RU2246501C2 - Ligands for melanocortin receptors - Google Patents

Abstract

FIELD: organic chemistry, medicine.

SUBSTANCE: invention represents ligands MC-4 and/or MC-3 of the formula (I):

, wherein X means hydrogen atom, -OR¹, -NR¹R^1' and -CHR¹R^1' wherein R¹ and R^1' are taken among the group: hydrogen atom, (C₁-C₆)-alkyl and acyl; (1) each R² is taken independently among the group: hydrogen atom, (C₁-C₆)-alkyl; or (2) (a) R² bound with carbon atom that is bound with X and Z¹ and substitute R⁵ can be optionally bound to form carbocyclic or heterocyclic ring that is condensed with phenyl ring J; or (b) R² bound with carbon atom that is bound with ring Ar can be bound with R⁷ to form ring condensed with ring Ar; each among Z¹, Z² and Z³ is taken independently from the following groups: -N(R^3e)C(R³)(R^3a)-, -C(R³)(R^3a)N(R^3e)-, -C(O)N(R^3d)-, -N(R^3d)C(O)-, -C(R³)(R^3a)C(R^3b)(R^3c)-, -SO₂N(R^3d)- and -N(R^3d)SO₂- wherein each among R³, R^3a, R^3b and R^3c, R^3d, R^3e when presents is taken independently among hydrogen atom and (C₁-C₆)-alkyl; p is a whole number from 0 to 5 wherein when p above 0 then R⁴ and R^4' are taken among hydrogen atom, (C₁-C₆)-alkyl and aryl; R⁵ represents 5 substitutes in phenyl ring J wherein each R⁵ is taken among hydrogen atom, hydroxy-, halogen atom, thiol, -OR¹², -N(R¹²)(R^12'), (C₁-C₆)-alkyl, nitro-, aryl wherein R¹² and R^12' are taken among hydrogen atom and (C₁-C₆)-alkyl; or two substitutes R⁵ can be bound optionally to form carbocyclic or heterocyclic ring that is condensed with phenyl ring J; q = 0, 1, 2, 3, 4 or 5 wherein when q above 0 then R⁶ and R^6' are taken among hydrogen atom and (C₁-C₆)-alkyl; Ar is taken among the group consisting of phenyl, thiophene, furan, oxazole, thiazole, pyrrole and pyridine; R⁷ are substitutes at ring Ar wherein each R⁷ is taken among hydrogen, halogen atom, -NR¹³R^13', (C₁-C₆)-alkyl and nitro- wherein R¹³ and R^13' are taken among hydrogen atom and (C₁-C₆)-alkyl; r is a whole number from 0 to 7 wherein when r is above 0 then R⁸ and R^8' are taken among hydrogen atom and (C₁-C₆)-alkyl; B is taken among -N(R¹⁴)C(=NR¹⁵)NR¹⁶R¹⁷, -NR²⁰R²¹, heteroaryl ring and heterocycloalkyl ring wherein R¹⁴-R¹⁷, R²⁰ and R²¹ are taken independently among hydrogen atom and (C₁-C₆)-alkyl; s = 0, 1, 2, 3, 4 or 5 wherein when s is above 0 then R and R^9' are taken among hydrogen atom and (C₁-C₆)-alkyl; R¹⁰ is taken among the group consisting of optionally substituted bicyclic aryl ring and optionally substituted bicyclic heteroaryl ring; D is taken among hydrogen atom, amino- and -C(O)R¹¹ wherein R¹¹ is taken among the following group: hydroxy-, alkoxy-, amino-, alkylamino-, -N(R¹⁹)CH₂C(O)NH₂ wherein R¹⁹ represents (C₁-C₆)-alkyl, -NHCH₂CH₂OH and -N(CH₃)CH₂CH₂OH, or its isomers, salts, hydrates or biohydrolysable ester, amide or imide.

EFFECT: valuable medicinal properties of compounds.

18 cl, 107 ex

Description

Technical field

The present invention relates to new ligands for melanocortin (MC) receptors. These ligands preferably exhibit selectivity for MC-4 and / or MC-3 receptors compared to other melanocortin receptors (in particular, MC-1 receptor).

State of the art

Melanocortin peptides (melanocortins) are naturally occurring animal and human peptide hormones that bind to and stimulate MC receptors. Examples of melanocortins are α-MSH (melanocyte-stimulating hormone), β-MSH, γ-MSH, ACTH (adrenocorticotropic hormone) and their peptide fragments. MSH is mainly known for its ability to regulate peripheral pigmentation (Eberle 1988), while ACTH is known as inducing steroidoneogenesis (Simpson and Waterman, 1988). In addition, melanocortin peptides mediate a number of other physiological actions. It is reported that they affect motivation, learning, memory, behavior, inflammation, body temperature, pain, blood pressure, heart rate, vascular tone, natriuresis, blood supply to the brain, nerve growth and regeneration, placenta development, aldosterone synthesis and release, thyroxine release, spermatogenesis, ovarian mass, prolactin and FSH secretion (follicle-stimulating hormone), uterine bleeding in women,

secretion of sebaceous glands and pheromone, sexual activity, penile erection, blood glucose levels, intrauterine development of the fetus; behavior associated with the regulation of appetite, as well as other physiological manifestations associated with childbirth.

The peptide sequences of ACTH and various MSH have a common tetrapeptide skeleton of His-Phe-Arg-Trp. All these peptides are obtained by proteolytic processing of the preopiomelanocortin propeptide (POMC). Over the past few years, five different subtypes of the melanocortin receptor have been identified. Such MC receptors belong to class 7 transmembrane receptors associated with the G-protein domain. Five MC receptors, called MC-1, MC-2, MC-3, MC-4, and MC-5, all bind in a stimulatory manner to cAMP. Of the above receptors, the MC-2 receptor represents the ACTH receptor, while others represent subtypes of MSH receptors. The MC-1 receptor is present on melanocytes and melanoma. The MC-2 receptor is present primarily in the adrenal gland. mRNA (mRNA) for the MC-3 receptor has been found in the brain, as well as in the placental and intestinal tissues (Gantz et al. 1993a, Desarnaud et al. 1994, Roselli Rehfuss et al. 1993). The MC-4 receptor was originally found in the brain (Gantz et al. 1993b; Mountjoy et al 1994). The MC-5 receptor is expressed in the brain as well as in individual peripheral tissues (Chhajlani et al 1993; Gantz et al 1994; Griffon et al 1994; Labbu et al. 1994; Barrett et al. 1994; Fathi et al. 1995). More recent data from humans indicate that all cloned MC receptors have a broader

tissue distribution (Chhajlani, 1996) than originally thought.

As discussed above, representatives of the family of melanocortin receptors can be differentiated based on their distribution in the tissues. MC-4 receptors, like MC-3 receptors, have been found in the hypothalamus, an area of the brain that is thought to be involved in modulating eating behavior. Compounds demonstrating selectivity for MC-4 / MC-3 receptors have been shown to change attitudes toward food intake following intracerebroventricular and peripheral injection in rodents. In particular, it has been shown that agonists regulate nutrition in the direction of decreasing appetite, while antagonists have been shown to regulate nutrition in the direction of increasing appetite. See, Fan, W. et al., “Role of Melanocortinergic Neurons in Feeding and the Agouti Obesity Syndrome”, Nature, 385 (6612), pp. 165-8 (Jan. 9,1997).

The role of the MC-4 receptor subtype in regulating food intake and body weight regulation has been clearly confirmed in mammals. See, for example, Huszer, D. et al., “Targeted Disruption of the Melanocortin-4 Receptor Results in Obesity in Mice”, Cell, Vol. 88, pp. 131-141 (1997); Klebig, M.L. et al., “Ectopic Expression of the Agouti Gene in Transgenic Mice Causes Obesity, Features of Type II Diabetes, and Yellow Fur”, Proc. Natl Acad Sci., Vol. 92, pp. 4728-32 (1995); Karbon, W. et al., “Expression and Function of Argt, a Novel Gene Related to Agouti”, Abstract from the Nineteenth Annual Winter Neuropeptide

Conference (1998); Fan, W. et al., “Role of Melanocortinergic Neurons in Feeding and the Agouti Obesity Syndrome”, Nature, Vol. 385, pp. 165-168 (1997); Seely, R.J., “Melanocortin Receptors in Leptin Effects”, Nature, Vol. 390, p. 349 (1997); Comuzzie, A.G., “A Major Quantitative Trait Locus Determining Serum Leptin Levels and Fat Mass is Located on Human Chromosome 2”, Nat. Gen., Vol. 15, pp. 273-276 (1997); Chagnon, Y.C. et al., “Linkage and Association Studies Between the Melanocortin Receptors 4 and 5 Genes and Obesity-Related Phenotypes in the Quebec Family Study”, Mol. Med., Vol. 3 (10), pp. 663-673 (1997); Lee, F. and Huszar, D, “Screening Methods for Compounds Useful in the Regulation of Body Weight”, World Patent Publication WO 97/47316 (1997); and Shutter, J.R. et al., “Hypothalamic Expression of ART, a Novel Gene Related to Agouti, is Up-Regulated in Obese and Diabetic Mutant Mice”, Gen. & Dev. Vol. 11, pp. 593-602 (1997). Stimulation of the MC-4 receptor by its endogenous ligand, α MSH, produces a saturation signal and can mediate a decrease in the saturation signal regulated by leptin. It is believed that by providing potent MC-4 receptor agonists, appetite can be suppressed and beneficial results in weight loss can be achieved.

The role of the MC-3 receptor subtype in regulating body weight and energy distribution has recently been determined. See, for example, Chen, A.S. et al., “Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass”, Nature Genetics, Vol. 26, pp. 97-102 (2000); Butler, A.A. et al., “A Unique Metabolic Syndrome Causes Obesity in the

Melanocortin-3 Receptor-Deficient Mouse ”, Endocrinology, Vol 141, pp 3518-3521 (2000). It is believed that MC-3 receptor agonists can modulate energy distribution and can provide beneficial results in weight loss.

The above studies imply a non-duplicative role of the MC-3 receptor, in comparison with the MC-4 receptor, in energy homeostasis. Therefore, compounds that stimulate both MC-3 receptors and MC-4 receptors can have a greater effect on weight loss compared to compounds that are selective for either the MC-3 receptor subtype or the MC-4 receptor subtype .

Applicants have discovered a class of compounds that unexpectedly had high affinity for MC-4 and / or MC-3 receptor subtypes, and which are usually selective for precisely these MC receptor subtypes relative to other melanocortin receptor subtypes, in particular the MC-1 subtype. Accordingly, it is an object of the present invention to provide compounds that have affinity for subtypes of MC-4 and / or MC-3 receptors. Another objective of the invention is a method of administering the above compounds to animals or humans. Further objectives of the invention will be apparent from the following disclosure.

SUMMARY OF THE INVENTION

The invention relates to a class of compounds that are ligands for MC-4 receptors and / or MC-3 subtype. In particular, the invention relates to a compound having a structure,

corresponding to the formula (I):

Where:

(A) X is selected from hydrogen, fluoro, aryloxy, acyloxy, OR ¹ , SR ¹ , —NR ¹ R ^{1 ′} and –CHR ¹ R ^{1 ′} , where R ¹ and R ^{1 ′ are} independently selected from the group consisting of hydrogen, alkyl and acyl;

(B) (1) each R ^{2 is} independently selected from the group consisting of hydrogen, alkyl, halogen, and heteroalkyl; or

(2) (a) two adjacent R ² substituents, or adjacent R ² and R ³ substituents, may be combined to form a (3-8) membered carbocyclic or heterocyclic ring; or

(b) R ² bonded to a carbon atom that is bonded to X and Z ¹ and the substituent R ⁵ may optionally combine to form a carbocyclic or heterocyclic ring that is fused to the phenyl ring J; or;

(c) R ² bonded to a carbon atom that is bonded to an Ar ring can combine with R ⁷ to form a ring fused to an Ar ring; or

(d) R ² bonded to a carbon atom that is bonded to Z ² and Z ³ may optionally bind to R ⁸ to form a carbocyclic or heterocyclic

ring; or

(e) R ² bonded to a carbon atom that is bonded to Z ³ and D may optionally bind to R ¹⁰ to form a carbocyclic or heterocyclic ring;

(C) each of Z ¹ , Z ² and Z ^{3 is} independently selected from —OC (R ³ ) (R ^3a ) -; -C (R ³ ) (R ^3a ) O-; -S (O) _a C (R ³ ) (R ^3a ) -, where a is 0, 1 or 2; —C (R ³ ) (R ^3a ) S (O) _b -, where b is 0, 1 or 2; -N (R ^3e ) C (R ³ ) (R ^3a ) -; -C (R ³ ) (R ^3a ) N (R ^3e ) -; -C (O) N (R ^3d ) -; -N (R ^3d ) C (O) -; -C (O) C (R ³ ) (R ^3a ) -; -C (R ³ ) (R ^3a ) C (O) -; -C (R ³ ) (R ^3a ) C (R ^3b ) (R ^3c ) -; -C (R ³ ) = C (R ^3a ) -; -C≡ C-; -SO ₂ N (R ^3d ) -; -N (R ^3d ) SO ₂ -; -C (R ³ ) (R ^3a ) P (= O) (OR ^3f ) -; -P (= O) (OR ^3f ) C (R ³ ) (R ^3a ) -; -N (R ^3d ) P (= O) (OR ^3f ) -; -P (= O) (OR ^3f ) N (R ^3d ) -; -P (= O) (OR ^3f ) O-; -OP (= O) (OR ^3f ) -; cycloalkyl having from 3 to 8 ring atoms and heterocycloalkyl having from 4 to 8 ring atoms; Where

(1) each of R ³ , R ^3a , R ^3b and R ^3c , when present, is independently selected from hydrogen, hydroxy, alkoxy, aryloxy, acyloxy, thiol, alkylthio, acylthio, arylthio, amino, alkylamino, acylamino and alkyl;

(2) R ^3d , when present, is selected from hydrogen, alkyl and aryl;

(3) R ^3e , when present, is selected from hydrogen, alkyl, aryl and acyl; and

(4) R ^3f , when present, is selected from hydrogen and alkyl;

(D) p is 0, 1, 2, 3, 4 or 5; Where

(1) when p is greater than 0, each R ⁴ and R ^{4 ′ is} independently selected from hydrogen, alkyl, aryl, halogen, hydroxy, alkoxy, amino, and

acylamino;

(2) when p is greater than 1, two R ⁴ substituents, together with the carbon atoms to which they are bonded, can join to form a heterocycloalkyl, cycloalkyl or aryl ring; and

(3) when p is greater than 1, the R ⁴ substituents at two adjacent carbon atoms can both be zero, so that a double bond is formed between two adjacent carbon atoms, or both R ⁴ substituents and R ^{4 '} substituents at two adjacent carbon atoms are all zero, so that a triple bond is formed between two adjacent carbon atoms;

(E) R ⁵ represents 5 substituents (i.e., positions 2-6) in the phenyl ring J, where each R ^{5 is} independently selected from hydrogen, hydroxy, halogen, thiol, —OR ¹² , —SR ¹² , —SO ₂ N (R ^1Z ) (R ^{12 ′} ), —N (R ¹² ) (R ^{12 ′} ), alkyl, acyl, alkene, alkyno, cyano, nitro, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; where each R ¹² and R ^{12 ′ is} independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; or two R ⁵ substituents may optionally combine to form a carbocyclic or heterocyclic ring that is fused to the phenyl ring J;

(F) q is 0, 1, 2, 3, 4, or 5; Where

(1) when q is greater than 0, each R ⁶ and R ^{6 ′ is} independently selected from hydrogen, alkyl, aryl, halogen, hydroxy, alkoxy, amino, and acylamino;

(2) when q is greater than 1, two R ⁶ substituents, together with the carbon atoms to which they are bonded, can combine with

the formation of a heterocycloalkyl, cycloalkyl or aryl ring; and

(3) when q is greater than 1, the substituents R ⁶ at two adjacent carbon atoms can be zero, so that a double bond is formed between two adjacent carbon atoms, or both substituents R ⁶ and R ^{6 '} at two adjacent carbon atoms can be all are equal to zero, so that a triple bond is formed between two adjacent carbon atoms;

(G) Ar represents an aryl or heteroaryl ring selected from the group consisting of phenyl, thiophene, furan, oxazole, thiazole, pyrrole and pyridine;

(H) R ⁷ represents all substituents on the Ar ring, where each R ^{7 is} selected from hydrogen, halogen, —NR ¹³ R ^{13 ′} , alkyl, acyl, alkene, alkyno, cyano, nitro, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; where each R ¹³ and R ^{13 ′ is} independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; or two R ⁷ substituents may optionally combine to form a carbocyclic or heterocyclic ring fused to the Ar ring;

(I) r is 0, 1, 2, 3, 4, 5, 6, or 7; Where

(1) each R ⁸ and R ^{8 ′ is} independently selected from hydrogen, alkyl, halogen, hydroxy, alkoxy, and amino;

(2) when r is greater than 1, two R ⁸ substituents, together with the carbon atoms to which they are bonded, can join to form a heterocycloalkyl, cycloalkyl or aryl ring; and

(3) when r is greater than 1, the substituents R ⁸ when two adjacent

carbon atoms can be zero, so that a double bond is formed between two adjacent carbon atoms, or both both R ⁸ and both R ^{8 ′} substituents at two adjacent carbon atoms can all be zero, so that a triple bond is formed between two adjacent carbon atoms;

(J) B is selected from —N (R ¹⁴ ) C (= NR ¹⁵ , = O or = S) NR ¹⁶ R ¹⁷ , —NR ²⁰ R ²¹ , cyano (—CN), a heteroaryl ring, for example, thiophene, alkyl- or a dialkylamine, a heteroaryl ring containing at least one nitrogen atom in the ring, and a heterocycloalkyl ring containing at least one nitrogen atom in the ring, where R ¹⁴ , R ¹⁵ R ¹⁶ , R ¹⁷ , R ²⁰ and R ^{21 are} independently selected from hydrogen, alkyl, alkene, and alkyn; where, in addition, a combination of two or more R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ may optionally combine with the atoms to which they are attached to form a monocyclic or bicyclic ring; preferred are —N (R ¹⁴ ) C (= NR ¹⁵ ) NR ¹⁶ R ¹⁷ , cyano, N (R ¹⁴ ) C (= O) NR ¹⁶ R ¹⁷ , a heteroaryl ring containing at least one nitrogen atom in the ring and a heterocycloalkyl ring containing at least one nitrogen atom in the ring. More preferred are —N (R ¹⁴ ) C (= NR ¹⁵ ) NR ¹⁶ R ¹⁷ , N (R ¹⁴ ) C (= O) NR ¹⁶ R ¹⁷ , cyano and triazole and imidazole;

(K) s is 0, 1, 2, 3, 4 or 5; Where

(1) when s is greater than 0, each R ⁹ and R ^{9 ′ is} independently selected from hydrogen, alkyl, aryl, halogen, hydroxy, alkoxy, amino, and acylamino;

(2) when s is greater than 1, two substituents of R ⁹ , together with the carbon atoms to which they are bonded, can combine,

forming a heterocycloalkyl, cycloalkyl or aryl ring; and

(3) when s is greater than 1, the substituents R ⁹ at two adjacent carbon atoms can be zero, so that a double bond is formed between two adjacent carbon atoms, or both the substituents R ⁹ and both substituents R ^{9 '} at two adjacent carbon atoms can all be zero, so that a triple bond is formed between two adjacent carbon atoms;

(L) R ^{10 is} selected from the group consisting of an optionally substituted bicyclic aryl ring and an optionally substituted bicyclic heteroaryl ring; and

(M) D is independently selected from hydrogen, fluoro, hydroxy, thiol, acylthio, alkoxy, aryloxy, alkylthio, acyloxy, cyano, amino, acylamino, —C (O) R ¹¹ and —C (S) R ¹¹ ; where R ¹¹ selected from the group consisting of hydroxy; alkoxy; amino; alkylamino; -NHOR ¹⁸ , where R ^{18 is} selected from hydrogen and alkyl; —N (R ¹⁹ ) CH ₂ C (O) NH ₂ wherein R ¹⁹ is alkyl; -NHCH ₂ CH ₂ OH; -N (CH ₃ ) CH ₂ CH ₂ OH; and —NHNHC (= Y) NH ₂ , where Y is selected from O, S, and NH; and

(N) where, if at least one of Z ¹ , Z ² or Z ³ is other than -C (O) N (R ^3d ) - or -N (R ^3d ) C (O) -, then X and D may optionally be joined together via a linking group (linker), L, which contains all covalent bonds or covalent bonds and an ionic bond, so as to form a cyclic peptide analogue;

or its optical isomer, diastereomer or enantiomer; its pharmaceutically acceptable salt, hydrate or its biohydrolyzable ester, amide or imide.

In addition, the invention relates to pharmaceutical compositions containing the above compounds, and to methods for treating disorders mediated by the MC-3 or MC-4 receptor by administering the compounds.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions:

“Amino acid” refers to alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C), glutamic acid (Glu; Q), glutamine (Gln; E), glycine (Gly; G), histidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine ( Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y) and valine (Val; V). Common 3-letter and 1-letter abbreviations are shown in parentheses. The following modified amino acids are listed below (3-letter abbreviation for each substituent is indicated in parentheses): p-benzoylphenylalanine (Bpa); β - (1-naphthyl) alanine (1-Nal); β - (2-naphthyl) alanine (2-Nal); β-cyclohexylalanine (Cha), 3,4-dichlorophenylalanine (3,4-Dcp); 4-fluorophenylalanine (4-Fpa); 4-nitrophenylalanine (4-Npa); 2-thienylalanine (Tha); 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic); 3-benzothienylalanine (3-Bal); 4-cyanophenylalanine (4-Ypa); 4-iodophenylalanine (4-Ipa); 4-bromophenylalanine (4-Rpa); 4,4’-biphenylalanine (Bip); Ornithine (Orn); sarcosine (Sar); pentafluorophenylalanine (Pfp) and β, β-diphenylalanine (Dip). As for the substituents represented in structural formulas (I) and (A), the substituents indicated in them using

single letter designations are as defined and do not apply to single letter amino acids corresponding to the same letter designations.

