyl)-3-oxo-4-((S)-2-phenylbutyl)-1,4-diazepan-2-yl)ethylcarbamate acid;
- (S)-6-chloro-N-((3-(1-isopropylpiperazine-4-yl)-2-oxo-1-(2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime;
- 6-chloro-N-(((3S,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime;
- 5-(4-chlorophenyl)-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)-ethyl)-1,4-diazepan-5-yl)methyl isoxazol-3-carboxamide;
- 2,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide;
- N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-6-methoxy-2-naptime;
- 6-chloro-N-(([5-13C,a 415N](3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)-ethyl)-1,4-diazepan-5-yl)[13C]methyl)-2-naptime;
- N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-1-methoxy-2-naptime;
- (E)-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-(4-(triptoreline)phenyl)acrylamide;
- 5-(4-chlorophenyl)-N-(((3S,5S)-2-oxo-1-((S)-2-phenyl�scrap)-3-(2-(piperidine-1-yl)-ethyl)-1,4-diazepan-5-yl)methyl isoxazol-3-carboxamide;
- 2,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide;
- 5,6-dichloro-2-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)isoindoline-1,3-dione;
- (E)-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-(3-fluoro-4-(triptoreline)phenyl)acrylamide;
- 6-methoxy-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime;
- 1-methoxy-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime;
(E)-3-(3-fluoro-4-(triptoreline)phenyl)-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide;
- 6-xnop-N-(([5,6,6-2H3](3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)-ethyl)-1,4-diazepan-5-yl)[2N2]methyl)-2-naptime;
- 6-chloro-N-(((3R,5R)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime;
- 6-chloro-N-(((3S,5R)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime;
- 6-chloro-N-(((3R,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime;
- 6-chloro-N-(((3S,5R)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime;
- 6-chloro-N-(((3R,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naptime;
- 6-chloro-N-(((3R,5R)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidine-1-yl)ethyl)-1,4-di�sepan-5-yl)methyl)-2-naptime;
- N-(((3R,5S)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime;
- N-(((3R,5R)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime;
- N-(((3S,5R)-1-(2,2-diphenylether)-3-(3-guanidinopropionic)-2-oxo-1,4-diazepan-5-yl)-methyl)-2-naptime;
or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

possessing properties of binding with delta opioid receptors. In formula I R1 is selected from the group, consisting of phenyl, pyridinyl and thiazolyl, with R1 being optionally substituted with one or two substituents, independently selected from the group, consisting of C1-4alkoxy, fluorine atom, chlorine atom, bromine atom and cyanogroup; in addition, R1 is optionally substituted with di(C1-4alkyl)aminocarbonyl; Y represents O, S, H3, vinyl, ethinyl or S(O); R2 represents a substituent, selected from the group, consisting of hydrogen, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine atom, chlorine atom, bromine atom and hydroxy; Ra represents hydrogen or methyl; R3 is selected from the group, consisting of pyrrolidin-2-ylmethyl; pyrrolidin-3-ylmethyl; piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, piperidin-2-ylethyl, piperidin-3-ylethyl, piperidin-4-ylethyl, pyridine-4-yl-(C1-2)alkyl, azetidin-3-ylmethyl; morpholin-2-ylmethyl, morpholin-3-ylmethyl, imidazolylmethyl, thiazolylmethyl, (amino)-C3-6cycloalkyl, 3-hydroxy-2-aminopropyl, 8-azabicyclo[3.2.1]octanyl, 1-azabicyclo[2.2.2]octanyl, guanidinylethyl, 4-(imidazol-1-yl)phenylmethyl, 2-(methylamino)ethyl, 2-diethylaminoethyl, 4-diethylaminobut-2-yl, piperidin-3-yl, piperidin-4-yl and pyrrolidin-3-yl; with piperidin-3-yl being optionally substituted on a carbon atom with phenyl; with pyrrolidin-2-yl in pyrrolidin-2-yl-methyl, pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl being optionally substituted on a nitrogen atom with methyl, phenylmethyl, phenethyl or methylcarbonyl.

EFFECT: compounds can be used in the treatment of pain, induced by diseases or conditions, such as osteoarthritis, rheumatoid arthritis, migraine, burn, fibromyalgia, cystitis, rhinitis, neuropathic pain, idiopathic neuralgia, toothache, etc.