The symbol “D” preceding the above three-letter abbreviations, for example, as in “D-Nal” or “D-Phe”, denotes the D-form of the amino acid. The “L” preceding the three-letter abbreviation for an amino acid denotes the natural L-form of the amino acid. In the present description, unless otherwise indicated, the absence of a “D” or “L” designation indicates that the abbreviation refers to both D- and L-forms. When using the usual single-letter abbreviation, the capitalization designation refers to the L-form and the small (lowercase) designation refers to the D-form, unless otherwise specified.

“Ac” refers to acetyl (ie, CH ₃ C (= O) -).

“Acylamino” refers to R-C (= O) N-.

“Acyloxy” refers to R-C (= O) O-.

“Acylthio” refers to R-C (= O) S-.

“Alkoxy” is an oxygen-containing substituent having a hydrocarbon chain, wherein the hydrocarbon chain is alkyl or alkene (ie, —O-alkyl or —O-alkene). Preferred alkoxy groups include (for example) methoxy (MeO), ethoxy, propoxy and allyloxy.

“Alkyl” is a saturated hydrocarbon chain having 1-15 carbon atoms, preferably 1-10, more preferably 1-4 carbon atoms. “Alken” is a hydrocarbon chain having at least one (preferably only one) carbon-carbon double bond and

having 2-15 carbon atoms, preferably 2-10, more preferably 2-4 carbon atoms. “Alkin” is a hydrocarbon chain having at least one (preferably only one) carbon-carbon triple bond and having 2-15 carbon atoms, preferably 2-10, more preferably 2-4 carbon atoms. Alkyl, alkene and alkynyl chains (collectively referred to as “hydrocarbon chains”) may be straight or branched and may be unsubstituted or substituted. Preferred branched alkyl, alkene and alkyne chains have one or two branches, preferably one branch. Preferred chains are alkyl. Alkyl, alkene and alkyne hydrocarbon chains, each, may be unsubstituted or substituted with 1 to 4 substituents; in case of substitution, mono-, di- or trisubstituted are preferred chains. Alkyl, alkene and alkynyl hydrocarbon chains each may be substituted with halogen, hydroxy, aryloxy (e.g. phenoxy), heteroaryloxy, acyloxy (e.g. acetoxy), carboxy, aryl (e.g. phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, amido, acylamino, keto, thioketo, cyano, or any combination thereof. Preferred hydrocarbon groups include methyl (Me), ethyl, propyl, isopropyl, butyl, vinyl, allyl and butenyl.

In addition, the “lower” alkyl, alkene or alkine (eg, “lower alkyl”) described herein represents a chain consisting of 1-6, preferably 1 to 4, carbon atoms in the case of alkyl, and 2-6, preferably 2 -4, carbon atom in

case of alkene and alkyne.

“Alkylthio” is a sulfur-containing substituent having a hydrocarbon chain, wherein the hydrocarbon chain is alkyl or alkene (ie, -S-alkyl or -S-alkene). Preferred alkylthio groups include (for example) methylthio (MeS) and ethylthio.

“Aryl” is an aromatic hydrocarbon ring. Aryl rings are monocyclic or fused bicyclic ring systems. Monocyclic aryl rings contain 6 carbon atoms in the ring. Monocyclic aryl rings are also called phenyl rings. Bicyclic aryl rings contain from about 8 to about 17 carbon atoms, preferably from about 9 to about 12 carbon atoms in the ring. Bicyclic aryl rings include ring systems where one ring represents aryl and the other ring represents aryl, cycloalkyl or heterocycloalkyl. Preferred bicyclic aryl rings include 5-, 6- or 7-membered rings fused to 5-, 6- or 7-membered rings. Aryl rings may be unsubstituted or substituted with 1 to 4 substituents in the ring. Aryl may be substituted with halogen, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, aryloxy, heteroaryloxy, or any combination thereof. Preferred aryl rings include naphthyl, tolyl, xylyl and phenyl. The most preferred aryl ring radical is phenyl.

“Aryloxy” is an oxygen-containing aryl

substituent (i.e., -O-aryl). Preferred aryloxy groups include (for example) phenoxy, naphthyloxy, methoxyphenoxy and methylenedioxyphenoxy.

As used herein, the term “basic amino acids” refers to His, Lys, and Arg.

“Bc” refers to butanoyl (ie, CH ₃ CH ₂ CH ₂ C (= O) -).

“Cycloalkyl” is a saturated or unsaturated hydrocarbon ring. Cycloalkyl rings are non-aromatic rings. Cycloalkyl rings are monocyclic or fused, spiro or bridged bicyclic ring systems. Monocyclic cycloalkyl rings contain from about 3 to about 9 carbon atoms, preferably from 3 to 7 carbon atoms in the ring. Bicyclic cycloalkyl rings contain from 7 to 17 carbon atoms, preferably from about 7 to about 12 carbon atoms in the ring. Preferred bicyclic cycloalkyl rings include 4-, 5-, 6-, or 7-membered rings fused to 5-, 6-, or 7-membered rings. Cycloalkyl rings may be unsubstituted or substituted with 1 to 4 substituents on the ring. Cycloalkyl may be substituted with halogen, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaryloxy, or any combination thereof. Preferred cycloalkyl rings include cyclopropyl, cyclopentyl and cyclohexyl.

The term “fused” refers to cyclic fragments having at least two common ring atoms,

moreover, the preferred number of condensed rings is three.

“Halogen” represents (F), chlorine (Cl), bromine (Br) or iodine (I).

“Heteroatom” represents an atom of nitrogen, sulfur or oxygen with which one or more parts may be bonded according to the valency of the heteroatom; in the case of nitrogen, one oxygen atom may optionally be bound to it by a covalent coordination bond, such as forming an N-oxide. Groups containing more than one heteroatom may contain different heteroatoms.

“Heteroalkyl” is a saturated or unsaturated chain containing carbon and at least one heteroatom where there are no two heteroatoms adjacent. Heteroalkyl chains contain from 2 to about 15 atom members (carbon and heteroatoms) in the chain, preferably from 2 to about 10, more preferably from 2 to about 5. For example, alkoxy (i.e., -O-alkyl or -O- heteroalkyl) radicals are included in heteroalkyl. Heteroalkyl chains may be straight or branched. Preferred branched heteroalkyls have one or two branches, preferably one branch. Preferred heteroalkyls are saturated. Unsaturated heteroalkyls have one or more double bonds (also called “heteroalkenyl”) and / or one or more triple bonds (also called “heteroalkynyl”). Preferred unsaturated heteroalkyls have one or two double bonds or one triple bond, more preferably one double bond.

Heteroalkyl chains may be unsubstituted or substituted with 1 to 4 substituents. Preferred substituted heteroalkyls are mono-, di- or trisubstituted. Heteroalkyl may be substituted with lower alkyl, halogen, hydroxy, aryloxy, heteroaryloxy, acyloxy, carboxy, monocyclic aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, acylamino, amido, keto, thioketo, cyano or any of them.

“Heterocycloalkyl” is a saturated or unsaturated, non-aromatic ring containing carbon and from 1 to about 4 (preferably 1-3) heteroatoms in the ring, where there are no two heteroatoms adjacent to the ring and there is no carbon which, having a heteroatom bonded to it, would also have a hydroxyl, amino or thiol radical associated with it. Heterocycloalkyl rings are monocyclic or fused, bridged or spiro bicyclic ring systems. Monocyclic heterocycloalkyl rings contain from about 4 to about 9 atom members (carbon and heteroatoms), preferably from 5 to 7 atom members in the ring. Bicyclic heterocycloalkyl rings contain from about 7 to about 17 atoms, preferably from 7 to 12 atoms. Bicyclic heterocycloalkyl rings may be fused, spiro or bridged ring systems. Preferred bicyclic heterocycloalkyl rings include 5-, 6- or 7-membered rings fused to 5-, 6- or 7-membered rings. Heterocycloalkyl rings may be unsubstituted or

substituted by 1 to 4 substituents in the ring. Heterocycloalkyl may be substituted with halogen, cyano, hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amido, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy, or any combination thereof. Preferred substituents on heterocycloalkyl include fluoro and alkyl.

“Heteroaryl” is an aromatic ring containing carbon and from 1 to about 4 heteroatoms in the ring. Heteroaryl rings are monocyclic or fused bicyclic ring systems. Monocyclic heteroaryl rings contain from about 5 to about 9 atom members (carbon and heteroatoms), preferably 5 or 6 atom members in the ring. Bicyclic heteroaryl rings contain from about 8 to about 17 atom members, preferably about 8 to about 12 atom members in the ring. Bicyclic heteroaryl rings include ring systems where one ring is heteroaryl and the other ring is aryl, heteroaryl, cycloalkyl or heterocycloalkyl. Preferred bicyclic heteroaryl ring systems include 5-, 6- or 7-membered rings fused to 5-, 6- or 7-membered rings. Heteroaryl rings may be unsubstituted or substituted with 1 to 4 substituents on the ring. Heteroaryl may be substituted with halogen, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, aryloxy, heteroaryloxy, or any combination thereof. Preferred heteroaryl rings include thienyl, thiazolo, imidazyl, purinyl, pyrimidyl, pyridyl and furanyl.

As used herein, the terms “MC-4 agonist” and “MC-3 agonist” refer to a compound having affinity for the MC-4 receptor or the MC-3 receptor, respectively, the effects of which can lead to measurable biological activity in the cells , tissues or organisms that contain the MC-4 or MC-3 receptor. As used herein, the term “MC-4 / MC-3 agonist” refers to a compound that is both an MC-4 agonist and an MC-3 agonist, in accordance with the terminology defined above. Tests that reveal the agonistic activity of compounds with respect to MC-4 and / or MC-3 are well known in the art. One such commonly used test is the BioTrak ™ Enzyme Immunoassay (EIA) system, manufactured by Amersham Pharmacia Biotech (Piscataway, NJ), for the direct determination of cAMP, which quantifies the response of cAMP cells to MC ligands. Another test used is cAMP screening, Tropix cAMP Screen ™, manufactured by Tropix. Such systems allow a quantitative assessment of total cellular cAMP in cells exposed to ligands. Briefly summarized: HEK cells stably transfected with MC-1, MC-3 or MC-4 receptors are placed in 96-well microtiter plates and cultured overnight. The corresponding ligand MC is metered into the cells for 1 hour and then lysed. The lysed cell extract fraction was transferred to an assay plate. ELISA analysis is carried out in accordance with the instructions attached to the kit. Each tablet contains a number of cAMP standards for

constructing a calibration curve, as well as a full range of MC agonists as a positive control for each MC receptor. CAMP activity is calculated as% of the maximum cAMP activity of the full complex of MC control agonists.

As used herein, the terms “MC-4 antagonist” and “MC-3 antagonist” refer to a compound having affinity for the MC-4 receptor or MC-3 receptor, respectively, and which blocks the stimulation of a known MC agonist. As used herein, the term “MC-4 / MC-3 antagonist” refers to a compound that is both an MC-4 antagonist and an MC-3 antagonist, in accordance with the terminology defined above. Tests that detect compounds with antagonism to MC-4 and / or MC-3 are well known in the art. One particularly useful test is competitive binding using europium labeled NDP-MSH. In summary: HEK cells stably transfected with MC-1, MC-3, MC-4, or MC-5 receptors are placed in 96-well microtiter plates and cultured overnight. Cells are dosed with the appropriate MC ligand in the presence of europylated NDP-MSH for 60 minutes, the cells are washed several times, a solution is added to enhance and fluorescence is measured. The IC ₅₀ and Ki values for each receptor for each MC ligand can be calculated using standard graphics programs such as GraphPad Prism, (GraphPad Software Inc., San Diego, CA).

As used herein, the terms “MC-3 receptor” and “MC-4 receptor” mean the known MC-3 and MC-4 receptors and their

spliced variants and undescribed receptors. MC-3 receptors are described by Gantz et at, supra (human MC-3); Desarnaud et al., Supra (mouse MC-3) and L. Reyfuss et al., “Identification of a Receptor for Gamma Melanotropin and Other Proopiomelanocortin Peptides in the Hypothalamus and Limbic System.”, Proc. Natl. Acad. Sci USA, vol. 90, pp. 8856-8860 (1993) (rat MC-3). MC-4 receptors are described by Gantz et al., Supra (human MC-4), J.D. Alvaro et al., “Morphine Down-Regulates Melanocortin-4 Receptor Expression in Brain Regions that Mediate Opiate Addiction”, Mol-Pharmacol Sep, vol. 50 (3), pp. 583-91 (1996) (rat MC-4) and Takeuchi, S. and Takahashi, S., “Melanocortin Receptor Genes in the Chicken-Tissue Distributions”, Gen-Comp-Endocrinol, vol. 112 (2), pp 220-31 (Nov. 1998) (chicken MC-4).

Used in this description, the term "measurable" means that the biological effect is both reproducible and significantly different from the basic spread of the analysis data.

The term “pharmaceutically acceptable salt” means a cationic counterion formed with any acidic (carboxylic acid) group, or an anionic counterion formed with any basic (eg amino) group. Many such salts are known in the art, as described in international patent publication 87/05297, Johnston et al., Published September 11, 1987, incorporated herein by reference. Preferred cationic salts include alkali metal salts (such as sodium and potassium), alkaline earth metal salts (such as magnesium and calcium) and organic salts. Preferred Anionic Salts

include halides (such as chloride salts), sulfonates, carboxylates, phosphates, trifluoroacetate (TFA) and the like. Obviously, among such salts, additive salts are provided that can provide an optical center in cases where it was not. For example, a chiral tartrate salt can be obtained from the compounds of the invention, and this definition includes such chiral salts.

The presence of such salts is obvious to a person skilled in the art, and such a specialist is capable of producing any number of salts provided that they are known in the art. In addition, it is obvious that specialists in this field may prefer one of the salts on the basis of its solubility, stability, ease of preparation, etc. The determination and optimization of such salts is within the practical competence of a person skilled in the art.

As used herein, the term “selective” means a preference for activating a particular receptor over other receptors, which can be quantified based on tests of a whole cell, tissue, or organism that can detect receptor activity, such as an enzyme immunoassay (EIA) system for the direct definition of cAMP, which was discussed above. The selectivity of the compound is determined from a comparison of EC ₅₀ values for the receptors in question to be compared. Unless otherwise noted, the use of the term “selective compared to other MC receptors” implies selectivity for other melanocortin receptors, including

receptors MC-1, MC-2 and MC-5. For example, a compound having an EC _{50 of} 8 nM for the MC-4 receptor and an EC _5O ≥ 80 nM for the MC-1, MC-2 and MC-5 receptors has a selectivity ratio for the MC-4 receptor compared to other MC receptors, according to at least 1:10. In addition, it is obvious that selectivity can also be assigned to one of the receptors MC-1, MC-2 or MC-5, individually. For example, a compound having an EC _{50 of} 8 nM for the MC-4 receptor and an EC _{50 of} 80 nM for the MC-1 receptor has a selectivity ratio for the MC-4 receptor compared to the MC-1 receptor 1:10. Such a compound is selective compared to the MC-1 receptor, regardless of its EC ₅₀ value for MC-2 or MC-5. Selectivity is described in more detail below and can be determined using, for example, Prism v 2.0 software, which is available from GraphPad, Inc.

A “solvate” is a complex formed by a combination of a solute (eg, the inventive ligand of the MC-4 / MC-3 receptor) and a solvent (eg, water). See J. Honig et al., The Van Nostrand Chemist's Dictionary, p. 650 (1953). Pharmaceutically acceptable solvents used in accordance with this invention include solvents that do not interfere with the biological activity of the compound (e.g., water, ethanol, ethers, acetic acid, N, N-dimethylformamide and other known or readily determined by a person skilled in the art) .

A “spirocycle” is an alkyl or heteroalkyl diradical substituent of an alkyl or heteroalkyl substituent, wherein said diradical substituent has a total carbon and wherein said

the biradical substituent forms a ring, said ring containing from about 4 to about 8 atom members (carbon or heteroatoms), preferably 5 or 6 atom members.

II. Connections

The compounds of the present invention are MC-4 and / or MC-3 receptor ligands having a structure corresponding to formula (I):

where R ² , R ⁴ , R ^{4 '} , R ⁵ , R ⁶ , R ^6' , R ⁷ , R ⁸ , R ^{8 '} , R ⁹ , R ^9' , R ¹⁰ , Ar, Z ¹ , Z ² , Z ³ , X, B, D, p, q, r, and s are as described in the Summary of the Invention above.

In addition to the compounds described by formula (I), it is assumed that the peptide residues of the skeleton can be modified by PEG in order to increase the therapeutic value, for example, to increase the effectiveness by prolonging the half-life of the drug in vivo. Methods for modifying PEG peptides are well known in the literature. For example, this is described in the following sources, the description of each of which is incorporated into this description by reference: Lu, Y.A. et al., “Pegylated peptides. II. Solid-phase synthesis of amino-, carboxy- and side-chain pegylated peptides ”, Int. J. Pept. Protein Res., Vol. 43 (2), pp. 127-38 (1994); Lu, Y.A. et al., “Pegylated peptides. I. Solid-

phase synthesis of N alpha-pegylated peptides using Fmoc strategy ”, Pept. Res., Vol. 6 (3), pp. 140-6 (1993); Felix, A.M. et al., “Pegylated peptides. IV. Enhanced biological activity of site-directed pegylated GRF analogs. ”, Int. J. Pept. Protein Res., Vol. 46 (3-4), pp. 253-64 (1995); Gaertner, H.F. et al., “Site-specific attachment of functionalized poly (ethylene glycol) to the amino terminus of proteins”, Bioconjug Chem., Vol. 7 (1), pp. 38-44 (1996); Tsutsumi, Y. et al., “PEGylation of interleukin-6 effectively increases its thrombopoietic potency”, Thromb Haemost, Vol. 77 (1), pp. 168-73 (1997); Francis, G.E. et al., “PEGylation of cytokines and other therapeutic proteins and peptides: the importance of biological optimization of coupling techniques”, Int. J. Hematol., Vol. 68 (1), pp. 1-18 (1998); Roberts, M.J. et al., “Attachment of degradable poly (ethylene glycol) to proteins has the potential to increase therapeutic efficacy”, J. Pharm. Sci, Vol 87 (11), pp. 1440-45 (1998); and Tan, Y. et al., “Polyethylene glycol conjugation of recombinant methioninase for cancer therapy”, Protein Expr. Purif, Vol. 12 (1), pp. 45-52 (1998). The compounds of formula (I) can be directly modified by PEG, or a “linker (binding branch)” can be introduced into the compounds to facilitate the modification of PEG.

Regarding formula (I), a non-limiting list of preferred substituents is provided below:

X is selected from hydrogen, fluoro, aryloxy, acyloxy, OR ¹ , SR ¹ , —NR ¹ R ^{1 ′} and —CHR ¹ R ^{1 ′} . Preferred are hydrogen (when D is not also hydrogen), —NR ¹ R ^{1 ′} and —CHR ¹ R ^{1 ′} . More preferred —NR ¹ R ^{1 ′}

and —CHR ¹ R ^{1 ′} . Even more preferred is —NR ¹ R ^{1 ′} .

R ¹ and R ^{1 ′ are} independently selected from the group consisting of hydrogen, alkyl and acyl. A preferred case is when R ¹ is hydrogen or alkyl and R ^{1 '} is acyl.

R ² independently selected from the group consisting of hydrogen, alkyl halogen and heteroalkyl. Hydrogen is preferred. Alternatively, two successive substituents R ² or successive substituents R ² and R ³ may combine to form a (3-8) membered carbocyclic or heterocyclic ring. In another alternative, R ² bonded to a carbon atom that is bonded to X and Z ¹ and the substituent R ⁵ may optionally combine to form a carbocyclic or heterocyclic ring that is fused to the phenyl ring J. In another alternative, R ² bonded to the carbon atom that is bonded to the Ar ring can combine with R ⁷ to form a ring fused to the Ar ring. In another alternative, R ² bonded to a carbon atom that is bonded to Z ² and Z ³ may optionally bind to R ⁸ to form a carbocyclic or heterocyclic ring. In a further alternative embodiment, R ² bonded to a carbon atom that is bonded to Z ³ and D may optionally bind to R ¹⁰ to form a carbocyclic or heterocyclic ring. With regard to the above, it is preferable when R ² does not form a ring with another R ² , and when R ² does not form a ring with R ³ , R ⁷ or R ⁸ . More preferably, when R ² does not form a ring with R ¹⁰ . Preferably, when the rings formed between R ² and another substituent have 5-8 ring atoms.

Each of Z ¹ , Z ² and Z ^{3 is} independently selected from —OC (R ³ ) (R ^3a ) -; -C (R ³ ) (R ^3a ) O-; -S (O) _a C (R ³ ) (R ^3a ) -, where a is 0, 1 or 2; —C (R ³ ) (R ^3a ) S (O) _b -, where b is 0, 1 or 2; -N (R ^3e ) C (R ³ ) (R ^3a ) -; -C (R ³ ) (R ^3a ) N (R ^3e ); -C (O) N (R ^3d ) -; -N (R ^3d ) C (O) -; -C (O) C (R ³ ) (R ^3a ) -; -C (R ³ ) (R ^3a ) C (O) -; -C (R ³ ) (R ^3a ) C (R ^3b ) (R ^3c ) -; -C (R ³ ) = C (R ^3a ) -; -C≡ C-; -SO ₂ N (R ^3d ) -; -N (R ^3d ) SO ₂ -; -C (R ³ ) (R ^3a ) P (= O) (OR ^3f ) -; -P (= O) (OR ^3f ) C (R ³ ) (R ^3a ) -; -N (R ^3d ) P (= O) (OR ^3f ) -; -P (= O) (OR ^3f ) N (R ^3d ) -; -P (= O) (OR ^3f ) O-; -OP (= O) (OR ^3f ) -; cycloalkyl having from 3 to 8 ring atoms, and heterocycloalkyl having from 4 to 8 ring atoms. Preferred are —OC (R ³ ) (R ^3a ) -; -C (R ³ ) (R ^3a ) O-; -S (O) _a C (R ³ ) (R ^3a ) -, where a is 2; —C (R ³ ) (R ^3a ) S (O) _b -, where b is 2; -N (R ^3e ) C (R ³ ) (R ^3a ) -; -C (R ³ ) (R ^3a ) N (R ^3e ) -; -C (O) N (R ^3d ) -; -N (R ^3d ) C (O) -; -C (R ³ ) (R ^3a ) C (R ^3b ) (R ^3c ) -; -C (R ³ ) = C (R ^3a ) -; -C≡ C-; -SO ₂ N (R ^3d ) -; -N (R ^3d ) SO ₂ -; -C (R ³ ) (R ^3a ) P (= O) (OR ^3f ) -; and -P (═O) (OR ^3f ) C (R ³ ) (R ^3a ) -. More preferred are —OC (R ³ ) (R ^3a ) -; -C (R ³ ) (R ^3a ) O-; -C (R ³ ) (R ^3a ) N (R ^3e ) -; -C (O) N (R ^3d ) -; -C (R ³ ) (R ^3a ) C (R ^3b ) (R ^3c ) -; -C (R ³ ) = C (R ^3a ) -; -SO ₂ N (R ^3d ) - and -P (= O) (OR ^3f ) C (R ³ ) (R ^3a ) -. Most preferred are —C (R ³ ) (R ^3a ) O—; —C (O) N (R ^3d ) - and —C (R ³ ) (R ^3a ) C (R ^3b ) (R ^3c ) -. In another aspect, preferred compounds are those wherein at least one of Z ¹ , Z ^2, or Z ³ is other than —C (O) N (R ^3d ) -. Compounds wherein at least two of Z ¹ , Z ² or Z ³ are other than —C (O) N (R ^3d ) - are more preferred. In addition, compounds are preferred where (i) at least one of Z ¹ , Z ² or Z ^{3 is} other than —C (O) N (R ^3d ) -, and (ii) (a) X is other than —NR ¹ R ^{1 ′} , where R ^{1 ′} is acyl, and / or (b) D is other than —C (O) R ¹¹ .

Each of R ³ , R ^3a, R ^3b, and R ^3c , if present, is independently selected from hydrogen, hydroxy, alkoxy, aryloxy, acyloxy, thiol, alkylthio, acylthio, arylthio, amino, alkylamino, acylamino, and alkyl. Preferred are hydrogen, hydroxy, alkoxy, aryloxy and alkyl. Most preferably, when each of R ³ , R ^3a , R ^3b and R ^3c represents hydrogen.

R ^3d , if present, is selected from hydrogen, alkyl and aryl. Preferably, when R ^3d selected from hydrogen and alkyl.

R ^3e , if present, is selected from hydrogen, alkyl, aryl and acyl. Preferably, when R ^{3e is} selected from hydrogen and alkyl.

R ^{3f is} selected from hydrogen and alkyl. When R ^3f is alkyl, branched alkyl, preferably isopropyl, is preferred.

p is 0, 1, 2, 3, 4 or 5. Preferably p is 1 or 2, more preferably 1.

When p is greater than 0, each R ⁴ and R ^{4 ′ is} independently selected from hydrogen, alkyl, aryl, halogen (preferably fluorine), hydroxy, alkoxy, amino, and acylamino. When p is greater than 1, two R ⁴ substituents, together with the carbon atoms to which they are bonded, can join to form a heterocycloalkyl, cycloalkyl or aryl ring. When p is greater than 1, the substituents R ⁴ at two adjacent carbon atoms can both be zero, so that a double bond is formed between two adjacent carbon atoms, or both substituents R ⁴ and R ^{4 '} at two adjacent carbon atoms can all be equal zero, so that a triple bond is formed between two adjacent carbon atoms. Preferably each R ⁴ , if present, is hydrogen

and each R ^{4 ′} , if present, is hydrogen or alkyl. Most preferably, when there is no unsaturation in the chain linking ring J to the X-containing carbon atom of formula (I).

R ⁵ represents 5 substituents (i.e., positions 2-6) in the phenyl ring J, where each R ^{5 is} independently selected from hydrogen, hydroxy, halogen, thiol, —OR ¹² , —SR ¹² , —SO ₂ N (R ¹² ) (R ^{12 '} ), -N (R ¹² ) (R ^12' ), alkyl, acyl, alkene, alkyno, cyano, nitro, aryl, heteroaryl, cycloalkyl and heterocycloalkyl. Each R ¹² and R ^{12 ′ is} independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; or two R ⁵ substituents may optionally combine to form a carbocyclic or heterocyclic ring that is fused to the phenyl ring J.

Preferred R ⁵ substituents are hydrogen, hydroxy, halogen, thiol, —OR ¹² , where R ¹² is lower alkyl or acyl, —SR ¹² , where R ¹² is lower alkyl or acyl, —SO ₂ N (R ¹² ) (R ^{12 '} ), -N (R ¹² ) (R ^12' ), alkyl, cyano, nitro, aryl, heteroaryl, cycloalkyl and heterocycloalkyl. More preferred R ⁵ substituents are hydrogen, hydroxy, halogen, thiol, —SO ₂ N (R ¹² ) (R ^{12 ′} ), where R ¹² and R ^{12 ′ are} both hydrogen, —N (R ¹² ) (R ^{12 ′} ) where R ¹² and R ^{12 '} each represent hydrogen or alkyl. Even more preferred R ⁵ substituents are hydrogen, hydroxy, chloro, fluoro, —N (R ¹² ) (R ^{12 ′} ), where R ¹² and R ^{12 ′} are each hydrogen or alkyl. Most preferred R ⁵ substituents are hydrogen, hydroxy, chloro, fluoro and nitro.

Regarding ring J, it is preferred that four of

R ⁵ substituents are hydrogen. In addition, it is preferable when in position 4 is not hydrogen. Most preferably, when position 4 is not hydrogen, but the remaining 4 substituents are hydrogen.

q is 0, 1, 2, 3, 4 or 5, preferably q is 0, 1 or 2, more preferably q is 1.

When q is greater than 0, each R ⁶ and R ^{6 ′ is} independently selected from hydrogen, alkyl, aryl, halogen (preferably fluorine), hydroxy, alkoxy, amino, and acylamino. When q is greater than 1, two R ⁶ substituents, together with the carbon atoms to which they are bonded, can join to form a heterocycloalkyl, cycloalkyl or aryl ring. When q is greater than 1, the substituents R ⁶ at two adjacent carbon atoms can be zero, so that a double bond is formed between two adjacent carbon atoms, or both the substituents R ⁶ and the substituents R ^{6 '} at two adjacent carbon atoms can be all are zero, so that a triple bond is formed between two adjacent carbon atoms. Preferably, each R ⁶ , if present, is hydrogen, and each R ^{6 '} , if present, is hydrogen or alkyl. Most preferably, when there is no unsaturation in the chain linking the Ar ring to a carbon atom of formula (I), which is bonded to Z ¹ and Z ² .

Ar represents an aryl or heteroaryl ring selected from the group consisting of phenyl, thiophene, furan, oxazole, thiazole, pyrrole and pyridine. Ar is preferably phenyl, thiophene or furan. Most preferably, Ar is phenyl.

R ⁷ represents substituents on the Ar ring, where each R ^{7 is} independently selected from hydrogen; halogen; —NR ¹³ R ^{13 ′} , where R ¹³ and R ^{13 ′} each represents hydrogen or alkyl; alkyl; acyl; alkene; alkyne; cyano; nitro; aryl; heteroaryl; cycloalkyl and heterocycloalkyl. Optionally, the two R ⁷ substituents may combine to form a carbocyclic or heterocyclic ring fused to the Ar ring. When Ar is phenyl, it is preferred that four of the five R ⁷ substituents are hydrogen or all five R ⁷ substituents are hydrogen. It is also preferred that the two R ⁷ substituents are selected from fluoro, chloro, cyano, bromo, iodo, nitro, alkoxy and alkyl; or two R ⁷ substituents combine to form a carbocyclic or heterocyclic ring fused to the phenyl ring. More preferably, when position 4 of the phenyl ring is hydrogen, fluoro, chloro, cyano, bromo, iodo, nitro and alkyl, and the other four substituents are hydrogen. Most preferably, when in position 4 of the phenyl ring is hydrogen or fluorine, and the remaining four substituents are hydrogen.

When Z ¹ and Z ² both represent —C (O) N (R ^3d ) -, compounds are preferred where the carbon atom that is bonded to Z ¹ and Z ² is in the R configuration according to the Kahn-Ingold nomenclature Prelog.

r is 0, 1, 2, 3, 4, 5, 6 or 7. Preferably r is 2, 3, 4 or 5. More preferably r is 2, 3 or 5. Most preferably r is 3.

Each R ⁸ and R ^{8 ′ is} independently selected from hydrogen, alkyl,

halogen (preferably fluorine), hydroxy, alkoxy and amino. Optionally, when r is greater than 1, two R ⁸ substituents, together with the carbon atoms to which they are bonded, form a heterocycloalkyl, cycloalkyl or aryl ring. Preferably, each R ⁸ and R ^{8 ′ is} independently selected from hydrogen and alkyl. Most preferably, each R ⁸ and R ^{8 ′} is hydrogen. Optionally, when r is greater than 1, the substituents R ⁸ at two adjacent carbon atoms may be zero, so that a double bond is formed between two adjacent carbon atoms, or both the substituents R ⁸ and the substituents R ^{8 '} at two adjacent carbon atoms can all be zero, so that a triple bond is formed between two adjacent carbon atoms.

B is selected from —N (R ¹⁴ ) C (= NR ¹⁵ , = O or = S) NR ¹⁶ R ¹⁷ , —NR ²⁰ R ²¹ , cyano (—CN), a heteroaryl ring, for example, thiophene; an alkyl or dialkylamine, a heteroaryl ring containing at least one nitrogen atom in the ring, and a heterocycloalkyl ring containing at least one nitrogen atom in the ring. Preferred are —N (R ¹⁴ ) C (= NR ¹⁵ ) NR ¹⁶ R ¹⁷ , a heteroaryl ring containing at least one nitrogen atom in the ring, and a heterocycloalkyl ring containing at least one nitrogen atom in the ring. More preferred are —N (R ¹⁴ ) C (= NR ¹⁵ ) R ¹⁶ R ¹⁷ , cyano, N (R ¹⁴ ) C (= O) NR ¹⁶ R ¹⁷ , a heteroaryl ring containing at least one nitrogen atom in a ring, and a heterocycloalkyl ring containing at least one nitrogen atom in the ring. More preferred are —N (R ¹⁴ ) C (= NR ¹⁵ ) NR ¹⁶ R ¹⁷ , N (R ¹⁴ ) C (= O) NR ¹⁶ R ¹⁷ , cyano, triazole and imidazole.

R ¹⁴ and R ^{15 are} independently selected from hydrogen, alkyl, alkene and alkyn. Preferred are hydrogen and alkyl. R ¹⁶ and R ^{17 are} independently selected from hydrogen, alkyl, alkene and alkyn. Hydrogen and alkyl are preferred. R ²⁰ and R ^{21 are} independently selected from hydrogen, alkyl, alkene and alkyn. Hydrogen and alkyl are preferred.

Alternatively, a combination of two or more of R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ combines to form a monocyclic or bicyclic ring. For example, R ¹⁴ and R ¹⁵ , together with the atoms to which they are bonded, can combine to form heterocycloalkyl or heteroaryl. In addition, R ¹⁴ and R ¹⁶ , together with the atoms to which they are bonded, can combine to form heterocycloalkyl or heteroaryl. In addition, R ¹⁵ and R ¹⁶ , together with the atoms to which they are bonded, can combine to form heterocycloalkyl or heteroaryl. In addition, R ¹⁶ and R ¹⁷ may optionally combine to form a heteroaryl or heterocycloalkyl ring. Preferably, when R ¹⁵ and R ^{16 are} combined to form a ring.

s is 0, 1, 2, 3, 4 or 5. Preferably s is 1 or 2, more preferably 1.

When s is greater than 0, each R ⁹ and R ^{9 ′ is} independently selected from hydrogen, alkyl, aryl, halogen (preferably fluorine), hydroxy, alkoxy, amino, and acylamino. Preferably, each R ⁹ , if present, is hydrogen, and each R ^{9 '} , if present, is hydrogen or alkyl. Optionally, when s is greater than 1, two R ⁹ substituents, together with the carbon atoms to which they are bonded, combine to form

heterocycloalkyl, cycloalkyl or aryl ring. In addition, when s is greater than 1, the substituents R ⁹ at two adjacent carbon atoms can both be zero, so that a double bond is formed between two adjacent carbon atoms. In addition, when s is greater than 1, both R ⁹ and both R ^{9 ′} at two adjacent carbon atoms can all be zero, so that a triple bond is formed between two adjacent carbon atoms. Most preferably, when there is no unsaturation in the chain linking R ¹⁰ with a D-containing carbon atom of the formula (I).

R ^{10 is} selected from the group consisting of an optionally substituted bicyclic aryl ring and an optionally substituted bicyclic heteroaryl ring. Preferred bicyclic aryl rings include 1-naphthyl, 2-naphthyl, indane, 1H-indene, benzocyclobutane and benzocyclobutene. Preferred bicyclic heteroaryl rings include indole, indoline, pyridine, dihydropyridine, octahydropyridine, benzothiophene, benzofuran, benzimidazole, benzopyran, quinoline, quinoline and isoquinoline. More preferably, when R ¹⁰ is 1-naphthyl, 2-naphthyl, indole, indane, 1H-indene, benzothiophene, benzofuran and benzopyran. Most preferably, when R ¹⁰ is 1-naphthyl, 2-naphthyl or indole (in particular 3-indole).

D is selected from hydrogen, fluoro, hydroxy, thiol, alkoxy, aryloxy, alkylthio, acyloxy, cyano, amino, acylamino, —C (O) R ¹¹ and —C (S) R ¹¹ . Preferred are fluoro, hydroxy, thiol, alkoxy, aryloxy, alkylthio, acyloxy, cyano, amino, acylamino, —C (O) R ¹¹ and —C (S) R ¹¹ . More preferred are alkoxy,

cyano, amino, acylamino, -C (O) R ¹¹ and -C (S) R ¹¹ . Even more preferred are —C (O) R ¹¹ and —C (S) R ¹¹ . Most preferred is —C (O) R ¹¹ .

R ¹¹ selected from the group consisting of amino; alkylamino; -NHOR ¹⁸ , where R ^{18 is} selected from hydrogen and alkyl; —N (R ¹⁹ ) CH ₂ C (O) NH ₂ wherein R ¹⁹ is alkyl (preferably lower alkyl); -NHCH ₂ CH ₂ OH; -N (CH ₃ ) CH ₂ CH ₂ OH; and —NHNHC (= Y) NH ₂ , where Y is selected from O, S, and NH. Preferred R ¹¹ are amino; alkylamino; -NHOR ¹⁸ , where R ^{18 is} selected from hydrogen and alkyl (preferably hydrogen); —N (R ¹⁹ ) CH ₂ C (O) NH ₂ wherein R ¹⁹ is alkyl (preferably lower alkyl); -NHCH ₂ CH ₂ OH; and -N (CH ₃ ) CH ₂ CH ₂ OH. More preferred R ¹¹ are amino; alkylamino; -NHOR ¹⁸ , where R ^{18 is} selected from hydrogen and alkyl (preferably hydrogen); and —N (R ¹⁹ ) CH ₂ C (O) NH ₂ where R ¹⁹ is alkyl. Most preferred are amino and alkylamino.

As indicated in relation to formula (I), if at least one of Z ¹ , Z ² or Z ³ is other than —C (O) N (R ^3d ) - or —N (R ^3d ) C (O ) -, then X and D may optionally be linked via linker L, which contains all covalent bonds or covalent bonds and an ionic bond, thereby forming a cyclic analog of the peptide. Such cyclic peptides have a structure corresponding to the following formula (II):

For cyclic compounds containing a linker L, the bridge connecting X and D may be in the form of bonds of a covalent nature or, alternatively, may include a salt bridge resulting from the formation of ionic bonds. The linker may be entirely peptide in nature (i.e., containing only amino acids), non-peptide in nature (i.e., containing no amino acids) or it may include both substituents of a peptide nature and non-peptide nature introduced with using well-known chemical synthesis methods. The linker may include aliphatic residues, aromatic residues or heteroaromatic residues, or any combination thereof. In one embodiment, the linker may include long chain omega amino acids in which the amino and carboxyl groups are separated by chain sections of about 4 to about 24 methylene groups, or a combination of these omega amino acids and aminobenzoic acids.

In another embodiment, which is the preferred embodiment, the linker may contain all covalent bonds, such as amide bonds. For example, the linker may include an amide formed by chemically combining amino groups of the amino acid side chains, such as Lys or Orn, and

a carboxyl group of a side chain of an amino acid residue such as Asp or Glu. Alternatively, the linker may include an amide formed between the amino and carboxylate groups linked to the α-carbon of the amino acids forming a bridging group (hereinafter referred to as the “α-amino" amino acid group or the "α-carboxyl" amino acid group). In another alternative, the linker may include an amide formed between any combination of an amino group of a side chain or a carboxyl group of a side chain (amino acid) and α-amino and α-carboxyl groups. Binding moieties can be amine or carboxyl-containing structures other than naturally occurring amino acids, including, for example, 6-aminohexanoic acid as an amine-containing residue and succinic acid as a carboxyl-containing residue. In addition, the invention allows for binding using other types of chemical functional groups. In this case, such binding residues may contain various groups and substituents, including aliphatic, heteroalkyl, aromatic and heterocyclic. When covalently linked, the linker may include, but is not limited to, amide, ester, ether, thioether, aminoalkyl, aminoaryl, alkyl, other heteroalkyl, alkene, alkine, heterocycloalkyl, aryl and heteroaryl. Preferably, the linker may include ether, aminoalkyl, aminoaryl, alkyl, another heteroalkyl, alkene, alkine, heterocycloalkyl, aryl and heteroaryl. More preferably, the linker may include ether, aminoalkyl, alkyl, alkene and alkine. When L contains only

covalent bonds, preferred are compounds having from about 12 to about 32 ring atoms, more preferred are compounds having from about 22 to about 28 ring atoms.

The linker may alternatively include an ionic bond / association, which favors the formation of a cyclic structure. Such an “ionic” bridge includes a salt-forming basic or acidic functionality. For example, the bond may include an ionic bond formed between the amino group of the side chain of an amino acid, such as Lys or Orn, and the carboxyl group of the side chain of an amino acid residue, such as Asp or Glu. Alternatively, the linker may include an ionic bond formed between the amino and carboxylate groups linked to the α-carbon of the amino acids forming the linker. In another alternative, the linker may include an amide formed between any combination of an amino group of a side chain or a carboxyl side chain (amino acid) and an α-amino and α-carboxyl group. When L contains an ionic bond, the formed ring may preferably contain from about 22 to about 28 ring atoms.

It should be borne in mind that any free peptide α-carboxy and α-amino groups (i.e., α-carboxy and α-amino groups of amino acids) that are not involved in ring formation may optionally be in the form of a carboxyamide or acylamino group, respectively. The most preferred L-containing compounds are analogues, where X and D form covalently

connected cyclic structures.

With respect to the compounds of the present invention, in general, although alkyl, heteroalkyl, cycloalkyl and heterocycloalkyl groups may be substituted with hydroxy, amino and amido groups, as stated above, the invention does not provide for the following:

1. Enols (OH attached to carbon carrying a double bond).

2. Amino groups attached to carbon bearing a double bond (with the exception of vinyl logical amides).

3. More than one hydroxy, amino or amido group attached to one carbon (except when two nitrogen atoms are bonded to one carbon atom and all three atoms are members of a heterocycloalkyl ring).

4. A hydroxy, amino or amido group attached to a sp ³ -hybridized carbon, which also has a heteroatom bonded to it.

5. A hydroxy, amino or amido group attached to carbon, which also has a halogen attached to it.

A preferred subclass of compounds of formula (I), where there is no L linker necessary for the formation of a macrocyclic ring, is a subclass of compounds having the structure of formula (A), as follows:

In the above preferred subgenus of the compounds, the substituents R ¹ , R ^{1 ′} , Z ¹ , R ⁴ , R ^{4 ′} , R ⁵ , R ⁶ , R ^{6 ′} , R ⁷ , B, R ¹⁰ and R ¹¹ are as defined in relation to formula (I). Referring to formula (I), the compounds of formula (A) are compounds wherein the ring J of the formula is a phenyl ring, where all of the 2, 3, 5 and 6 positions are hydrogen, so that the ring is substituted only at the 4 position with R ⁵ , which is as defined in relation to formula (I). Similar to the description of formula (I), the substituent R ^{5 of the} ring and the substituent R ² may optionally be combined to form a ring fused to the phenyl ring shown. In such an embodiment, the fused ring may join the phenyl ring at a position other than position 4. In formula (A), the Ar ring of formula (I) is a phenyl ring, where all positions 2 ′, 3 ′, 5 ′ and 6 ′ are hydrogen, and position 4 ′ represents R ⁷ , which is as defined above. In this regard, it is preferred that R ^{7 is} selected from hydrogen and fluoro.

With respect to formula (A), p and q are independently 1 or 2, preferably q is 1. Furthermore, it is preferred that R ⁴ , R ^{4 '} , R ⁶ and R ^6' are all hydrogen. Further preferred are compounds wherein B is

-N (R ¹⁴ ) C (= NR ¹⁵ ) NR ¹⁶ R ¹⁷ or -NR ²⁰ R ²¹ .