24 cl, 3 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-(1,2,5-oxadiazol-3-yl)benzamides of formula , in which R stands for an alkyl with 1-6 carbon atoms, halogenalkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, cyano, nitro, methylsulphenyl, acetylamino, methoxycarbonyl, methylcarbonyl, piperidinylcarbonyl, halogen, amino, or heteroaryl, selected from the group, including 1,2,3-triazolyl, 1,2,4-triazolyl, benzisoxazolyl, thiophenyl, pyridinyl and benzimidazol-2-yl, or heterocyclyl, selected from the group, including piperidinyl, respectively selected with s residues, selected from the group, including methyl, ethyl, methoxy and halogen; X and Z independently on each other respectively stand for nitro, halogen, cyano, alkyl with 1-6 carbon atoms, halogenalkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, OR1, S(O)nR2, alkyl-OR1 with 1-6 carbon atoms in alkyl, or heteroaryl, selected from the group, including 1,2,4-triazolyl; Y stands for nitro, halogen, OR1, S(O)nR2, NR1COR1, O-alkylheterocyclyl with 1-6 carbon atoms in the alkyl, and where heterocyclyl is selected from 1,4-dioxan-2-yl, O-alkyl heteroaryl with 1-6 carbon atoms in the alkyl, and where the heteroaryl is selected from pyrazolyl, alkyl-OR1 with 1-6 carbon atoms in the alkyl, alkyl-NR1SO2R2 with 1-6 carbon atoms in the alkyl, NR1R2, tetrahydrofuranyloxymethyl, tetrahydrofuranylmethoxymethyl, O(CH2)-3,5-dimethyl-1,2-oxazol-4-yl, O(CH2)2-O(3,5-dimethoxypyrimidin-2-yl, O(CH2)-5-pyrrolidin-2-one, O(CH2)-5-2,4-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one, or heteroaryl, selected from the group, including 1,2,3-triazolyl and pyrazolyl, or heterocyclyl, selected from the group, including 4,5-dihydro-1,2-oxazol-3-yl and tetrahydropyrimidi-2(1H)-on-1-yl, respectively substituted with s residues, selected from the group, including methyl, methoxy and cyanomethyl; R1stands for hydrogen, alkyl with 1-6 carbon atoms, alkinyl with 2-6 carbon atoms, cycloalkyl with 3-6 carbon atoms, cycloalkylalkyl with 2-6 carbon atoms in the cycloalkyl and 1-6 carbon atoms in the alkyl, phenyl or phenylalkyl with 1-6 carbon atoms in the alkyl, with six last residues being substituted with s residues, selected from the group, including a halogen, OR3 and CON(R3)2; R2 stands for alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-6 carbon atoms, phenyl or phenyl with 1-6 carbon atoms alkyl, with the five last residues being substituted with s residues, selected from the group, including a halogen, OR3, OCOR3, CO2R3, COSR3 and CON(R3)2; R3 stands for hydrogen or alkyl with 1-6 carbon atoms; n stands for 0, 1 or 2; s stands for 0, 1, 2 or 3. The invention also relates to the application of N-(1,2,5-oxadiazol-3-yl)benzamides of formula (I), as a herbicidal preparation and for fighting undesirable plants.

EFFECT: N-(1,2,5-oxadiazol-3-yl)benzamides, possessing herbicidal activity.

9 cl, 11 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula I, possessing ability of binding with delta-opioid receptors. In formula R1 is selected from the group, consisting of i) phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxyl, di(C1-4alkyl), aminocarbonyl, chlorine and fluorine, in such a way that only one di(C1-4alkyl)aminocarbonyl is present; ii) naphthyl; iii) pyridinyl, optionally substituted with one substituent, selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxy, fluorine, chlorine and cyano; iv) pyrimidin-5-yl; v) furanyl; vi) thienyl; vii) 5-oxo-4,5-dihydro-[1,2,4]oxodiazol-3-yl; and viii) di(C1-2alkyl)aminocarbonyl; Y represents ethyl, vinyl or bond; or Y represents O, when R1 represents optionally substituted phenyl, where substituent represents C1-4alcoxy; R2 represents phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, fluorine, chlorine and cyano, trifluoromethoxy and hydroxy; or R2 represents phenyl, substituted with one aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C1-4alcoxycarbonyl or carboxysubstituent; R3 is selected from the group, consisting of i) 3-aminocyclohexyl; ii) 4-aminocyclohexyl; iii) piperidin-3-yl; iv) piperidin-4-yl; v) pyrrolodin-2-yl-methyl, in which pyrrolodin-2-yl is optionally substituted by 3-rd or 4-th position with one or two fluorine-substituents; vi) azetidin-3-yl; vii) 2-(N-methylamino)ethyl; viii) 3-hydroxy-2-aminopropyl; ix) piperidin-3-yl-methyl; x) 1-azabicyclo[2.2.2]octan-3-yl; and xi) 8-azabicyclo[3.2.1]octan-3-yl; or R3 together with Ra and nitrogen atom, which they both are bound to, form piperazinyl, optionally substituted with 4-C1-4alkyl; Ra represents hydrogen, 2-(N-methylamino)ethyl or C1-2alkyl, optionally substituted with azetidin-3-yl.