A preferred subclass of compounds of formula (II) are compounds having a structure corresponding to formula (B) as follows:

where X, Z ¹ , Z ² , Z ³ , D, R ⁴ , R ^{4 '} , R ⁵ , R ⁶ , R ^6' , R ⁷ , R ⁸ , R ^{8 '} , B, R ⁹ , R ^9' and R ¹⁰ are as defined above, and p is 1 or 2. Preferred are compounds wherein R ⁶ and R ^{6 ′} are both hydrogen. Compounds wherein B is —N (R ¹⁴ ) C (= NR ¹⁵ ) NR ¹⁶ R ¹⁷ or –NR ²⁰ R ^{21 are} also preferred. It is also preferred that R ⁸ , R ^{8 ′} , R ⁹ and R ^{9 ′} represent all hydrogen. Preferably, when R ⁷ selected from hydrogen and fluorine. Preferred are —N (R ¹⁴ ) C (= NR ¹⁵ ) NR ¹⁶ R ¹⁷ , cyano, N (R ¹⁴ ) C (= O) NR ¹⁶ R ¹⁷ , a heteroaryl ring containing at least one nitrogen atom in the ring and a heterocycloalkyl ring containing at least one nitrogen atom in the ring. More preferred are N (R ¹⁴ ) C (= NR ¹⁵ ) NR ¹⁶ R ¹⁷ , N (R ¹⁴ ) C (= O) NR ¹⁶ R ¹⁷ , cyano and triazole and imidazole.

The following is a non-limiting list of preferred compounds of formula (I). With respect to compounds depicted by the above chemical structures, “linear” compounds (i.e., compounds where

there is no linker L, which provides a macrocyclic molecule), and macrocyclic compounds of the formula (II).

The following list uses one- and / or three-letter abbreviations of the amino acids discussed above.

YfRW-NH ₂ Ac-YfRW-NH ₂ Y (2-Nal) RW-NH ₂ Ac-yfrw Y (1-Nal) RW-NH ₂ Ac-Y (D-1-Nal) RW-NH ₂ Ac-a [DYfRWK] -NH ₂ Ac-a [DY (D-Phe (4-Cl)) RWK] -NH ₂ Ac-Y (2-Nal) RW-NH ₂ Ac- [EYfRWGK] -NH ₂ Ac-Y (D-2-Nal) RW-NH ₂ Ac-YFRW-NH ₂ Ac-Y (2-Nal) RW Ac-Y (D-Phe (4-F)) RW-NH ₂ Ac- (Phe (4-F)) fRW-NHCH ₃ Ac- (Phe (4-Cl)) fRW-NH ₂ Ac- (Phe (4-Cl)) fRW-NHCH ₃ Ac-YfKW-NH ₂ Ac-YfK (2-Nal) -NH ₂ Ac-YfK (2-Nal) -NHCH ₃ Ac-YfR (2-Nal) -NHCH ₃ Ac-YfR (2-Nal) -NH ₂ Ac-YfR (1-Nal) -NH ₂ (des-NH ₂ Tyr) YfR (2-Nal) -NHCH ₃ Ac-TICfRW-NHCH ₃ Ac-a [EYfRWGK] -NH ₂ Ac- (Phe (4-NO ₂ )) fRW-NH ₂ Ac- (Phe (4-Cl)) (D-Phe (4-F)) RW-NH ₂ Ac- (Phe (4-Cl) (D-Phe (4-F)) RW-NHCH ₃ Bc-YfRW (Sar) -NH ₂ Ac- (Phe (4-Cl)) fR (2-Nal) -NHCH ₃ Bc- (Phe (4-Cl) (fRW (Sar) -NH ₂ Ac-YfHW-NH ₂ Ac-Yf (homo-His) W-NH ₂ Ac- (Phe (4-Cl)) (Phe (4-F) R (2-Nal) -NHCH ₃ Ac-Y (Phe (4-F) R (2-Nal) -NHCH ₃ Ac-FfRW-NH ₂ Ac-FfR (2-Nal) -NHCH ₃

Ac-yfRW-NH ₂ yfRW-NH ₂ Ac-YyRW-NH ₂ Ac-Y (D-Phe (4-I)) KW-NH ₂ Ac-Y (D-Phe (4-I)) HW-NH ₂ Ac-Y (D-Phe (4-I)) RW-NH ₂ Ac-WfRW-NH ₂ Ac-YfR (Trp (5-F) -NH ₂ , Ac-Y (D-Phe (4Br)) RW-NH ₂ Ac- (D-Phe (3-OH)) fRW-NH ₂ Ac-F (D-Phe (4-I)) KW] -NH ₂ Ac-YfR (Trp (5-OMe) -NH ₂ Ac-YfR (Trp (5-Br) -NH ₂ Ac-YfR (Trp (5-Me) -NH ₂ Ac-a [DYfR (Trp (6-F) GK] -NH ₂ Ac-YfR (Trp (1-Me) -NH ₂ Ac-a [DYfR (Trp (4-F) GK] -NH ₂ Ac-YfR (Trp (6-Br) -NH ₂ Ac-a [DYfR (Trp (7-Me) GK] -NH ₂ Ac-YfR (Trp (5-OH)) - NH ₂ Ac-YfR (Trp (6-OH)) - NH ₂ Ac-YfR (Trp (6-Cl)) - NH ₂ Ac- (Tyr (Me)) fRWG-NH ₂ Ac- (Tyr (CH ₂ Ph)) fRW-NH ₂ Ac- (Tyr (3-NH ₂ )) fRW-NH ₂ Ac (Tyr (3-Cl)) fRW-NH ₂ Ac- (Tyr (3-MeO)) fR-NH ₂ Ac-Y (D-Phe (5-F)) RW-NH ₂

III. Synthesis of Compounds

Compounds of the present invention can be obtained using a number of methods, including solid-phase synthesis and liquid-phase synthesis in solution. Below is a general description of the methods of both solid-phase and liquid-phase synthesis in solution. Section VII provides several representative examples for each of the above synthesis methods (peptides).

A. Solid Phase Synthesis

Synthesis of linear peptides: Compounds are synthesized manually (a brief description is provided in section VII-C below) or automatically either on a Perkin-Elmer Applied Biosystem Division (PE-ABD) Model 433 automated synthesizer or on a SyntraPrep reaction unit (manufactured by SyntraChem, Charlottesville, VA ) All reagents used for the synthesis of peptides can be supplied by PE-ABD. In the case of a PE-ABD automatic synthesizer, a standard chemical

0.25 mmol FastMoc program with control of each stage of connection by conductivity measurement. In general, the (stepwise) synthesis of a peptide using Fmoc-protecting groups in the case of using the SPPS (solid-phase synthesis of peptides) technique involves the following steps: 1) cleavage of the Fmoc-protecting groups by piperidine; 2) activation of the carboxyl group of amino acids; and 3) the interaction of activated amino acids with the amino end of the peptide chain associated with the polymer, with the formation of peptide bonds. FastMoc cycles in which amino acids are activated with 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU). 1.0 mmol of dry protected amino acid in the cartridge is dissolved in a solution of HBTU, N, N-diisopropylethylamine (DIEA) and 1-hydroxybenzotriazole (HOBt) in N, N-dimethylformamide (DMF) with additional N-methylpyrrolidone (NMP) is added. An activated Fmoc amino acid is formed almost instantly, and the solution is transferred directly to the reaction vessel. The deprotection step Fmoc (deprotection step Fmoc) is monitored and controlled by measuring conductivity. The peptide chain is built on the Rink Amide resin, since a C-terminal amide is required. An acetyl or butyl group is introduced at the N-terminus of the peptide chain after the full length of the peptide chain is obtained. This is carried out by the reaction of acetic anhydride or butyric anhydride, (4.75% by volume: vol. Of acetic anhydride or butyric anhydride, 0.2% HOBt mass: vol., 2.25% DIEA in NMP with the α-amino group of the N-terminal amino acid residue The final product of the synthesis is washed with NMP and dichloromethane (DCM) for a sufficient time when used for peptide synthesis

SyntraChem reaction unit, O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) is used as an activation reagent that replaces HBTU.

Deprotection: Polymers containing synthesized peptides are unloaded from the synthesizer and briefly dried in air. Using 4.0-10.0 ml of a cocktail for splitting (91% trifluoroacetic acid (TFA), 2.3% ethanodithiol, 2.3% thioanisole and 2.3% phenol (w / v) in water) for 1.5-3.0 hours at room temperature, the peptides are cleaved from the resin and at the same time the side chain protecting groups are removed [O-tert-butyl (OtBu) for Asp, Glu, Tyr and Ser, pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) for Arg, tert-butoxycarbonyl (Boc) for Trp, Orn, Lys] under deprotection. The solution containing the cleavage products is separated from the resin by filtration. The peptide is then precipitated in the filtrate by adding 40 ml of chilled ether. The peptide precipitate was filtered off and washed with chilled ether (4 x 40 ml). For peptides that do not precipitate in the ether solution due to their high hydrophobicity, the ether is evaporated in a stream of nitrogen. The peptides are then frozen and lyophilized for more than 24 hours. Peptides are regenerated in the solution by the addition of acetic acid.

Purification and characterization: The peptide powder, together with other by-products, is redissolved in a 50% acetic acid solution and purified by injection into a Vydac C-8 column, size: 1.0 cm ID, 25 cm length, 5 μm particle size and size 300 A. A Beckman System Gold HPLC system with a UV detector with detection at two wavelengths is used. For

separating the peptide product from other substances establishes a programmed elution mode with a linear gradient of acetonitrile and is introduced into the column. The eluate is collected in a Pharmacia fraction collector and the individual fractions after separation are analyzed by both analytical HPLC and electrospray mass spectrometry (MS) to identify products to ensure their identity and purity.

B. The method of liquid-phase synthesis of peptides in solution

Commercially available solvents and reagents are used without purification. The reaction mixtures are stirred using a magnetic stirrer and their composition is controlled either by analytical high performance liquid chromatography (HPLC) or thin layer chromatography (TLC). The solutions are concentrated in a conventional manner using a Buchi rotary evaporator at 15-25 mm Hg. Art. TLC was performed using plates precoated with silica gel 60 F254 with a fluorescent indicator. Visualization is carried out in a standard way using UV radiation (254 nm). Flash chromatography was carried out on E. Merck silica gel 60 (230-400 mesh) using the desired eluents; chromatographic separation was monitored by TLC analysis. Analytical HPLC was carried out either on 4.6 x 250 mm MetaChem Kromasil C ₄ columns or reverse phase Polaris C ₁₈ (particle size 3.5 μm or 3.0 μm for C ₄ or C ₁₈ , respectively) using a mixture gradient 0.1% phosphoric acid in water (A) / acetonitrile (B) (5% B for C ₄ or 20% B for C ₁₈ to 100% over 20 min, retention 5 min) at a volume flow

1.0 ml / min; UV detection both at 214 nm and at 254 nm. Preparative HPLC was performed on a column Polaris C ₁₈ reverse phase size of 50 x 250 mm (particle size 10 micron, pore size 100 U) or column Rainin Dynamax C ₄ reverse size 41.4 x 250 mm phase (particle size 8 μm, pore size 300 U), using a gradient of a mixture of 0.1% trifluoroacetic acid in water (A) / acetonitrile (B) (5% → 100% B for 55 minutes, holding for 10 minutes); UV detection at 214 nm.

C. General comments

It is recognized that it is preferable to use a protecting group for any reactive functional group such as carboxyl, hydroxyl and the like. This is a common practice, the use of which is within the experimental experience of a specialist in this field.

These steps may vary to increase the yield of the desired product. For a specialist it is obvious that a reasonable selection of reactants, solvents and temperatures is an important factor for the successful implementation of any synthesis. Determination of optimal conditions, etc. is a common practice. Accordingly, one skilled in the art can obtain a variety of compounds, guided by the above general descriptions, along with the recommendations of the examples of Section VII.

Obviously, a person skilled in the art of organic chemistry can easily perform conventional manipulations with organic compounds without further guidance; those. the implementation of such manipulations is within

qualifications and practical experience of a specialist in this field. The above manipulations include, but are not limited to, the reduction of carbonyl compounds to their corresponding alcohols, the oxidation of hydroxyl groups, etc., acylation, aromatic substitutions, both electrophilic and nucleophilic, esterification to obtain ethers and esters, and saponification, etc. .P. Examples of the above manipulations are discussed in conventional publications such as March, Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (Vol. 2) and other publications that are known to those skilled in the art.

It is obvious to a person skilled in the art that certain reactions are best carried out when the potentially reactive functional groups in the molecule are masked or protected, which makes it possible to prevent any undesirable side reactions and / or increase the yield of the target reaction. Often, a specialist in this field uses protective groups in order to increase the yield of the target reaction or to avoid adverse reactions. Such reactions are available in the literature and are also well known to those skilled in the art. Examples of many such manipulations can be found, for example, in T. Greene, Protecting Groups in Organic Synthesis. Of course, amino acids with reactive side chains used as starting materials are preferably blocked in order to prevent undesired side reactions.

IV. Functional activity and selectivity for melanocortin receptors

Functional activity can be assessed using various methods known in the art. Examples of such methods are the measurement of responses of a secondary messenger, in particular cAMP, the use of modified cell systems that can give a color reaction after accumulation of elements of a second messenger, such as cAMP, for example, Chen et al. 1995 (Anal Biochem. 1995, 226, 349-54), Cytosensor Microphysiometer techniques (see Boyfield et al. 1996), or you can use the study of the physiological effects caused by the compounds of the invention, using the compounds of the invention, as such, or in combination with natural or synthetic MSH peptides.

The compounds of the present invention can preferably interact (i.e. selectively) with MC-4 and / or MC-3, compared to other melanocortin receptors. Selectivity is especially important when the compounds are administered to humans or other animals in order to minimize a number of side effects associated with their administration. The selectivity of the compound for MC-3 / MC-4 is defined as the ratio of the EC _{50 of the} compound for MC-1 receptor (“EC ₅₀ -MC-1”) to the EC _{50 of the} compound for MC-3 receptor (EC ₅₀ -MC-3) / MC-4 (EC ₅₀ -MC-4), with EC ₅₀ values determined as described above. The formulas are as follows:

MC-3 selectivity = [EC ₅₀ -MC-1] / [EC ₅₀ -MC-3]

MC-4 selectivity = [EC ₅₀ -MC-1] / [EC ₅₀ -MC-4]

The compound is believed to exhibit “selectivity for the MC-3 receptor” when the above

the ratio “MC-3 selectivity” is at least about 10, preferably at least about 100, and more preferably at least about 500.

A compound is defined as having “selectivity for the MC-4 receptor” when the above ratio “MC-4 selectivity” is at least about 10, preferably at least about 100, and more preferably at least about 500.

V. Methods of use and composition:

Based on the ability of the claimed compounds to exhibit agonism or antagonism with respect to the MC-4 and / or MC-3 receptor, the present invention also relates to the use of the ligands described herein in methods for treating obesity and other disorders associated with deviations in body weight, including, for example, anorexia and cachexia. In addition, the compounds can be used in methods of treating disorders that result from disorders related to body weight, including, but not limited to, insulin resistance, glucose intolerance, Type II diabetes mellitus, coronary heart disease, high blood pressure, hypertension , dyslipidemia, cancer (e.g., endometrial cancer, brain cancer, ovarian cancer, breast cancer, prostate cancer, gall bladder cancer, colon cancer), menstrual abnormalities, hirsutism, infertility, gall bladder disease, limitations ennoe pulmonary lesions, sleep apnea, gout, osteoarthritis, and thromboembolic disease. Besides,

The invention relates to the treatment of disorders related to physiological behavior, memory (including learning), cardiovascular function, inflammation, sepsis, cardiogenic and hypovolemic shock, sexual dysfunction, penile erection, muscle atrophy, nerve growth and regeneration, intrauterine development of the fetus etc.

As used herein, the term “treatment” means that at least administration of a compound of the present invention attenuates a disorder by acting through the MC-3 or MC-4 receptor. Thus, the terms include: preventing the development of a disease state in a mammal, in particular when it is predisposed to acquire such a disease, but not yet diagnosed with it; inhibition of the development of this disease state; and / or alleviating or reversing such a condition of the disease.

The compounds of the present invention can be formulated into pharmaceutical compositions for use in the treatment or prophylaxis of the above disease conditions. For this, standard drug preparation techniques are used, such as those described in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., Latest edition and Peptide and Protein Drug Delivery, Marcel Dekker, NY, 1991.

Compositions of the present invention include:

a. a safe and effective amount of a compound of formula (I); and

b. pharmaceutically acceptable excipient.

A “safe and effective amount” of a compound of formula (I) is an amount that is effective for interacting with the MC-4 and / or MC-3 receptor for an animal, preferably a mammal, more preferably a human, without unduly manifesting undesirable side effects (such as toxicity, irritation, or allergic reaction) commensurate with the acceptable benefit / risk ratio when using the method of the present invention. Obviously, the specific “safe and effective amount” may vary depending on factors such as the particular condition being treated; the physical condition of the patient, the duration of treatment, the nature of concomitant therapy (if any), the specific dosage form to be used; the excipient used, the solubility of the compound of formula (I) and the dosage regimen necessary for the composition.

In addition to the proposed compound, the compositions of the present invention contain one or more pharmaceutically acceptable excipients. As used herein, the term “pharmaceutically acceptable excipient” means one or more compatible solid or liquid components that are suitable for administration to an animal, preferably a mammal, more preferably a human. Used in this description, the term “compatible” means that the components of the composition can be mixed with the proposed compound and with each other to some extent, so that there will be no interaction that could reduce

the pharmaceutical effectiveness of the composition in normal situations of its use. Pharmaceutically acceptable excipients should, of course, have a sufficiently high purity and sufficiently low toxicity to be suitable for administration to an animal, preferably a mammal, more preferably a person to be treated.

Some examples of substances that may be useful as pharmaceutically acceptable excipients or components for the composition are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and theobromine oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; agar; alginic acid, moisturizers and lubricants, such as sodium lauryl sulfate; dyes; flavorings; tabletting aids; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and buffers such as phosphate, citrate and acetate.

The choice of pharmaceutically acceptable excipients to be used in combination with the compound of the invention is mainly determined by the way in which the compound is to be

introduction. If the compound is to be administered by injection, the preferred pharmaceutically acceptable excipient is sterile water, physiological (saline) solution or mixtures thereof, the pH of which is preferably adjusted to about 4-10 with a pharmaceutical buffer; It is also possible to use a compatible suspending agent.

In particular, pharmaceutically acceptable excipients for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, lactose, vegetable oils, synthetic oils, polyols, alginic acid, phosphate, acetate and citrate buffers, emulsifiers , isotonic saline and pyrogen-free water. Preferred pharmaceutically acceptable excipients for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol and sesame oil. Preferably, the pharmaceutically acceptable excipient, in compositions for parenteral administration, comprises at least about 90% of the mass. of the total weight of the composition.

The compositions of the present invention are preferably formulated in unit dosage form. As used herein, the term “unit dosage form” is a composition of the present invention containing an amount of a compound of formula (I) that is suitable for administration to an animal, preferably a mammal, more preferably a human, in a unit dose, according to established medical practice. The above compositions

preferably contain from about 1 mg to about 750 mg, more preferably from about 3 mg to about 500 mg, even more preferably from about 5 mg to about 300 mg of the compound of formula (I).

The compositions of the present invention can be presented in any of a variety of forms suitable for oral, rectal, local, nasal, ophthalmic, transdermal, pulmonary or parenteral administration. Depending on the desired particular route of administration, a number of pharmaceutically acceptable excipients known in the art may be used. Such excipients include solid or liquid fillers, diluents, hydrotropes, surfactants, and encapsulating substances. Optional pharmaceutically active substances may be included that do not substantially interfere with the inhibitory activity of the compound of formula (I). The amount of excipient used in combination with the compound of formula (I) should be sufficient to ensure the practical introduction of an amount of a substance corresponding to a unit dose of the compound. Methods and compositions for the preparation of dosage forms used in the methods of the present invention are described in the following publications, which are incorporated by reference: Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2d Edition (1976).

Various oral dosage forms may be used, including solid forms such as tablets, capsules,

granules and loose powders. Said oral forms include a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50%, of a compound of formula (I). The tablets may be compressed, powder-coated, enteric-coated, sugar-coated, film-coated or compressed from several layers, may contain suitable binders, lubricants, diluents, disintegrants, colorants, flavorants, flow-promoting and melting-promoting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting aids , colorants and flavorings.

Pharmaceutically acceptable excipients suitable for the preparation of oral dosage forms are well known in the art. Tablets typically include conventional pharmaceutically compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin, polyvinylpyrrolidone and sucrose; disintegrants such as starch, alginic acid and croscarmellose; lubricating agents such as magnesium stearate, stearic acid and talc. To improve the flow characteristics of the powder mixture can be used

glidants, such as silicon dioxide. Dyestuffs such as FD&C dyes can be used to give an appearance. Sweeteners and flavors such as aspartame, saccharin, menthol, peppermint and fruit flavors are useful adjuvants for chewable tablets. Capsules typically include one or more of the solid diluents described above. The choice of excipient components depends on the envisaged secondary characteristics, such as taste, cost and storage stability, which are not essential for the purposes of the present invention, the selection of appropriate excipients can be easily made by a person skilled in the art.

Oral compositions also include liquid solutions, emulsions, suspensions, and the like. Pharmaceutically acceptable excipients suitable for the preparation of such compositions are well known in the art. Typical excipient components for syrups, elixirs, emulsions and suspensions include ethanol, glycerin, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, Avicel® RC-591, tragacanth and sodium alginate; typical humectants include lecithin and polysorbate 80; and typical preservatives include methyl paraben, propyl paraben and sodium benzoate. Oral liquid compositions may also contain one or more components, such as sweeteners, flavors, and colorants, as described above.

In addition, such compositions may be coated.

film-forming coating by conventional methods, usually the solubility of such coatings is pH-dependent or time-dependent in nature, so that the claimed compound is released in the gastrointestinal tract near the desired place of application, or at different times, prolonging the desired effect. Such dosage forms typically include, but are not limited to, one or more film-forming, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit® coatings, waxes and shellac.

Since the compounds of the present invention are peptide in nature, the preferred route of administration is parenteral (more preferably intravenous injection) or nasal administration, in unit dosage form. Preferred unit dosage forms include suspensions and solutions containing a safe and effective amount of a compound of formula (I). When administered parenterally, a unit dosage form usually comprises from about 1 mg to about 3 g, more preferably from about 10 mg to about 1 g, of a compound of formula (I), although the amount of compound administered may depend, for example, on its relative affinity for the subtypes receptors MS-4 / MS-3, its selectivity in comparison with other receptors, including other melanocortin receptors, etc.

The compositions of the present invention may optionally include other active drug substances.

Other compositions used to achieve systemic

delivery of the claimed compounds include sublingual and buccal dosage forms. Such compositions typically include one or more soluble excipients, such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. The above glidants, lubricants, sweeteners, colorants, antioxidants, and flavorings may also be included.

VI. Administration Methods:

As noted, the compositions of the present invention can be entered topically or systemically. Systemic use includes any method of introducing a compound of formula (I) into body tissues, for example, intraarticular, intrathecal, epidermal, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal, nasal, pulmonary and oral administration. The compounds of formula (I) of the present invention are preferably administered systemically, more preferably parenterally and most preferably by intravenous injection.

The individual dose of the compound to be administered, as well as the duration of treatment, whether the treatment is local or systemic, are interdependent. The dose and treatment regimen will also depend on factors such as the particular compound of formula (I) used, indication for treatment, personal characteristics of the subject (such as body weight), adherence to the treatment regimen, and the presence and severity of any side effects of the treatment.

Typically, for an adult, about 70 kilograms in weight, is administered per day with systemic administration from about 1 mg to about 6 g, more typically from about 100 mg to about 3 g, of a compound of formula (I). Obviously, these dose limits are presented only as an example, and that daily administration can be adjusted depending on the factors listed above.

As is known and practiced in this field, all formulations for parenteral administration must be sterile. For mammals, especially humans, (assuming an approximate body weight of the subject is 70 kilograms), individual doses of from about 0.001 mg to about 100 mg are preferred.

The preferred method of systemic administration is intravenous delivery. Using this delivery method, individual doses of from about 0.01 mg to about 100 mg, preferably from about 0.1 mg to about 100 mg, are preferred.

In all of the above methods of administration, of course, the compounds of the present invention can be introduced, as such, or in the form of mixtures, and, in addition, the compositions may contain additional drugs or excipients, if appropriate for the indication.

The compound of the present invention can be delivered to a preferred location in the body (human or animal) using a suitable drug delivery system. Drug delivery systems are well known in the art. For example, a drug delivery technique,

used for the compounds of the present invention consists in conjugating a compound to an active molecule capable of being transported across a biological barrier (see, for example, Zlokovic, BV, Pharmaceutical Research, Vol. 12, pp. 1395-1406 (1995). A specific example is the binding of a compound of the present invention with insulin fragments for transporting a drug across the blood-brain barrier (Fukuta, M., et al. Pharmaceutical Res., Vol. 11, pp. 1681-1688 (1994)). As a general overview of drug delivery technologies suitable for I of the compounds of the invention, see Zlokovic, B.V., Pharmaceutical Research, Vol. 12, pp. 1395-1406 (1995) and Pardridge, WM, Pharmacol. Toxicol, Vol. 71, pp. 3-10 (1992).

VII. Typical Synthesis Examples

In the following examples, the invention is described in more detail with reference to a number of preferred variants of its implementation, which are given only for purposes of illustration, and it should be borne in mind that these examples in no way limit the invention.

In the examples, the following abbreviations are used:

Ac: acetyl [-C (O) CH ₃ ]

Atc: (D, L) -2-aminotetralin-2-carboxylic acid

Aun: Aminoundecane

Bc: butanoyl [-C (O) (CH ₂ ) ₂ CH ₃ ]

Boc: tert-butyloxycarbonyl

DCM: Dichloromethane

DEA: diethylamine

DMF: N, N-dimethylformamide

DMAP: 4-dimethylaminopyridine

DME: 1,2-dimethoxyethane

DIEA: diisopropylethylamine

DPPA: diphenylphosphorylazide

EtOAc: ethyl acetate

EDCI: 1-ethyl-3- (3’-dimethylaminopropyl) carbodiimide hydrochloride

Fmoc: 9-fluorenylmethoxycarbonyl

HOBt: N-hydroxybenzotriazole monohydrate

HOAt: 1-hydroxy-7-azabenzotriazole

i-PrOH: 2-propanol

MeOH: methanol

NMM: N-methylmorpholine

OtBu: tert-butoxy [-OC (CH ₃ ) ₃ ]

Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl PMc: 2,2,5,7,8-pentamethyl-6-chromanesulfonylp-TSA: p-toluenesulfonate

PyBOP: benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate

PyBroP: bromo-tris-pyrrolidinophosphonium hexafluorophosphate

tBu: tert-butyl [-C (CH ₃ ) ₃ ]

TEA: triethylamine

TFA: trifluoroacetic acid

THF: tetrahydrofuran

A. Automatic Solid Phase Peptide Synthesis

Example 1

Synthesis of Ac-YfRW-NH ₂

Based on the degree of substitution of the Rink Amide resin of 0.55 mmol / g, 0.45 g of resin is weighed for a 0.25 mmol synthesis scale. The functioning of the PE-ABD 433 peptide synthesizer is tested prior to use by various in-line tests to ensure accurate reagent delivery. Fmoc amino acids: Tyr-OtBu, Arg-Pmc and Trp-Boc were commercially available in 1 mmol cartridges. Fmoc-phe (387 mg, 1 mmol) was determined and added to synthesis cartridges. A freshly prepared solution of acetic anhydride is loaded into the flask # 4 installation. Other reagents and solvents for the synthesis are supplied commercially and loaded into the unit in accordance with the attached instructions. For the synthesis of the peptide, a chemical program called NAc-0.25 mmol MonPrePk is used. The deprotection of Fmoc is monitored and regulated by measuring conductivity, with established conductivity criteria of 5% or less compared to the previous deprotection cycle.

The resin was air dried and transferred to a glass vessel and freshly prepared cleavage reagent (10 ml) was added. The deprotection reaction is carried out for 2 hours at room temperature with constant stirring. Then the supernatant is separated from the resin by filtration. The synthesized peptide is then precipitated in the ether layer by adding 40 ml of chilled ether. Precipitation peptide centrifuged (Heraeus Labofuge 400, Rotor # 8179) at 3500 rpm for four

minutes. The ether is drained and 40 ml of fresh chilled ether are added to wash the precipitate of the peptide. The washing steps are repeated three times to remove by-products from the deprotection reaction. Precipitation of the final peptide is freeze-dried overnight. The identification and purity of the peptide is determined by both MS and HPLC. The expected molecular weight of the peptide is determined.

The peptide was redissolved in 50% acetic acid and purified by reverse phase HPLC (C8) using a linear gradient of 0-70% solvent B with solvent A for 70 minutes at a volume flow of 3 ml / min. The composition of solvents A and B is as follows: A: 0.1% TFA, 2% acetonitrile in water; B: 0.1% TFA in 95% acetonitrile. Fractions are collected every 0.25 minutes. Aliquots of each fraction are analyzed by both MS and reverse phase HPLC (RP-HPLC). Fractions that contain one absorption peak at 220 nm with the expected mass of the peptide are combined and lyophilized. The final purity of the peptide is determined by analytical RP-HPLC of the combined fractions.

The peptides described in examples 2-54 below are synthesized without difficulty in accordance with the procedure of example 1, but with the changes that are specifically mentioned.

Example 2

Synthesis of Ac-YFRW-NH ₂

Receive according to example 1, except that use Fmoc-L-Phe instead of Fmoc-D-Phe.

Example 3

Synthesis of Ac-FfRW-NH ₂

Receive according to example 1, except that use Fmoc-L-Phe instead of Fmoc-L-Tyr (OtBu).

Example 4

Synthesis of Ac-PFRW-NH ₂

Receive according to example 1, except that use Fmoc-L-Pro instead of Fmoc-L-Tyr (OtBu).

Example 5

Synthesis of Ac-AfRW-NH ₂

Receive according to example 1, except that use Fmoc-L-Ala instead of Fmoc-L-Tyr (OtBu).

Example 6

Synthesis of Ac- (2-Nal) fRW-NH ₂

Receive according to example 1, except that use Fmoc-L- (2-Nal) instead of Fmoc-L-Tyr (OtBu).

Example 7

Synthesis of Ac-YfR (2-Nal) -NH ₂

Receive according to example 1, except that use Fmoc-L- (2-Nal) instead of Fmoc-L-Trp (Boc).

Example 8

Synthesis of Ac-YfR (1-Nal) -NH ₂

Receive according to example 1, except that use Fmoc-L- (1-Nal) instead of Fmoc-L-Trp (Boc).

Example 9

Synthesis of Ac-YfHW-NH ₂

Receive according to example 1, except that use Fmoc-L-His (Trt) instead of Fmoc-L-Arg (Pmc).

Example 10

Synthesis of Ac-Y (D-2-Nal) RW-NH ₂

Receive according to example 1, except that use Fmoc-D- (2-Nal) instead of Fmoc-D-Phe.

Example 11

Synthesis of Ac-Y (LN-Me-Phe) RW-NH ₂

Receive according to example 1, except that use Fmoc-L-N-Me-Phe instead of Fmoc-D-Phe.

Example 12

Synthesis of Ac-A (DN-Me-Phe) RW-NH ₂

Obtained according to example 1, except that Fmoc-D-N-Me-Phe is used instead of Fmoc-L-Phe, and Fmoc-L-Ala is used instead of Fmoc-L-Tyr (OtBu).

Example 13

Synthesis of Ac-YF (L-N-Me-Arg) W-NH

Prepared according to Example 1, except that Fmoc-L-N-Me-Arg (Mtr) was used instead of Fmoc-L-Arg (Pmc), and Fmoc-L-Phe was used instead of Fmoc-D-Phe.

Example 14

Synthesis of Ac-Yf (LN-Me-Arg) W-NH ₂

Receive according to example 1, except that use Fmoc-L-N-Me-Arg (Mtr) instead of Fmoc-L-Arg (Pmc).

Example 15

Synthesis of Ac- (LN-Me-Tyr) FRW-NH ₂

Prepared according to Example 1, except that Fmoc-L-N-Me-Tyr (Bzl) was used instead of Fmoc-L-Tyr (OtBu) and Fmoc-L-Phe was used instead of Fmoc-D-Phe.

Example 16

Synthesis of Ac- (LN-Me-Tyr) fRW-NH ₂

Receive according to example 1, except that use Fmoc-L-N-Me-Tyr (Bzl) instead of Fmoc-L-Tyr (OtBu).

Example 17

Synthesis of Ac-Y (D-4-chloro-Phe) RW-NH ₂

Receive according to example 1, except that use Fmoc-D-4-chloro-Phe instead of Fmoc-D-Phe.

Example 18

Synthesis of Ac-Y (D-4-fluoro-Phe) RW-NH ₂

Receive according to example 1, except that use Fmoc-D-4-fluoro-Phe instead of Fmoc-D-Phe.

Example 19

Synthesis of Ac-Y (D-3,4-Dichloro-Phe) RW-NH ₂

Receive according to example 1, except that use Fmoc-D-3,4-dichloro-Phe instead of Fmoc-D-Phe.

Example 20

Synthesis of Ac-Y (D-4-Me-Phe) RW-NH ₂

Receive according to example 1, except that use Fmoc-D-4-Me-Phe instead of Fmoc-D-Phe.

Example 21

Synthesis of Ac-Y (D-4-nitro-Phe) RW-NH ₂

Receive according to example 1, except that use Fmoc-D-4-nitro-Phe instead of Fmoc-D-Phe.

Example 22

Synthesis of Ac-Y (D-phenylglycine) RW-NH ₂

Receive according to example 1, except that

use Fmoc-D-phenylglycine instead of Fmoc-D-Phe.

Example 23

Synthesis of Ac-Y (D-4-homo-Phe) RW-NH ₂

Receive according to example 1, except that use Fmoc-D-4-homo-Phe instead of Fmoc-D-Phe.

Example 24

Synthesis of Ac-Y (D-styrylalanine) RW-NH ₂

Receive according to example 1, except that they use Fmoc-D-styrylalanine instead of Fmoc-D-Phe.

Example 25

Synthesis of Ac-Y (D-4-thienylalanine) RW-NH ₂

Receive according to example 1, except that they use Fmoc-D-4-thienylalanine instead of Fmoc-D-Phe.

Example 26

Synthesis of Ac-Y (D-3-fluoro-Phe) RW-NH ₂

Receive according to example 1, except that use Fmoc-D-3-fluoro-Phe instead of Fmoc-D-Phe.

Example 27

Synthesis of Ac- (L-4-fluoro-Phe) (D-4-fluoro-Phe) RW-NH ₂

Prepared according to Example 1, except that Fmoc-L-4-fluoro-Phe was used instead of Fmoc-L-Tyr (OtBu) and Fmoc-D-4-fluoro-Phe was used instead of Fmoc-D-Phe.

Example 28

Synthesis of Ac-Y (D-2-fluoro-Phe) RW-NH ₂

Receive according to example 1, except that use Fmoc-D-2-fluoro-Phe instead of Fmoc-D-Phe.

Example 29

Synthesis of Ac- (L-4-chloro-Phe) (D-4-fluoro-Phe) RW-NH ₂

Obtained according to example 1, except that Fmoc-L-4-chloro-Phe is used instead of Fmoc-L-Tyr (OtBu) and Fmoc-D-4-fluoro-Phe is used instead of Fmoc-D-Phe.

Example 30

Synthesis of Ac- (L-4-chloro-Phe) (D-4-fluoro-Phe) RW (N-Me-Gly) NH ₂

Prepared according to Example 1, except that Fmoc-L-4-chloro-Phe is used instead of Fmoc-L-Tyr (OtBu), Fmoc-D-4-fluoro-Phe is used instead of Fmoc-D-Phe and additionally Fmoc is used -N-Me-Gly.

Example 31

Synthesis of Ac- (L-4-chloro-Phe) fRW (N-Me-Gly) -NH ₂

Receive according to example 1, except that they use Fmoc-L-4-chloro-Phe instead of Fmoc-L-Tyr (OtBu) and use additional Fmoc-N-Me-Gly.

Example 32

Synthesis of Ac- (L-4-chloro-Phe) (D-4-fluoro-Phe) R-NH ₂

Prepared according to Example 1, except that Fmoc-L-4-chloro-Phe is used instead of Fmoc-L-Tyr (OtBu), Fmoc-D-4-fluoro-Phe is used instead of Fmoc-D-Phe and not Fmoc -L-Trp (Boc).

Example 33

Synthesis of Ac- (L-4-chloro-Phe) (D-4-fluoro-Phe) RG-NH ₂

Prepared according to Example 1, except that Fmoc-L-4-chloro-Phe is used instead of Fmoc-L-Tyr (OtBu), Fmoc-D-4-fluoro-Phe is used instead of Fmoc-D-Phe and Fmoc-L -Gly use

instead of Fmoc-L-Trp (Boc).

Example 34

Synthesis of Ac- (L-3,4-difluoro-Phe) fRW-NH ₂

Prepared according to Example 1, except that Fmoc-L-3,4-difluoro-Phe was used instead of Fmoc-L-Tyr (OtBu).

Example 35

Synthesis of Ac-Y (D-2-Me-Phe) RW-NH ₂

Receive according to example 1, except that use Fmoc-D-2-Me-Phe instead of Fmoc-D-Phe.

Example 36

Synthesis of Ac- (L-4-bromo-Phe) fRW-NH ₂

Receive according to example 1, except that use Fmoc-L-4-bromo-Phe instead of Fmoc-L-Tyr (OtBu).

Example 37

Synthesis of Ac- (L-4-iodo-Phe) fRW-NH ₂

Receive according to example 1, except that use Fmoc-L-4-iodine-Phe instead of Fmoc-L-Tyr (OtBu).

Example 38

Synthesis of Ac- (L-Pentafluoro-Phe) fRW-NH ₂

Receive according to example 1, except that they use Fmoc-L-pentafluoro-Phe instead of Fmoc-L-Tyr (OtBu).

Example 39

Synthesis of Ac- (L-4-nitro-Phe) fRW-NH ₂

Receive according to example 1, except that use Fmoc-L-4-nitro-Phe instead of Fmoc-L-Tyr (OtBu).

Example 40

Synthesis of Ac- (L-aminomethyl-Phe) fRW-NH ₂

Receive according to example 1, except that use Fmoc-L-aminomethyl-Phe (Boc) instead of Fmoc-L-Tyr (OtBu).

Example 41

Synthesis of Ac- (L-tetraisoquinoline-3-carboxylic acid) fRW-NH ₂

Prepared according to Example 1, except that Fmoc-L-tetraisoquinoline-3-carboxylic acid was used instead of Fmoc-L-Tyr (OtBu).

Example 42

Synthesis of Ac- (L-homo-Phe) fRW-NH ₂

Obtained according to example 1, except that Fmoc-L-homo-Phe is used instead of Fmoc-L-Tyr (OtBu).

Example 43

Synthesis of Ac- (L-biphenylalanine) fRW-NH ₂

Obtained according to example 1, except that they use Fmoc-L-biphenylalanine instead of Fmoc-L-Tyr (OtBu).

Example 44

Synthesis of Ac- (L-4-SO ₃ -Phe) fRW-NH ₂

Receive according to example 1, except that use Fmoc-L-4-SO ₃ -Phe instead of Fmoc-L-Tyr (OtBu).

Example 45

Synthesis of Ac- (L-2,6-dimethyl-Phe) fRW-NH ₂

Receive according to example 1, except that use Fmoc-L-2,6-dimethyl-Phe instead of Fmoc-L-Tyr (OtBu).

Example 46

Synthesis of Ac- (L-4-methyl-Phe) fRW-NH ₂

Receive according to example 1, except that use Fmoc-L-4-methyl-Phe instead of Fmoc-L-Tyr (OtBu).

Example 47

Synthesis of Ac- (L-4-NH-Phe) fRW-NH ₂

Receive according to example 1, except that use Fmoc-L-4-NH-Phe (Boc) instead of Fmoc-L-Tyr (OtBu).

Example 48

Synthesis of Ac-YfKW-NH ₂

Receive according to example 1, except that use Fmoc-L-Lys (Boc) instead of Fmoc-L-Arg (Pmc).

Example 49

Synthesis of Ac-Yf (Orn) W-NH ₂

Receive according to example 1, except that use Fmoc-L-Orn (Boc) instead of Fmoc-L-Arg (Pmc).

Example 50

Synthesis of Bc-HFRW (N-Me-Gly) -NH ₂

Prepared according to Example 1, except that Fmoc-L-His (Trt) is used instead of Fmoc-L-Tyr (OtBu), Fmoc-L-Phe is used instead of Fmoc-D-Phe, butyric anhydride is used instead of acetic anhydride and used optional Fmoc-LN-Me-Gly.

Example 51

Synthesis of Bc-HfRW (N-Me-Gly) -NH ₂

Obtained according to example 1, except that Fmoc-L-His (Trt) is used instead of Fmoc-L-Tyr (OtBu), butyric anhydride is used instead of acetic anhydride and additionally Fmoc-L-N-Me-Gly is used.

Example 52

Synthesis of Bc-YfRW (N-Me-Gly) -NH ₂

Obtained according to example 1, except that butyric anhydride is used instead of acetic anhydride and additionally Fmoc-L-N-Me-Gly is used.

Example 53

Synthesis of Bc-YFRW (N-Me-Gly) -NH ₂

Obtained according to example 1, except that they use Fmoc-L-Phe instead of Fmoc-D-Phe, butyric anhydride is used instead of acetic anhydride and additionally Fmoc-L-N-Me-Gly is used.

Example 54

Synthesis of Bc-FfRW (N-Me-Gly) -NH ₂

Obtained according to example 1, except that they use Fmoc-L-Phe instead of Fmoc-L-Tyr (OtBu), butyric anhydride is used instead of acetic anhydride and additionally Fmoc-L-N-Me-Gly is used.

B. Liquid-phase synthesis in solution

Example 55

Synthesis of (naphthalen-1-ylmethyl) amide 5-guanidino-2- [3-phenyl-2- (3-phenylpropylamino) propionylamino] pentanoic acid

2- (S) - (2- (R) -tert-butoxycarbonylamino-3-phenylpropionylamino) -5-nitroguanidinopentanoic acid methyl ester

To a solution of 2- (R) - (2-tert-butoxycarbonylamino-3-phenylpropionic acid (2.0 g, 7.54 mmol) and methyl ether

2- (S) -amino-5-nitroguanidino-pentanoic acid (2.0 g, 1.1 equiv.) In 100 ml of anhydrous DMF add 1- [3- (dimethylamino) propyl) -3-ethylcarbodiimide hydrochloride (1.5 g 1.5 equivalents), 1-hydroxybenzotriazole (2.16 g, 1.4 equivalents) and triethylamine (3.0 ml, 3 equivalents). The resulting solution was stirred at room temperature for 20 hours, and then the solvents were removed under reduced pressure. The resulting residue was partitioned between 10% sodium carbonate (100 ml) and methylene chloride (100 ml). The organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The resulting crude material was purified by flash chromatography on silica gel (90: 9: 1 chloroform: methanol: ammonium hydroxide) to give the title compound.

2- (S) - (2- (R) -tert-Butoxycarbonylamino-3-phenylpropionylamino) -5-nitroguanidinopentanoic acid

To a solution of 2- (S) - (2- (R) -tert-butoxycarbonylamino-3-phenylpropionylamino) -5-nitroguanidinopentanoic acid methyl ester (3.6 g, 7.5 mmol) in tetrahydrofuran (100 ml) was added hydroxide monohydrate lithium (387 mg, 1.2 equiv.) and water (10 ml). After stirring at room temperature for one hour, the reaction mixture was neutralized with trifluoroacetic acid (0.7 ml) and the solvents were removed under reduced pressure. The resulting residue was partitioned between water (200 ml) and ethyl acetate (200 ml). The aqueous layer was extracted with ethyl acetate (3 × 250 ml), the organic phase was combined and dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. Unpeeled

the substance is used without further purification.