EFFECT: compounds can be used in treatment of pain in the range from medium to strong, caused by diseases or conditions, such as osteoarthritis, migraine, burn, fibromyalgia, cystitis, rhenite, neuropathic pain, idiopathic neuralgia, toothache, etc.

21 cl, 4 tbl, 26 ex

FIELD: medicine.

SUBSTANCE: invention relates to a method of treatment or relieving the severity of cystic fibrosis in a patient, where the patient has the cystic fibrosis transmembrane receptor (CFTR) with R117H mutation, including a stage of introduction to the said patient of an effective quantity of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-N-methyl-4-oxo-1H-quinoline-3-carboxamide.

EFFECT: elaborated is the method of treating cystic fibrosis, based on the application of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-N-methyl-4-oxo-1H-quinoline-3-carboxamide.

3 cl, 4 tbl, 30 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to azetidine-substituted isoxazoline derivatives of formula (1), where A represents phenyl, naphtyl or heteroaryl, where said heteroaryl represents 5-6-membered aromatic monocyclic ring and contains 1 N heteroatom; each of R1a, R1b and R1c independently represents hydrogen, halogen, cyano, nitro or C1-C6halogenalkyl; R2 represents halogen, cyano or nitro; R3 represents hydrogen, halogen, hydroxyl, cyano, N3 or -NHR4; R4 represents hydrogen, -C(O)R5, -C(S)R5, -C(O)NRaR5, -S(O)pRc, -S(O)2NRaR5 or -C(NR7)R5; R5 represents hydrogen, C1-C6alkyl, C2-C6alkenyl, C0-C6alkylC3-C6cycloalkyl, C0-C6alkylphenyl, C0-C6alkylheteroaryl, representing 5-6-membered aromatic monocyclic ring, containing from 1 to 3 heteroatoms, each of which is independently selected from N, O and S, or C0-C6alkylheterocycle, where said heterocycle represents 4-membered monocyclic ring, containing 1 heteroatom, selected from N, O and S; R6 represents C1-C6halogenalkyl; R7 represents cyano; Ra represents hydrogen, C1-C6alkyl or C0-C3alkylC3-C6cycloalkyl; Rb represents hydrogen, C1-C6alkyl or C3-C6cycloalkyl; Rc represents C1-C6alkyl, C1-C6halogenalkyl, C1-C6halogenalkylC3-C6cycloalkyl, C0-C3alkylC3-C6cycloalkyl or C0-C3alkylphenyl, each of which is possibly substituted with at least one substituent, selected from cyano or halogen, each of groups C1-C6alkyl or C0-C3alkylC3-C6cycloalkyl ad R5 can be possibly and independently substituted with at least one substituent, selected from cyano, halogen, hydroxyl, C1-C6alkoxy, C1-C6halogenalkoxy, C1-C6halogenalkyl, -S(O)pRc, -SH, -S(O)pNRaRb, -NRaC(O)Rb, -SC(O)Rc and -C(O)NRaRb; and where grouping C0-C6alkylheteroaryl or C1-C6alkylheterocycle as R5 can be possibly additionally substituted with at least one substituent, selected from halogen, oxo, hydroxyl, C1-C6alkyl and -SH; n represents integer number 0 or 1, and p represents integer number 0, 1 or 2 and its stereoisomers. Invention also relates to pharmaceutical or veterinary composition, possessing parasiticidal activity, containing therapeutic amount of formula (I) derivative and pharmaceutically or veterinarily acceptable excipient, diluents or carrier.

EFFECT: azetidine-substituted isoxazoline derivatives of formula (1), intended for manufacturing means for treatment or control of parasitic infection or invasion in animal.