(1- (S) - {4-nitroguanidino-1- [naphthalen-1-ylmethyl) carbamoyl] butylcarbamoyl} -2- (R) -phenylethyl) carbamic acid tert-butyl ester

To a solution of 2- (S) - (2- (R) -tert-butoxycarbonylamino-3-phenylpropionylamino) -5-guanidinopentanoic acid (1.0 g, 2.15 mmol) and C-naphthalen-1-ylmethylamine (0.377 ml , 1.2 equiv.) In 50 ml of anhydrous DMF add 1- [3- (dimethylamino) propyl) -3-ethylcarbodiimide hydrochloride (532 mg, 1.5 equiv.), 1-hydroxybenzotriazole (376, 1.4 equiv. ) and triethylamine (0.9 ml, 3 equiv.). The resulting solution was stirred at room temperature for 20 hours, and then the solvents were removed under reduced pressure. The resulting residue was partitioned between 10% sodium carbonate (75 ml) and chloroform (75 ml). The organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The resulting crude material was purified by flash chromatography on silica gel (90: 9: 1 chloroform: methanol: ammonium hydroxide, to give the title compound.

Salt of trifluoroacetic acid (naphthalen-1-ylmethyl) amide 2- (S) - (2- (R) -amino-3-phenylpropionylamino) -5-nitroguanidinopentanoic acid

To a solution of (1- (S) - {4-nitroguanidino [1-naphthalen-1-ylmethylcarbamoyl] butylcarbamoyl} -2- (R) -phenylethyl) carbamic acid (1.1 eq., 1.82) tert-butyl ester mmol) in methylene chloride (100 ml) add trifluoroacetic acid (50 ml). The resulting solution was stirred at room temperature in

for three hours and then the solvents are removed under reduced pressure. The crude material was purified by reverse phase preparative HPLC to give the title compound.

(Naphthalen-1-ylmethyl) 5-nitroguanidino-2- [3-phenyl-2- (3-phenylpropylamino) propionylamino] pentanoic acid amide

To a suspension of (naphthalen-1-ylmethyl) amide 2- (S) - (2- (R) -amino-3-phenylpropionylamino) -5-guanidinopentanoic acid (750 mg, 1.21 mmol), 3-phenylpropionaldehyde (0.159 ml , 1.0 equiv.) And activated molecular sieves (4 angstroms, crushed) add triethylamine (0.247 ml, 1.5 equiv.). The resulting suspension was stirred at room temperature for 24 hours and then adjusted to pH 5 with acetic acid. Then add a 1.0 M solution of sodium cyanoborohydride in tetrahydrofuran (1.44 ml, 1.2 eq.) At a rate of 0.2 ml / min. using a syringe pump. The resulting suspension was stirred at room temperature for 24 hours, filtered through celite and the solvents were removed under reduced pressure. The crude material was purified by reverse phase HPLC to give the title compound.

(Naphthalen-1-ylmethyl) 5-guanidino-2- [3-phenyl-2- (3-phenylpropylamino) propionylamino] pentanoic acid amide

To a solution of (naphthalen-1-ylmethyl) amide 5-nitroguanidino-2- [3-phenyl-2- (3-phenylpropylamino) propionylamino] pentanoic acid (140 mg, 0.165 mmol) in methanol (30 ml) was added acetic acid (3 ml) and 5% palladium on barium sulfate (100 mg). The resulting suspension was hydrogenated at atmospheric pressure for twenty-four hours and then filtered through celite. The solvents are removed under reduced pressure and the crude

the product is purified by reverse phase HPLC.

Example 56

Synthesis of (2-naphthalen-2-yl-ethyl) -amide 5-guanidino-2- (S) - [3-phenyl-2- (R) -propylamino) propionylamino] pentanoic acid

2-Naphthalene-2-yl-ethyl ester of toluene-4-sulfonic acid

To a solution of 2-naphthalen-2-yl-ethanol (3.0 g, 17.4 mmol) in tetrahydrofuran (50 ml) was added p-toluenesulfonic anhydride (6.8 g, 1.2 equiv.) And triethylamine (7.1 ml) , 3 equiv.). The resulting solution was stirred at room temperature for one hour, and then the solvents were removed under reduced pressure. The crude material was purified by flash chromatography on silica gel (20% ethyl acetate / hexane) to give the title compound.

2- (2-Azidoethyl) naphthalene

To a solution of toluene-4-sulfonic acid 2-naphthalen-2-yl-ethyl ester (5.0 g, 15.3 mmol) in DMF (100 ml) was added sodium azide (1.3 g, 1.3 eq.). The resulting suspension was heated to 80 ° C for twenty-four hours and then cooled to room temperature. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (200 ml) and water (200 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvent is removed under reduced pressure,

receiving the title compound. The crude material is used without further purification.

2-naphthalene-2-yl-ethylamine

To a solution of 2- (2-azidoethyl) naphthalene (3.0 g, 15.2 mmol) in tetrahydrofuran (100 ml) was added triphenylphosphine (6.0 g, 1.5 equiv.) And water (5 ml). The resulting solution was refluxed for three hours and then cooled to room temperature. The solvents were removed under reduced pressure and the crude material was purified by flash chromatography on silica gel (90: 9: 1 chloroform: methanol: ammonium hydroxide). The purified material is then converted to the trifluoroacetic acid salt by adding an excess of trifluoroacetic acid, and subsequent removal of the excess acid by evaporation under reduced pressure gives the title compound.

{1- (S) - [4-nitroguanidino-1- (2-naphthalen-2-yl-ethylcarbamoyl) butylcarbamoyl] -2- (R) -phenylethyl} carbamic acid tert-butyl ester

To a solution of 2- (S) - (2- (R) -tert-butoxycarbonylamino-3-phenylpropionylamino) -5-nitroguanidinopentanoic acid (1.0 eq, 2.14 mmol) and 2- (2-azidoethyl) naphthalene (733 mg, 1.2 equiv.) in DMF (50 ml) add 1- [3- (dimethylamino) propyl) -3-ethylcarbodiimide hydrochloride (614 mg, 1.5 equiv), 1-hydroxybenzotriazole (434 mg, 1.5 equiv.) and triethylamine (0.877 ml, 3 equiv.). The resulting suspension was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The crude material was partitioned between 10% sodium carbonate (75 ml) and methylene chloride (75 ml).

The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents are removed under reduced pressure. The crude material was purified by flash chromatography on silica gel (90: 9: 1 chloroform: methanol: ammonium hydroxide) to give the title compound.

(2-Naphthalen-2-yl-ethyl) amide 2- (S) - (2- (R) -amino-3-phenylpropionylamino) -5-nitrooguanidinopentanoic acid

To a solution of {1- (S) - [4-nitroguanidino-1- (2-naphthalen-2-yl-ethylcarbamoyl) butylcarbamoyl] -2- (R) -phenylethyl} carbamic acid tert-butyl ester (1.5 g, 2, 04 mmol) in methylene chloride (100 ml) add trifluoroacetic acid (50 ml). The resulting solution was stirred at room temperature for twenty-four hours, and the solvents were removed under reduced pressure. The crude material was purified by flash chromatography on silica gel (90: 9: 1 chloroform: methanol: ammonium hydroxide) to give the title compound.

5-nitroguanidino-2- (S) - [3-phenyl-2- (R) -propylamino) propionylamino] pentanoic acid (2-Naphthalen-2-yl-ethyl) amide

To a solution of (2-naphthalen-2-yl-ethyl) amide 2- (S) - (2- (R) -amino-3-phenylpropylamino) -5-nitroguanidinopentanoic acid (600 mg, 1.15 mmol) in tetrahydrofuran (50 ml ) 3-phenylpropionaldehyde (0.121 ml, 0.8 equiv.) and molecular sieves (4 angstroms, ground) are added. The resulting suspension was stirred at room temperature for twenty four hours and then adjusted to pH 5 with acetic acid. Sodium cyanoborohydride (1.38 ml, 1.2 eq., 1.0 M solution in tetrahydrofuran) was added to the solution at a rate of 0.2 ml / h using a syringe

pump. The resulting suspension was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The crude material is filtered and then purified by reverse phase HPLC to give the title compound.

5-nitroguanidino-2- (S) - [3-phenyl-2- (R) -propylamino) propionylamino] pentanoic acid (2-Naphthalen-2-yl-ethyl) amide

To a solution of (2-naphthalen-2-yl-ethyl) amide 5-nitroguanidino-2- (S) - [3-phenyl-2- (R) -propylamino) propionylamino] pentanoic acid (294 mg, 0.46 mmol) in 50 ml of methanol add acetic acid (5 ml) and 5% palladium on barium sulfate (294 mg). The resulting suspension was hydrogenated at atmospheric pressure for twenty-four hours, filtered through celite and the solvents were removed under reduced pressure. The crude material was purified by reverse phase HPLC to give the title compound.

Example 57

Synthesis of (2-naphthalen-1-yl-ethyl) amide 5-guanidino-2- (S) - [3-phenyl-2- (R) - (3-phenylpropylamino) propionylamino] pentanoic acid

2-Naphthalene-1-yl-ethyl ester of toluene-4-sulfonic acid

To a solution of 2-naphthalen-1-yl-ethanol (3.0 g, 17.4 mmol) in tetrahydrofuran (50 ml) was added p-toluenesulfonic anhydride (6.8 g, 1.2 equiv.) And triethylamine (7.1 ml) , 3

equiv.). The resulting solution was stirred at room temperature for one hour, and then the solvents were removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (20% ethyl acetate / hexanes) to give the title compound.

1- (2-Azidoethyl) naphthalene

To a solution of toluene-4-sulfonic acid 2-naphthalene-1-yl-ethyl ester (5.2 g, 15.9 mmol) in DMF (100 ml) was added sodium azide (1.3 g, 1.3 eq). The resulting solution was heated to 80 ° C for twenty four hours, then cooled to room temperature and the solvents were removed under reduced pressure. The residue was partitioned between ethyl acetate and water, the organic phase was dried over anhydrous magnesium sulfate, filtered and the solvents were removed under reduced pressure to obtain the title compound. The crude product is used without further purification.

2-Naphthalen-1-yl-ethylamine

To a solution of 1- (2-azidoethyl) naphthalene (3.0 g, 15.23 mmol) in tetrahydrofuran (10 ml) was added triphenylphosphine (6.0 g, 1.5 equiv.) And water (5 ml). The resulting solution was refluxed for three hours and then cooled to room temperature. The solvents were removed under reduced pressure, and the crude product was purified by flash chromatography on silica gel (90: 9: 1 chloroform: methanol: ammonium hydroxide) to obtain the title compound. Adding excess trifluoroacetic acid followed by evaporation gives the trifluoroacetic acid salt.

{1- (S) - [4-nitroguanidino-1- (2-naphthalen-1-yl-ethylcarbamoyl) butylcarbamoyl] -2- (R) -phenylethyl] carbamic acid tert-butyl ester

To a solution of 2- (S) - (2- (R) -tert-butoxycarbonylamino-3-phenylpropionylamino) -5-nitroguanidinopentanoic acid methyl ester (1.0 g, 2.1 mmol) and 2-naphthalene-1-yl-ethylamine ( 733 mg, 1.2 equiv.) In DMF (50 ml) add 1-hydroxybenzotriazole (434 mg, 1.5 equiv.), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (614 mg, 1 5 eq.) And triethylamine (0.877 ml, 3 eq.). The resulting suspension was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The residue was partitioned between methylene chloride and 10% sodium carbonate, the organic phase was dried over magnesium sulfate, filtered and the solvents were removed under reduced pressure to obtain a crude product. The product was purified by flash chromatography on silica gel (90: 9: 1 chloroform: methanol: ammonium hydroxide) to obtain the title compound.

(2-Naphthalen-1-yl-ethyl) amide 2- (S) - (2- (R) -amino-3-phenylpropionylamino) -5-nitroguanidinopentanoic acid

To a solution of tert-butyl ester of {1- (S) - [4-nitroguanidino-1- (2-naphthalen-1-yl-ethylcarbamoyl) butylcarbamoyl] -2- (R) -phenylethyl] carbamic acid (1.3 g, 1, 77 mmol) in methylene chloride (100 ml) add trifluoroacetic acid (50 ml). After stirring at room temperature for twenty-four hours, the solvents were removed under reduced pressure and the residue was partitioned between 10% sodium carbonate (100

ml) and ethyl acetate (100 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents are removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (90: 9: 1 chloroform: methanol: ammonium hydroxide) to obtain the title compound.

5-nitroguanidino-2- (S) - [3-phenyl-2- (R) - (3-phenylpropylamino) propionylamino] pentanoic acid (2-Naphthalen-1-yl-ethyl) amide

To a solution of (2-naphthalen-1-yl-ethyl) amide 2- (S) - (2- (R) -amino-3-phenylpropionylamino) -5-nitroguanidinopentanoic acid (690 mg, 1.33 mmol) in tetrahydrofuran (50 ml ) 3-phenylpropionaldehyde (0.14 ml, 0.3 equiv.) and molecular sieves (500 mg, 4 U powder) are added. The resulting suspension was stirred at room temperature for twenty-four hours, and then the pH was adjusted to 5 with acetic acid. Sodium cyanoborohydride (1.6 ml, 1.2 eq., 1.0 M solution in tetrahydrofuran) is then added slowly (0.2 ml / h) using a syringe pump. Twenty-four hours later, the solvents were removed under reduced pressure and the crude product was purified by reverse phase HPLC to give the title compound.

5-guanidino-2- (S) - [3-phenyl-2- (R) - (3-phenylpropylamino) propionylamino] pentanoic acid (2-Naphthalen-1-yl-ethyl) amide

To a solution of (2-naphthalen-1-yl-ethyl) amide 5-nitroguanidino-2- (S) - [3-phenyl-2- (R) - (3-phenylpropylamino) propionylamino] pentanoic acid (280 mg, 0.44 mol ) acetic acid (5 ml) and 5% palladium on barium sulfate (280 mg) are added to 50 ml of methanol. The resulting suspension was hydrogenated at atmospheric pressure for twenty-four hours, filtered through celite and

solvents are removed under reduced pressure. The crude material was purified by reverse phase HPLC to give the title compound.

Example 58

Synthesis of [2- (1H-indol-3-yl) ethyl] amide 5-guanidino-2- (S) - (2- (S) - {[3- (4-hydroxyphenyl) propionyl] methylamino} -3-phenylpropionylamino pentanoic acid

2- (S) - [2- (S) - (tert-butoxycarbonylmethylamino) -3-phenylpropionylamino] -5-nitroguanidinopentanoic acid methyl ester

To a solution of 2- (S) - (tert-butoxycarbonylmethylamino) -3-phenylpropionic acid (2.0 g, 7.17 mmol) and 2- (S) -amino-5-nitroguanidinopentanoic acid methyl ester (1.83 g, 1.1 eq.) Add 1-hydroxybenzotriazole (1.45 g, 1.5 eq.), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (2.05 g, 1.5 eq.) and triethylamine (3.0 ml, 3 equiv.). The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The residue was partitioned between 10% sodium carbonate (150 ml) and methylene chloride (150 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents are removed under reduced pressure. The crude substance is purified flash

silica gel chromatography (90: 9: 1 chloroform: methanol: ammonium hydroxide) to give the title compound.

5-Nitroguanidino-2- (S) - (2- (S) methylamino-3-phenylpropionylamino) pentanoic acid methyl ester

To a solution of 2- (S) - [2- (S) - (tert-butoxycarbonylmethylamino) -3-phenylpropionylamino] -5-nitroguanidinopentanoic acid methyl ester (3.3 g, 6.68 mmol) in methylene chloride (200 ml) was added trifluoroacetic acid (100 ml). The resulting solution was stirred at room temperature and then the solvents were removed under reduced pressure. The residue was partitioned between methylene chloride (150 ml) and 10% sodium carbonate (150 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents are removed under reduced pressure. The crude material was purified by flash chromatography on silica gel (90: 9: 1 chloroform: methanol: ammonium hydroxide) to give the title compound.

5-nitroguanidino-2- (S) - (2- (S) - {[3- (4-hydroxyphenyl) propionyl] methylamino} -3-phenylpropionylamino) pentanoic acid methyl ester

To a solution of 5-guanidino-2- (S) - (2- (S) -methylamino-3-phenylpropionylamino) pentanoic acid methyl ester (1.0 g, 2.54 mmol) and 3- (4-hydroxyphenyl) propanoic acid (506 mg, 1.2 eq.) Add 1-hydroxybenzotriazole (513 mg, 1.5 eq.), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (727 mg, 1.5 eq.) and triethylamine (1.0 ml, 3 equiv.). The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced temperature.

pressure. The residue was partitioned between 10% sodium carbonate (100 ml) and methylene chloride (100 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents are removed under reduced pressure. The crude material was purified by flash chromatography on silica gel (90: 9: 1 chloroform: methanol: ammonium hydroxide) to give the title compound.

5-Nitroguanidino-2- (S) - (2- (S) - {[3- (4-hydroxyphenyl) propionyl] methylamino} -3-phenylpropionylamino) pentanoic acid

To a solution of 5-nitroguanidino-2- (S) methyl ester - (2- (S) - {[3- (4-hydroxyphenyl) propionyl] methylamino} -3-phenylpropionylamino) pentanoic acid (534 mg, 0.98 mmol) in tetrahydrofuran (50 ml), lithium hydroxide monohydrate (49 mg, 1.1 eq.) and water (3 ml) are added. The resulting solution was stirred at room temperature for twenty-four hours and then acidified with trifluoroacetic acid (1 equiv.). The solvents were removed under reduced pressure and the crude material was partitioned between ethyl acetate (75 ml) and water (75 ml). The organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvents were removed under reduced pressure to obtain the title compound.

[2- (1H-Indol-3-yl) ethyl] amide 5-nitroguanidino-2- (S) - (2- (S) - {[3- (4-hydroxyphenyl) propionyl] methylamino} -3-phenylpropionylamino) pentanoic acid

To a solution of 5-nitroguanidino-2- (S) - (2- (S) - {[3- (4-hydroxyphenyl) propionyl] methylamino} -3-phenylpropionylamino) pentanoic acid (460 mg, 0.87 mmol) and

[2- (1H-indol-3-yl) ethyl] amine (168 mg, 1.2 eq.) Add 1-hydroxybenzotriazole (176 mg, 1.5 eq.), 1- [3- (dimethylamino) propyl hydrochloride ] -3-ethylcarbodiimide (250 mg, 1.5 equiv.) And triethylamine (0.36 ml, 3 equiv.). The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The residue was partitioned between ethyl acetate (75 ml) and water (75 ml), the organic phase was dried over anhydrous magnesium sulfate, filtered and the solvents were removed under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound.

[2- (1H-Indol-3-yl) ethyl] amide 5-guanidino-2- (S) - (2- (S) - {[3- (4-hydroxyphenyl) propionyl] methylamino} -3-phenylpropionylamino) pentanoic acid

To a solution of [2- (1H-indol-3-yl) ethyl] amide 5-nitroguanidino-2- (S) - (2- (S) - {[3- (4-hydroxyphenyl) propionyl] methylamino} -3- phenylpropionylamino) pentanoic acid (250 mg, 0.37 mol) in 50 ml of methanol add acetic acid (5 ml) and 5% palladium on barium sulfate (250 mg). The resulting suspension was hydrogenated at atmospheric pressure for twenty-four hours, filtered through celite and the solvents were removed under reduced pressure. The crude material was purified by reverse phase HPLC to give the title compound.

Example 59

Synthesis of 5-guanidino-2- (S) - [3-phenyl-2- (R) - (3-phenylpropylamino) propionylamino] pentanoic acid benzylamide

[1- (S) - (1-benzylcarbamoyl-4-nitroguanidinobutylcarbamoyl) -2- (R) -phenylethyl] carbamic acid tert-butyl ester

To a solution of 2- (S) - (2- (R) -tert-butoxycarbonylamino-3-phenylpropionylamino) -5-nitroguanidinopentanoic acid (500 mg, 1.29 mmol), benzylamine (0.155 ml, 1.1 eq.) In DMF (50 ml) add 1-hydroxybenzotriazole (261 mg, 1.5 eq.), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (371 mg, 1.5 eq.) And triethylamine (0, 53 ml, 3 equiv.). The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The crude material was purified by flash chromatography on silica gel (90: 9: 1 chloroform: methanol: ammonium hydroxide) to give 526 mg of the title compound.

2- (S) - (2- (R) -amino-3-phenylpropionylamino) -5-nitroguanidinopentanoic acid benzylamide

To a solution of [1- (S) - (1-benzylcarbamoyl-4-nitroguanidinobutylcarbamoyl) -2- (R) phenylethyl] carbamic acid tert-butyl ester (512 mg, 1.12 mmol) in methylene chloride (50 ml) was added trifluoroacetic acid (25 ml). The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The crude product was purified by reverse phase HPLC to afford the title

connection header.

5-nitroguanidino-2- (S) - [3-phenyl-2- (R) - (3-phenylpropylamino) propionylamino] pentanoic acid benzylamide

To a suspension of 2- (S) - (2- (R) -amino-3-phenylpropionylamino) -5-nitroguanidinopentanoic acid benzylamide (370 mg, 0.65 mmol), 3-phenylpropionaldehyde (0.077 ml, 0.9 equiv.) and molecular sieves (370 mg, 4 E powdered) add triethylamine (0.177 ml, 2 equiv.). The resulting suspension was stirred at room temperature for twenty-four hours, and then the pH was adjusted to 5 with acetic acid. Sodium cyanoborohydride (0.70 ml, 1.0 M solution in tetrahydrofuran, 1 eq.) Is then added slowly (0.2 ml / h) using a syringe pump. After twenty-four hours, the suspension was filtered through celite and the solvents were removed under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound.

5-guanidino-2- (S) - [3-phenyl-2- (R) - (3-phenylpropylamino) propionylamino] pentanoic acid benzylamide

To a solution of 5-nitroguanidino-2- (S) - [3-phenyl-2- (R) - (3-phenylpropylamino) propionylamino] pentanoic acid benzylamide (80 mg, 0.14 mmol) in methanol (50 ml) was added acetic acid (5 ml) and 5% palladium on barium sulfate (80 mg). The resulting suspension was hydrogenated at atmospheric pressure for twenty-four hours, filtered through celite and the solvents were removed under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound.

Example 60

Synthesis of [1-carbamoyl-2- (1H-indol-3-yl) ethyl] amide 2- (S) - {2- (R) - [2- (S) -acetylamino-3- (4-hydroxyphenyl) propionylamino ] -3-phenylpropionylamino} -5-nitroguanidinopentanoic acid

(1- (S) - {1- [1-carbamoyl-2- (1H-indol-3-yl) ethylcarbamoyl] -4-nitroguanidinobutylcarbamoyl} -2- (R) -phenylethyl) carbamic acid tert-butyl ester

To a solution of 2- (S) - (2- (R) -tert-butoxycarbonylamino-3-phenylpropionylamino) -5-nitroguanidinopentanoic acid (800 mg, 1.7 mmol) and 2- (S) -amino-3- (1Н -indol-3-yl) propionamide (500 mg, 1.2 eq.) in DMF (50 ml) add 1-hydroxybenzotriazole (350 mg, 1.5 eq.), 1- [3- (dimethylamino) propyl hydrochloride] -3-ethylcarbodiimide (491 mg, 1.5 equiv.) And triethylamine (1.17 ml, 5 equiv.). The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The residue was partitioned between ethyl acetate (75 ml) and 10% sodium carbonate (75 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents are removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (90: 9: 1 chloroform: methanol: ammonium hydroxide) to obtain the title compound.

[1-Carbamoyl-2- (1H-indol-3-yl) ethyl] amide 2- (S) - (2- (R) -amino

3-phenylpropionylamino) -5-nitroguaidinopentanoic acid

To a solution of (1- (S) - {1- [1-carbamoyl-2- (1H-indol-3-yl) ethylcarbamoyl] -4-nitroguanidinobutylcarbamoyl} -2- (R) -phenylethyl) carbamic acid tert-butyl ester (1.16 g, 1.78 mmol) in methylene chloride (100 ml) add trifluoroacetic acid (50 ml). The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The crude material was purified by reverse phase HPLC to give the title compound.

[1-Carbamoyl-2- (1H-indol-3-yl) ethyl] amide 2- (S) - {2- (R) - [2- (S) -acetylamino-3- (4-hydroxyphenyl) propionylamino] -3-phenylpropionylamino} -5-nitroguanidinopentanoic acid

To a solution of [1-carbamoyl-2- (1H-indol-3-yl) ethyl] amide 2- (S) - (2- (R) -amino-3-phenylpropionylamino) -5-nitroguanidinopentanoic acid (250 mg, 0.378 mmol) and 2- (S) -acetylamino-3- (4-hydroxyphenyl) propionic acid (100 mg, 1.2 eq.) in DMF (50 ml) add 1-hydroxybenzotriazole (76 mg, 1.5 eq.) , 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (107 mg, 1.5 equiv.) and triethylamine (0.20 ml, 4 equiv.). The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The crude material was purified by reverse phase HPLC to give the title compound.

[1-Carbamoyl-2- (1H-indol-3-yl) ethyl] amide 2- (S) - {2- (R) - [2- (S) -acetylamino-3- (4-hydroxyphenyl) propionylamino] -3-phenylpropionylamino} -5-nitroguanidinopentanoic acid

To a solution of [1-carbamoyl-2- (1H-indol-3-yl) ethyl] amide 2- (S) -

{2- (R) - [2- (S) -acetylamino-3- (4-hydroxyphenyl) propionylamino] -3-phenylpropionylamino} -5-nitroguanidinopentanoic acid (100 mg, 0.13 mmol) in methanol (50 ml) add acetic acid (5 ml) and 5% palladium on barium sulfate (70 mg). The resulting suspension was hydrogenated at atmospheric pressure for twenty-four hours, filtered through celite and the solvents were removed under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound.

Example 61

Synthesis of [2- (S) - (1H-indol-3-yl) -1-methylcarbamoylethyl] amide 2- (2- (R) -amino-3-phenylpropionylamino) -5- (1-trityl-1H-imidazole- 4-yl) pentanoic acid

2-amino-5- (3H-imidazol-4-yl) pentanoic acid methyl ester

Anhydrous hydrogen chloride was added to a suspension of 2-tert-butoxycarbonylamino-5- (3H-imidazol-4-yl) pentanoic acid (2.0 g, 11.8 mmol) in methanol (60 ml) until the solution was saturated. The solution was then refluxed for twenty-four hours and then cooled to room temperature. Solvents were removed under reduced pressure to give the title compound.

2- (S) - (2- (R) -tert-butoxycarbonylamino-3- methyl ester

phenylpropionylamino) -5- (3H-imidazol-4-yl) pentanoic acid

To a solution of 2- (R) -2-tert-butoxycarbonylamino-3-phenylpropionic acid (500 mg, 1.88 mmol) and 2-amino-5- (3H-imidazol-4-yl) pentanoic acid methyl ester (500 mg 1.1 equiv.) Add hydroxybenzotriazole (381 mg, 1.5 equiv.), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (540 mg, 1.5 equiv.) And triethylamine (1, 28 ml, 5 equiv.). The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The residue was partitioned between ethyl acetate (75 ml) and 10% sodium carbonate (75 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents are removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (90: 9: 1 chloroform: methanol: ammonium hydroxide) to obtain the title compound.

2- (S) - (2- (R) -tert-butoxycarbonylamino-3-phenylpropionylamino) -5- (1-trityl-1H-imidazol-4-yl) pentanoic acid methyl ester

To a solution of 2- (S) - (2- (R) -tert-butoxycarbonylamino-3-phenylpropionylamino) -5- (3H-imidazol-4-yl) pentanoic acid methyl ester (500 mg, 0.72 mmol) in tetrahydrofuran (50 ml) add triphenylmethyl chloride (220 mg, 1.1 eq.) And triethylamine (0.2 ml, 2 eq.). The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (5% methanol / chloroform) to give the title compound.

2- (S) -2- (R) -tert-Butoxycarbonylamino-3-phenylpropionylamino) -5- (1-trityl-1H-imidazol-4-yl) pentanoic acid

To a solution of 2- (S) - (2- (R) -tert-butoxycarbonylamino-3-phenylpropionylamino) -5- (1-trityl-1H-imidazol-4-yl) pentanoic acid methyl ester (300 mg, 0.45 mmol) in tetrahydrofuran (30 ml), lithium hydroxide monohydrate (32 mg, 1.2 equiv.) and water (3 ml) were added, the resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The crude material is used directly in the next step.

tert-Butyl ether {1- (R) - [1- (2- (S) - (1H-indol-3-yl) -1-methylcarbamoylethylcarbamoyl] -4- (1-trityl-1H-imidazol-4-yl ) butylcarbamoyl] -2-phenylethyl} carbamic acid

To a solution of 2- (S) - (2- (R) -tert-butoxycarbonylamino-3-phenylpropionylamino) -5- (1-trityl-1H-imidazol-4-yl) pentanoic acid (293 mg, 0.45 mmol) and 2- (S) -amino-3- (1H-indol-3-yl) propionamide (117 mg, 1.3 eq.) add PyBOP (301 mg, 1.3 eq.) and triethylamine (0.18 ml , 3 equiv.). The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The residue was partitioned between ethyl acetate (75 ml) and 19% sodium carbonate (75 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents are removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (5% methanol / chloroform) to give the title compound.

[2- (S) - (1H-Indol-3-yl) -1-methylcarbamoylethyl] amide 2- (2- (R) amino-3-phenylpropionylamino) -5- (1-trityl-1H-imidazole-4 -yl) pentanoic acid

To a solution of tert-butyl ether {1- (R) - [1- [2- (S) - (1H-indol-3-yl) -1-methylcarbamoylethylcarbamoyl] -4- (1-trityl-1H-imidazole-4 -yl) butylcarbamoyl] -2-phenylethyl} carbamic acid (468 mg, 0.55 mmol) in methylene chloride (32 ml), trifluoroacetic acid (16 ml) was added. Then, triethylsilane is added dropwise until the bright yellow color disappears. The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The crude material was purified by reverse phase HPLC to give the title compound.

Example 62

Synthesis of 2- (R) - [2- (S) - (2-benzyl-6-phenylhexanoylamino) -5-guanidinopentanoylamino] -3-naphthalene-2-yl-propionic acid methyl ester

6-phenylhexanoic acid methyl ester

A solution of 6-phenylhexanoic acid (1.9 g, 9.89 mmol) in methanol (50 ml) was saturated with anhydrous hydrogen chloride and then refluxed for twenty-four hours. After cooling to room temperature, the solvents were removed under reduced pressure and the residue was partitioned between

chloroform and 10% sodium carbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure to obtain the title compound.

2-benzyl-6-phenylhexanoic acid methyl ester

To a cooled (-78 ° C) solution of 6-phenylhexanoic acid methyl ester (2.8 g, 13.5 mmol) in anhydrous tetrahydrofuran (50 ml), a 2.0 M solution of lithium diisopropylamide in hexane / tetrahydrofuran mixture (7.5 ml, 1.1 equiv.). The resulting solution was stirred at –78 ° C for fifty minutes and then benzyl bromide (1.92 ml, 1.2 eq.) Was slowly added. The resulting solution was warmed to room temperature overnight and then the solvents were removed under reduced pressure. Then, the residue was partitioned between ethyl acetate and water. The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents are removed under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound.

2-benzyl-6-phenylhexanoic acid

To a solution of 2-benzyl-6-phenylhexanoic acid methyl ester (2.17 g, 7.33 mmol) in tetrahydrofuran (100 ml) was added lithium hydroxide monohydrate (880 mg, 2 equiv.) And water (15 ml). The resulting solution was refluxed for forty-eight hours and then cooled to room temperature. The solvents were removed under reduced pressure and the residue was partitioned between ethyl acetate and 1M citric acid. The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents are removed under reduced pressure.

The crude product was purified by reverse phase HPLC to give the title compound.

2- (S) - (2-benzyl-6-phenylhexanoylamino) -5-nitroguanidino-pentanoic acid methyl ester

To a solution of 2-benzyl-6-phenylhexanoic acid methyl ester (513 mg, 1.82 mmol) and 2- (S) -amino-5-nitroguanidinopentanoic acid methyl ester (480 mg, 1.1 eq.) In DMF (50 ml) add 1-hydroxybenzotriazole (319 mg, 1.5 equiv.), hydrochloride of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (451 mg, 1.3 equiv.) and triethylamine (0.74 ml, 3 equiv.). The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The crude material was purified by reverse phase HPLC to give the title compound.

2- (S) - (2-Benzyl-6-phenylhexanoylamino) -5-nitrguanidinopentanoic acid

To a solution of 2- (S) - (2-benzyl-6-phenylhexanoylamino) -5-nitroguanidino-pentanoic acid methyl ester (700 mg, 1.5 mmol) in tetrahydrofuran (40 ml), lithium hydroxide monohydrate (180 mg, 2 eq. ) and water (3 ml). The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound.

2-amino-3-naphthalen-2-yl-propionic acid methyl ester

Anhydrous chloride is added to a suspension of 2-amino-3-naphthalen-2-yl-propionic acid (300 mg, 1.39 mmol) in methanol (40 ml)

hydrogen to saturate the solution. The resulting solution was refluxed for two hours and then cooled to room temperature and the solvents were removed under reduced pressure to obtain the title compound.

2- (R) - [2- (S) - (2-benzyl-6-phenylhexanoylamino) -5-nitroguanidinopentanoylamino] -3-naphthalen-2-yl-propionic acid methyl ester

To a solution of 2- (S) - (2-benzyl-6-phenylhexanoylamino) -5-nitroguanidinopentanoic acid (100 mg, 0.22 mmol) and 2-amino-3-naphthalen-2-ylpropionic acid methyl ester (65 mg, 1.1 equiv.) In DMF (30 ml) add 1-hydroxybenzotriazole (44 mg, 1 equiv.), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (63 mg, 1.5 equiv.) and triethylamine (0.09 ml, 3 equiv.). The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The crude material was purified by reverse phase HPLC to give the title compound.

2- (R) - [2- (S) - (2-benzyl-6-phenylhexanoylamino) -5-guanidinopentanoylamino] -3-naphthalen-2-yl-propionic acid methyl ester

To a solution of 2- (R) - [2- (S) - (2-benzyl-6-phenylhexanoylamino) -5-nitroguanidinopentanoylamino] -3-naphthalen-2-yl-propionic acid methyl ester (80 mg, 0.11 mmol) in methanol (30 ml) was added acetic acid (3 ml) and 5% palladium on barium sulfate (75 mg). The resulting suspension was hydrogenated at atmospheric pressure for twenty-four hours, filtered through celite and the solvents were removed under reduced pressure. Crude

the product was purified by reverse phase HPLC to give the title compound as a mixture of four diastereomers.

Example 63

Synthesis of [1- (S) -methylcarbamoyl-2-naphthalen-2-yl-ethyl] amide 5- (1H-imidazol-4-yl) -2- [3-phenyl-2- (R) - (3-phenylpropionylamino) propionylamino pentanoic acid

3-Phenyl-2- (R) - (3-phenylpropionylamino) propionic acid methyl ester

To a solution of 3-phenylpropionic acid (1.0 g, 6.66 mmol) and 2- (R) -amino-3-phenylpropionic acid methyl ester (1.19 g, 1 equiv.) In DMF (60 ml) was added 1 -hydroxybenzotriazole (1.35 g, 1.5 eq.), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1.90 g, 1.5 eq.) and triethylamine (2.7 ml, 3 equiv.). The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The residue was partitioned between water and ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the solvents were removed under reduced pressure to obtain the title compound.

3-Phenyl-2- (R) - (3-phenylpropionylamino) propionic acid

To a solution of 3-phenyl-2- (R) - (3-phenylpropionylamino) propionic acid methyl ester (1.5 g, 4.82 mmol) in tetrahydrofuran (70 ml) is added lithium hydroxide monohydrate

(434 mg, 1.5 equiv.) And water (5 ml). The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The crude material was purified by reverse phase HPLC to give the title compound.

5- (3H-Imidazol-4-yl) -2- [3-phenyl-2- (R) - (3-phenylpropionylamino) propionylamino] pentanoic acid methyl ester

To a solution of 3-phenyl-2- (R) - (3-phenylpropionylamino) propionic acid (376 mg, 1.26 mmol) and 2-amino-5- (3H-imidazol-4-yl) pentanoic acid methyl ester (355 mg, 1.1 equiv.) in DMF (50 ml) add 1-hydroxybenzotriazole (256 mg, 1.5 equiv.), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (362 mg, 1, 5 equiv.) And triethylamine (0.863 ml, 5 equiv.). The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound.

2- [3-Phenyl-2- (R) - (3-phenylpropionylamino) propionylamino] -5- (1-trityl-1H-imidazol-4-yl) pentanoic acid methyl ester

To a solution of 5- (3H-imidazol-4-yl) -2- [3-phenyl-2- (R) - (3-phenylpropionylamino) propionylamino] pentanoic acid methyl ester (473 mg, 1.02 mmol) in tetrahydrofuran ( 50 ml) triphenylmethyl chloride (341 mg, 1.2 eq.) And triethylamine (0.42 ml, 3 eq.) Are added. The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. Crude

the product was purified by flash chromatography on silica gel (5% methanol / chloroform) to obtain the title compound.

2- [3-Phenyl-2- (R) - (3-phenylpropionylamino) propionylamino] -5- (1-trityl-1H-imidazol-4-yl) pentanoic acid

To a solution of 2- [3-phenyl-2- (R) - (3-phenylpropionylamino) propionylamino] -5- (1-trityl-1H-imidazol-4-yl) -pentanoic acid methyl ester (380 mg, 0.54 mmol ) in tetrahydrofuran (80 ml), lithium hydroxide monohydrate (48 mg, 1.5 equiv.) and water (10 ml) are added. The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The crude material is used directly in the next step.

(1- (S) -methylcarbamoyl-2-naphthalen-2-yl-ethyl) carbamic acid tert-butyl ester

To a solution of 2- (S) -tert-butoxycarbonylamino-3-naphthalene-2-yl-propionic acid (1.5 g, 4.76 mmol) in DMF (50 ml), methylamine (3.0 ml of a 2.0 M solution in tetrahydrofuran was added ), PyBOP (3.7 g, 1.5 equiv.) And triethylamine (1.95 ml, 3 equiv.). The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The residue was partitioned between ethyl acetate and 10% sodium carbonate, the organic phase was dried over anhydrous magnesium sulfate, filtered and the solvents were removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (5% methanol / chloroform) to give the title compound.

2- (S) -Amino-N-methyl-3-naphthalen-2-ylpropionamide

To a solution of (1- (S) -methylcarbamoyl-2-naphthalen-2-yl-ethyl) carbamic acid tert-butyl ester (1.3 g, 3.96 mmol) in methylene chloride (100 ml) was added trifluoroacetic acid (50 ml). The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The crude material was purified by reverse phase HPLC to give the title compound.

(1- (S) -Metylcarbamoyl-2-naphthalen-2-yl-ethyl] amide 2- (S) - [3-phenyl-2- (R) - (3-phenylpropionylamino) propionylamino] -5- (1-trityl- 1H-imidazol-4-yl) pentanoic acid

To a solution of 2- [3-phenyl-2- (R) - (3-phenylpropionylamino) propionylamino] -5- (1-trityl-1H-imidazol-4-yl) pentanoic acid (383 mg, 0.53 mmol) in DMF (50 ml) was added 2- (S) -amino-N-methyl-3-naphthalen-2-ylpropionamide (147 mg, 0.8 equiv.), PyBOP (420 mg, 1.5 equiv.) And triethylamine ( 0.220 ml, 3 equiv.). The resulting solution was stirred at room temperature for forty-eight hours, and then the solvents were removed under reduced pressure. The residue was partitioned between ethyl acetate and 10% sodium carbonate, the organic phase was dried over anhydrous magnesium sulfate, filtered and the solvents were removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (5% methanol / chloroform) to give the title compound.

(1- (S) -Metylcarbamoyl-2-naphthalen-2-yl-ethyl] amide 5- (1H-imidazol-4-yl) -2- [3-phenyl-2- (R) - (3-phenylpropionylamino) propionylamino] pentanoic acid

To a solution of trifluoroacetic acid (20 ml) in methylene chloride (40 ml) was added (1-methylcarbamoyl-2-naphthalen-2-yl-ethyl] amide 2- (S) - [3-phenyl-2- (R) - (3-phenylpropionylamino ) propionylamino] -5- (1-trityl-1H-imidazol-4-yl) pentanoic acid (441 mg, 0.489 mmol). Then, triethylsilane was added dropwise until the bright yellow color disappeared. The resulting solution was stirred at room temperature for twenty four hours and then the solvents were removed under reduced pressure The crude product was purified by flash chromatography on silica gel (90: 9: 1 chloroform: methanol: hydr. ammonium oxide) to afford the title compound as a mixture of diastereomers The diastereomers were separated by reverse phase HPLC to give a diastereomer eluting earlier and a diastereomer eluting later.

Example 64

Synthesis of (1- (S) -methylcarbamoyl-2-naphthalen-2-yl-ethyl] amide 2- (S) - {2- (R) - [2- (S) -acetylamino-3- (4-hydroxyphenyl) propionylamino] -3-phenylpropionylamino} -5-guanidinopentanoic acid

{1- (R) - [4-nitroguanidino-1- (S) - (1- (S) -methylcarbamoyl-2-naphthalen-2-yl-ethylcarbamoyl) butylcarbamoyl] -2-phenylethyl} carbamic acid tert-butyl ester

To a solution of 2- (S) - (2- (R) -tert-butoxycarbonylamino-3-phenylpropionylamino) -5-nitroguanidinopentanoic acid (500 mg, 1.07 mmol) and 2- (S) -amino-N-methyl- 3-naphthalene-2-ylpropionamide

(440 mg, 1.2 equiv.) PyBOP (836 mg, 1.5 equiv.) And triethylamine (0.58 ml, 4 equiv.) Are added. The resulting solution was stirred at room temperature overnight, and then the solvents were removed under reduced pressure. The residue was partitioned between ethyl acetate and 10% sodium carbonate, dried over anhydrous magnesium sulfate, filtered and the solvents removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (90: 9: 1 chloroform: methanol: ammonium hydroxide) to obtain the title compound.

(1- (S) -Metylcarbamoyl-2-naphthalen-2-yl-ethyl] amide 2- (S) - (2- (R) -amino-3-phenylpropionylamino) -5-nitroguanidinopentanoic acid

To a solution of {1- (R) - [4-nitroguanidino-1- (S) - (1- (S) -methylcarbamoyl-2-naphthalen-2-yl-ethylcarbamoyl) butylcarbamoyl] -2-phenylethyl} carbamic acid solution (500 mg, 0.74 mmol) in methylene chloride (60 ml) trifluoroacetic acid (30 ml) was added. The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound.

(1- (S) -Metylcarbamoyl-2-naphthalen-2-yl-ethyl] amide 2- (S) - {2- (R) - [2- (S) -acetylamino-3- (4-hydroxyphenyl) propionylamino-3 -phenylpropionylamino} -5-nitroguanidinopentanoic acid

To a solution of (1- (S) -methylcarbamoyl-2-naphthalen-2-yl-ethyl] amide 2- (S) - (2- (R) -amino-3-phenylpropionylamino) -5-nitroguanidinopentanoic acid (400 mg, 0, 58 mmol) in DMF (60

ml) add 2- (S) -acetylamino-3- (4-hydroxyphenyl) propionic acid (155 mg, 1.2 equiv.), PyBOP (410 mg, 1.2 equiv.) and triethylamine (0.32 ml, 4 equiv.). The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The residue was partitioned between ethyl acetate and 10% sodium carbonate, the organic phase was dried over anhydrous magnesium sulfate, filtered and the solvents were removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (90: 9: 1 chloroform: methanol: ammonium hydroxide) to obtain the title compound.

(1- (S) -Metylcarbamoyl-2-naphthalen-2-yl-ethyl] amide 2- (S) - {2- (R) - [2- (S) -acetylamino-3- (4-hydroxyphenyl) propionylamino] - 3-phenylpropionylamino} -5-guanidinopentanoic acid

To a solution of (1- (S) -methylcarbamoyl-2-naphthalen-2-yl-ethyl] amide 2- (S) - {2- (R) - [2- (S) -acetylamino-3- (4-hydroxyphenyl) propionylamino ] -3-phenylpropionylamino} -5-nitroguanidinopentanoic acid (330 mg, 0.42 mmol) in methanol (50 ml) was added acetic acid (5 ml) and 5% palladium on barium sulfate (325 mg). The resulting suspension was hydrogenated at atmospheric pressure for twenty-four hours and then filtered through celite, the solvents were removed under reduced pressure, and the crude product was purified by reverse phase HPLC to give the title compound.