20 cl, 5 tbl, 225 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new aminotetraline derivatives of formula (I) and their physiologically tolerable salts. In formula

,

A means a benzene ring or a ring specified in a group consisting of a 5-merous ring

,

R means the group R1-W-A1-Q-Y-A2-X1-; R1 means hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, halogenated C1-C6-alkyl, tri-(C1-C4-alkyl)-silyl-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkyl, amino-C1-C4-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, an optionally substituted phenyl, C1-C6-alkoxy, di-C1-C6-alkylamino, an optionally substituted 5 or 6-merous heterocyclyl containing 1-3 heteroatoms specified in nitrogen and/or oxygen or sulphur; W means a bond; A1 means a bond; Q means -S(O)2- or -C(O)-; Y means -NR9- or a bond; A2 means C1-C4-alkylene, or a bond; X1 means -O-, C1-C4-alkylene, C2-C4-alkynylene; R2 means hydrogen, halogen, or two radicals R2 together with the ring atom to which they are attached form a benzene ring; R3 means hydrogen. The other radical values are specified in the patent claim. The invention also refers to intermediate products for preparing the compounds of formula (I).

EFFECT: compounds possess the properties of glycine transporter inhibitors, particularly GlyT1 and can find application in treating neurological and psychiatric disorders, such as dementia, bipolar disorder, schizophrenia, etc or for managing pain related to glycerinergic or glutamatergic neurotransmission dysfunction.

20 cl, 2 tbl, 326 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining (S)-2-methoxy-3-{4[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzo[b]thiophen-7-yl}propionic acid of formula (I) or its salts, in which formula (II) compound or its salt is hydrated in the presence of an iridium-including catalyst, in which the catalyst includes iridium and formula (III) compound, in which R1 stands for hydrogen, isopropyl, phenyl or benzyl and in which R2 stands for phenyl, 3,5-dimethylphenyl or 3,5-di-tert-butylphenyl. The invention also relates to the application of a complex of the catalyst, containing iridium and the formula (III) compound for obtaining the formula (I) compound.

EFFECT: obtaining the formula (I) compound with a high degree of conversion and enantiomeric purity.

6 cl, 4 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula I, or their racemic mixture, or their individual optic isomers, or pharmaceutically acceptable salts possessing the properties of TGR bile acid receptor agonist. The invention also refers to methods for preparing the compounds. In general formula I , X represents amino group R'R"N, wherein the substitutes R' and R" can be optionally identical, or represents hydrogen, C1-C6alkyl, C3-C6cycloalkyl; substituted C1-C6alkyl, wherein the substitute is specified in phenyl or phenoxy, each of which can be substituted by halogen in turn, C1-C3alkyl, C1-C3alkoxy, phenyloxy, C3-C6cycloalkyl, 5-6-merous heteroaryl with 1 nitrogen atom; aryl specified in phenyl optionally substituted by fluorine, C1-C3alkyl, C1-C3 alkoxy; 5-6-merous heteroaryl with nitrogen atom as heteroatom; C2-C4alkenyl, acyl specified in C1-C6alkylcarbonyl or C3-C6cycloalkylcarbonyl; or substituted oxygroup, which represents hydroxy group, wherein hydrogen is substituted by C1-C6alkyl optionally substituted by hydroxy, di(C1-C3alkyl)amino, phenyl, which can be substituted by halogen in turn, C1-C3alkyl, C1-C3alkoxy; C2-C4alkenyl; and 5-6-merous heterocyclyl with nitrogen atom, or sulphur atom, or oxygen atom as heteroatom; R1a and R1b represents hydrogen, C1-C3alkyl, or R1a and R1b together form methylene chain -(CH2)n-, wherein n=2-5; R1c and R1d represents hydrogen, C1-C3alkyl; R2 represents acyl group specified in C1-C6alkylcarbonyl, wherein alkyl can be substituted by phenyl or phenoxy, each of which can be substituted by halogen in turn, C1-C3alkyl, C1-C3alkoxy; C3-C6cycloalkylcarbonyl; phenylcarbonyl, which can be substituted by halogen, C1-C3alkyl, C1-C3alkoxygroup, oxygroup, C1-C3alkylene dioxygroup; 5-6-merous heteroarylcarbonyl with nitrogen atom, or oxygen atom, or sulphur atom as heteroatom, optionally substituted by carboxy, halogen or C1-C3alkoxycarbonyl, substituted aminocarbonyl group, wherein the substitute can be specified in C1-C6alkyl optionally substituted by C1-C3alkoxycarbonyl, halogen, 5-6-merous heteroaryl together with nitrogen atom, or oxygen atom or nitrogen atom as heteroatom; C3-C6cycloalkyl; phenyl optionally s