Example 65

Synthesis of (1- (S) -methylcarbamoyl-2-naphthalen-2-yl-ethyl] amide 5-guanidino-2- (S) - {2- (R) - [3- (4-hydroxyphenyl) propionylamino] -3-

phenylpropionylamino} pentanoic acid

To a solution of (1- (S) -methylcarbamoyl-2-naphthalen-2-yl-ethyl] amide 2- (S) - (2- (R) -amino-3-phenylpropionylamino) -5-nitroguanidinopentanoic acid (268 mg, 3, 88 mmol) and 3- (4-hydroxyphenyl) propionic acid (77 mg, 1.2 eq.) Add 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (111 mg, 1.5 eq.), 1-hydroxybenzotriazole (78 mg, 1.5 equiv.) And triethylamine (0.21 ml, 4 equiv.). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents were removed under reduced pressure. The crude material was purified by HPLC with reverse phase, semi Separated the title compound.

(1- (S) -Metylcarbamoyl-2-naphthalen-2-yl-ethyl] amide 5-guanidino-2- (S) - {2- (R) - [3- (4-hydroxyphenyl) propionylamino] -3-phenylpropionylamino} pentanoic acid

To a suspension of (1- (S) -methylcarbamoyl-2-naphthalen-2-yl-ethyl) amide 5-nitroguanidino-2- (S) - {2- (R) - [3- (4-hydroxyphenyl) propionylamino] -3- phenylpropionylamino} pentanoic acid (141 mg, 0.19 mmol) and 5% palladium on barium sulfate (100 mg) in methanol (45 ml) add acetic acid (5 ml). The resulting suspension was hydrogenated at atmospheric pressure for twenty-four hours, filtered through celite and

solvents are removed under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound.

Example 66

Synthesis of (1- (S) -methylcarbamoyl-2-naphthalen-2-yl-ethyl] amide 5-guanidino-2- (S) - [3-phenyl-2- (R) - (2-phenylethanesulfonylamino) propionylamino] pentanoic acid

2-Phenylethanesulfonyl chloride

Acetic acid (20 ml) was added to a two-phase solution of 2-phenylethanethiol (10.0 g, 72.5 mmol) in 100 ml of a mixture of water and ice. Then the solution is saturated with gaseous chlorine for five minutes. The aqueous solution was then extracted with ethyl ether, dried over anhydrous magnesium sulfate, filtered and the solvents were removed under reduced pressure to obtain the title compound.

3-Phenyl-2- (R) - (2-phenylethanesulfonylamino) propionic acid methyl ester

To a solution of 2-amino-3-phenylpropionic acid methyl ester (700 mg, 3.9 mmol) in tetrahydrofuran (30 ml) was added dropwise 2-phenylethanesulfonyl chloride (1.2 g, 5.88 mmol). Triethylamine (1.55 ml, 3 equiv.) Was added to the solution. Received

the solution was stirred at room temperature for twenty four hours and then the solvents were removed under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound.

3-Phenyl-2- (R) - (2-phenylethanesulfonylamino) propionic acid

To a solution of 3-phenyl-2- (R) - (2-phenylethanesulfonylamino) propionic acid methyl ester (890 mg, 2.56 mmol) in tetrahydrofuran (50 ml) is added lithium hydroxide monohydrate (260 mg, 1.5 equiv.) and water (5 ml). The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound.

[4-Nitroguanidino-1- (R) - (1- (S) -methylcarbamoyl-2-naphthalen-2-yl-ethylcarbamoyl) butyl] carbamic acid tert-butyl ester

To a solution of 2-amino-N-methyl-3-naphthalen-2-ylpropionamide (1.0 g, 2.92 mmol) and 2- (R) -tert-butoxycarbonylamino-5-nitroguanidinopentanoic acid (1.12 g, 1 , 2 eq.) Add 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (837 mg, 1.5 eq.), 1-hydroxybenzotriazole (592 mg, 1.5 eq.) And triethylamine (1, 2 ml, 3 equiv.). The resulting suspension was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The residue was partitioned between ethyl acetate and 10% sodium carbonate, the organic phase was dried over anhydrous magnesium sulfate,

filtered and the solvents removed under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound.

(1- (S) -methylcarbamoyl-2-naphthalen-2-yl-ethyl) amide of 2- (R) -amino-5-guanidinopentanoic acid

To a solution of [4-nitroguanidino-1- (R) - (1- (S) -methylcarbamoyl-2-naphthalen-2-yl-ethylcarbamoyl) butyl] carbamic acid tert-butyl ester (800 mg, 1.52 mmol) in methylene chloride ( 40 ml) trifluoroacetic acid (20 ml) is added. The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound as a trifluoroacetic acid salt.

(1- (S) -Metylcarbamoyl-2-naphthalen-2-yl-ethyl) amide 5-nitroguanidino-2- (S) - [3-phenyl-2- (R) - (2-phenylethanesulfonylamino) propionylamino] pentanoic acid

To a solution of 3-phenyl-2- (R) - (2-phenylethanesulfonylamino) propionic acid (150 mg, 0.45 mmol) and (1- (S) -methylcarbamoyl-2-naphthalen-2-yl-ethyl) amide 2- ( R) -amino-5-guanidinopentanoic acid (270 mg, 1.1 eq.) Add 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (130 mg, 1.5 eq.), 1-hydroxybenzotriazole ( 91 mg, 1.5 equiv.) And triethylamine (0.25 ml, 4 equiv.). The resulting solution was stirred at room temperature for twenty-four hours, and then the solvents were removed under reduced pressure. The crude product was purified by reverse phase HPLC to afford the title

connection header.

(1- (S) -Metylcarbamoyl-2-naphthalen-2-yl-ethyl) amide 5-guanidino-2- (S) - [3-phenyl-2- (R) - (2-phenylethanesulfonylamino) propionylamino] pentanoic acid

To a solution of (1- (S) -methylcarbamoyl-2-naphthalen-2-yl-ethyl) amide 5-nitroguanidino-2- (S) - [3-phenyl-2- (R) - (2-phenylethanesulfonylamino) propionylamino] pentanoic acid (230 mg, 0.31 mmol) in methanol (45 ml) add acetic acid (5 ml) and 5% palladium on barium sulfate (200 mg). The resulting suspension was hydrogenated at atmospheric pressure for twenty-four hours and then filtered through celite. The solvents were removed under reduced pressure and the crude product was purified by reverse phase HPLC to give the title compound as a trifluoroacetic acid salt.

Example 67

Synthesis of Ac- (Carb-Ff) -RW-NH ₂ (11)

The specified connection receive in accordance with the presented schemes IA and B:

[1- (4-Chlorobenzyl) -3- (2,2-dimethyl-4,6-dioxo [1,3] dioxan-5-yl) -3-oxopropyl] carbamic acid tert-butyl ester (1)

To a thoroughly mixed mixture of Boc- (S) -3-amino-4- (4-chlorophenyl) butyric acid (5.0 g, 16 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (2.54 g, 17.6 mmol) and DMAP (24 mmol) in DCM (160 ml) at 0 ° C., EDCI (24 mmol) was added in one portion. The resulting mixture was stirred at 0 ° C for 1 h, then at room temperature for 18 h. DCM (100 ml) was added and the mixture was washed with water (2 × 50 ml), 5% aqueous potassium hydrogen sulfate (3 × 50 ml), 5% aqueous sodium bicarbonate (1 × 50 ml) and brine (1 × 50 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain 1.

[1- (4-Chlorobenzyl) -3- (2,2-dimethyl-4,6-dioxo [1,3] dioxan-5-yl) propyl] carbamic acid tert-butyl ester (2)

Sodium borohydride (63.8 mmol, 4.0 equiv.) Is added portionwise over 1 hour to a thoroughly mixed solution of 1 (15.96 mmol) in a mixture of DCM (180 ml) and acetic acid (10 ml, 175 mmol, 11 , 0 equiv.) At 0 ° C. The reaction mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 64 hours. The reaction mixture was diluted with DCM (150 ml) and washed with water (1 × 50 ml) and saturated salt solution (2 × 50 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator, obtaining 2.

6- (4-Chlorobenzyl) piperidin-2-one (3a) and 2- (4-chlorobenzyl) -6-oxopiperidin-1-carboxylic acid tert-butyl ester (3b)

Stirred mixture of 2 (15.32 mmol) and xylene (140 ml)

refluxed for 6 hours. The solvent was removed by evaporation at 37 ° C in vacuo to give crude 3a. This material was mixed with di-tert-butyl dicarbonate (5.0 equiv.) And DMAP (0.3 equiv.) In DCM (100 ml) and the mixture was stirred at room temperature for 40 hours. The solvent was removed on a rotary evaporator and the residue was purified. flash chromatography on silica gel using a mixture of EtOAc-hexane (1:19, 500 ml and 1: 9, 1300 ml) as eluent, obtaining 3b.

3-Benzyl-6- (4-chlorobenzyl) -2-oxopiperidin-1-carboxylic acid tert-butyl ester (4)

Bis (trimethylsilyl) sodium amide (5.16 ml of a 1.0M solution in THF, 1.0 equiv.) Was added dropwise to a thoroughly mixed solution of 3b (1.67 g, 5.16 mmol) in a mixture of THF-DME (1 : 1, 100 ml) at –78 ° С in argon atmosphere and the resulting mixture was stirred for 0.5 h at –78 ° С. To a stirred cooled mixture was added a solution of benzyl bromide (0.882 g, 5.16 mmol, 1.0 eq. .) in THF (5 ml) and stirring is continued at –78 ° C under argon for 2 hours. The reaction mixture is quenched with a saturated aqueous solution of ammonium chloride (20 ml) and stirring is continued for 10 minutes. The mixture was then partitioned between DCM (80 ml) and water (40 ml) and the aqueous phase was extracted with DCM (2 × 40 ml). The combined organic phase was washed with water (1 × 40 ml), dried over anhydrous magnesium sulfate and concentrated to give crude compound 4, which was purified by flash chromatography on a silica gel column using EtOAc-hexane (1:39, 1000 ml and 1: 19, 1300 ml) as eluent, obtaining 4 (single

diastereomer).

2- (R) -Benzyl-5- (R) -tert-butoxycarbonylamino-6- (4-chlorophenyl) hexanoic acid (’Boc- (carba-4-Cl-Ff) -OH’, 5)

To a thoroughly mixed solution of 4 (1.152 g, 2.783 mmol) in a THF-water mixture (4: 1), lithium hydroxide monohydrate (0.467 g, 11.132 mmol, 4 equiv.) Is added in one portion and 35% hydrogen peroxide is added dropwise (1, 95 ml, 8.0 equiv.). The resulting mixture was stirred at 0 ° C for 1 h, and then at room temperature for 16 h. The reaction mixture was acidified with aqueous hydrochloric acid (11.5 ml, 1N) at 0 ° C and extracted with DCM (4 × 40 ml). The organic layer was dried over anhydrous magnesium sulfate, concentrated and the residue was triturated to give 5 (single diastereomer).

Boc-R (NO ₂ ) -W-NH ₂ (6)

HOBt (1.0 equiv.) Is added to the thoroughly mixed

a solution of Boc-R (NO ₂ ) -OH (0.639 g, 2.0 mmol) and HW-NH ₂ H l · (0.479 g, 2.0 mmol) in DMF (10 ml) at 0 ° C followed by the addition of EDCI (1.1 equiv.) And NMM (0.484 ml, 2.2 equiv.). The resulting mixture was stirred at 0 ° C for 1 h and then at room temperature for 4-18 h. The reaction mixture was diluted with EtOAc (100 ml) and washed with water (1 × 20 ml), 1N aqueous hydrochloric acid (2 × 10 ml), saturated aqueous sodium bicarbonate (2 × 10 ml) and saturated brine (1 × 10 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain 6.

p-TSA • HR (NO ₂ ) -W-NH ₂ (7)

A solution of 6 (0.697 g, 1.381 mmol) in a TFA-DCM-water mixture (10: 40: 0.5; 15 ml) was stirred at room temperature for 2-4 hours. P-Toluenesulfonic acid monohydrate was added to the reaction mixture (1, 0 equiv.). After stirring for 10 minutes, the mixture was concentrated by evaporation in vacuo and the residue was triturated with ether-hexane (1: 1) to give 2.

Boc- (Carba-4-Cl-Ff) -R (NO ₂ ) -W-NH ₂ (8)

Follow the procedure for obtaining compound 6 and subjected to 7 (0.5 mmol) interaction with Boc- (carba-4-Cl-Ff) -OH (5, 0.5 mmol, 1.0 equiv.), Getting 8.

p-TSA • H- (carba-4-Cl-Ff) -R (NO ₂ ) -W-NH ₂ (9)

Follow the procedure for obtaining compounds 7 and get 9 of 8.

Ac- (carba-4-Cl-Ff) -R (NO ₂ ) -W-NH ₂ (10)

The procedure for preparing compound 6 was followed and 9 (0.472 mmol) was reacted with acetic acid to give crude compound 10, which was purified by preparative HPLC

(C ₁₈ ), getting 10.

Ac- (Carba-Ff) -RW-NH ₂ (11)

A mixture of 10 (200 mg, 0.263 mmol) and 300 mg of 5% Pd-BaSO ₄ (unrestored) in a mixture of MeOH-HOAc (10: 1, 22 ml) was hydrogenated at a hydrogen pressure of 42 lbs / ⁱⁿ² (250 kPa) at room temperature within 17 hours. The catalyst was removed by filtration through a pad of celite, which was washed with MeOH. The filtrate was concentrated to give crude compound 11, which was purified by preparative HPLC (C ₁₈ ), and then the product was triturated with ether to give 11 as a TFA salt.

Examples 68 and 69

Synthesis of 3- (4-hydroxyphenyl) propanoyl-Atc-R-tryptamide (17) and 3-phenylpropanoyl-Atc-R-tryptamide (19)

The compounds of these examples receive in accordance with the presented scheme II:

Boc-R (NO ₂ ) -tryptamide (12)

HOBt (1.0 eq.) And EDCI (0.949 g, 4.95 mmol, 1.1 eq.) Are added sequentially to the thoroughly mixed mixture of Boc-R (NO ₂ ) -OH (1.447 g, 4.5 mmol) and tryptamine (0.721 g, 4.5 mmol) in DMF (20 ml) at 0 ° C. The resulting mixture was stirred for 30 min at 0 ° C and then at room temperature for ~ 20 h. The mixture was diluted with EtOAc (100 ml) and then washed successively with water (2 × 20 ml), 5% aqueous citric acid (3 × 10 ml), 5% aqueous sodium bicarbonate (2 × 10 ml) and brine (2 × 20 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give compound 12, which was used directly in the next step.

HR (NO ₂ ) -tryptamide (13)

A solution of 12 (1.985 g, 4.3 mmol) in a trifluoroacetic acid-dichloromethane-water (10: 40: 0.5; 50 ml) mixture was stirred at 0 ° C for 15 minutes, and then at room temperature for 16 hours The solvent was removed on a rotary evaporator and the residue was coevaporated with methanol (3 x 40 ml). The crude product is then purified by preparative HPLC to give 13.

Fmoc-Atc-R (NO ₂ ) -tryptamide (14)

HOAt (0.409 g, 3.005 mmol), EDCI (0.632 g, 3.306 mmol, 1.1 eq.) And TEA (1.1 eq.) Are added sequentially to a thoroughly mixed solution of 13 (1.086 g, 3.005 mmol) and Fmoc-Atc -OH (1.242 g, 3.005 mmol) in DMF (15 ml) at 0 ° C. The resulting mixture was stirred for 30 min at 0 ° C and then at room temperature

temperature for 21 hours. Treatment as described above for 12 gives crude 14. The resulting material is used in the next step without further purification.

H-Atc-R (NO ₂ ) -tryptamide (15)

A solution of 14 (2.27 g, 3.0 mmol) in a DEA-DMF mixture (1: 9, 30 ml) was stirred at room temperature for 3 hours. The solvent was removed by evaporation under reduced pressure and the residue was triturated with ether-hexane ( 1: 1, 100 ml), getting 15.

3- (4-Hydroxyphenyl) propanoyl-Atc-R (NO ₂ ) -tryptamide (16)

Preparation 12 is followed and 0.603 g of crude 16 of 15 (0.535 g, 1.0 mmol) and 3- (4-hydroxyphenyl) propanoic acid (0.166 g, 1.0 mmol) are obtained. The resulting crude product was purified by preparative HPLC to give 16.

3- (4-Hydroxyphenyl) propanoyl-Atc-R-tryptamide (17)

A mixture of 16 (0.270 g, 0.405 mmol) and 5% Pd-BaSO ₄ (unreduced, 0.270 g) in a mixture of MeOH-HOAc (10: 1, 22 ml) was hydrogenated at room temperature at atmospheric pressure for 17 hours. The catalyst was removed by filtration through a pad of celite and the filtrate was concentrated on a rotary evaporator. The residue was purified by preparative HPLC and triturated with ether to give 17.

3-Phenylpropanoyl-Atc-R (NO ₂ ) -tryptamide (18)

The procedure for obtaining 16 is followed and 18 of 0.535 g (1.0 mmol) of 15 and 3-phenylpropanoic acid (0.150 g, 1.0 mmol) are obtained.

3-Phenylpropanoyl-Atc-R-tryptamide (19)

Follow the procedure for obtaining 17 and get 19 in the form

hydrated TFA salt of 0.270 mg 18.

Example 70

Synthesis of 3-phenylpropanoyl-f-N (Me) R-tryptamide (25)

The compound of this example is obtained in accordance with the presented scheme III:

Boc-N (Me) -R (Tos) -tryptamide (20)

The preparation procedure 12 (Scheme I) is followed and crude 20 of 1.991 g (4.5 mmol) of Boc-N (Me) -R (Tos) -OH and 0.721 g (4.5 mmol) of tryptamide are obtained. The resulting crude material is used in the next step without further purification.

p-TSA • H-N (Me) -R (Tos) -tryptamide (21)

Follow the procedure for obtaining 7 (Scheme 0) and get 21 in the form of a p-TSA salt from 2.631 g (4.5 mmol) 20.

Boc-f-N (Me) -R (Tos) -tryptamide (22)

DIEA (0.310 ml, 1.772 mmol, 2.0 eq.) Is added to the thoroughly mixed mixture of 21 (0.4293 g, 0.886 mmol), Boc-f-OH (0.2351 g, 0.886 mmol) and PyBrop (0.3795 g, 0.886 mmol) in

DCM (10 ml) at 0 ° C. The resulting reaction mixture was stirred at room temperature for 16 hours and then diluted with EtOAc (50 ml). The organic layer was washed successively with water (1 × 10 ml), 5% aqueous sodium bicarbonate (2 × 10 ml) and saturated brine (2 × 10 ml), and dried over anhydrous sodium sulfate. Removing the desiccant of moisture and evaporating the volatiles under reduced pressure gives the crude 22.

H-f-N (Me) -R (Tos) -tryptamide (23)

A solution of 22 (0.609 g, 0.833 mmol) dissolved in a mixture of TFA-DCM-water (10: 40: 0.5; 10 ml) was stirred at 0 ° C for 1 h and then kept in a refrigerator at 4 ° C in for 72 hours. The solvent was removed by evaporation in vacuo and then the residue was twice coevaporated with DCM (10 ml each time). The crude material thus obtained was purified by preparative HPLC and triturated with ether to give 23.

3-Phenylpropanoyl-f-N (Me) -R (Tos) -tryptamide (24)

TEA (0.209 mmol, 1.1 eq.) Was added to a thoroughly mixed mixture of 23 (0.120 g, 0.19 mmol), 3-phenylpropanoic acid (0.19 mmol) and EDCI (0.209 mmol, 1.1 eq.) In DMF (3 ml) at 0 ° C. The resulting mixture was stirred at 0 ° C for 0.5 h and then at room temperature for 16 h. The reaction mixture was diluted with EtOAc (30 ml) and washed successively with water (2 × 5 ml ), 5% aqueous citric acid (3 × 3 ml), 5% aqueous sodium bicarbonate (2 × 3 ml) and saturated brine (2 × 5 ml). The organic layer was dried over anhydrous sodium sulfate, concentrated and then triturated with ether to give 24.

3-Phenylpropanoyl-f-N (Me) -R-tryptamide (25)

Compound 24 (100 mg, 0.13 mmol) was dissolved in liquid ammonia (25 ml) at –78 ° C, and small pieces of sodium metal were added to the solution with vigorous stirring with a magnetic stirrer until the blue color disappeared over 2 h. Excess reagent is destroyed with ammonium acetate and ammonia is removed by evaporation at room temperature. The residue was dissolved in methanol and the solution was filtered through a pad of silica gel, which was then washed with additional methanol. The combined methanol filtrates were concentrated on a rotary evaporator to give a crude material which was purified by preparative HPLC to give 25 as a hydrated TFA salt.

Examples 71-75

Synthesis of H-YfRW-NH ₂ (32), Bc-YfRW-NH ₂ (34), CH ₃ (CH ₂ ) ₈ CO-YfRW-NH ₂ (36), Bc-YfRW-tryptamide (40) and CH ₃ ( CH ₂ ) ₈ CO-YfRW-Tryptamide (42)

The compounds of these examples receive in accordance with the presented scheme IV:

Boc-fR (NO ₂ ) -OMe (26)

Boc-f-OH (7.64 g, 28.8 mmol), HW (NO ₂ ) -Ome l (6.72 g, 28.8 mmol), HOBt (3.94 g, 29.2 mmol) TEA (8 ml, 57.6 mmol) and

DMF (110 ml, anhydrous) was mixed, the mixture was cooled at 0 ° C, and EDCI (5.89 g, 30.8 mmol) was added thereto with stirring. After stirring at room temperature for 18 hours, the mixture was concentrated on a rotary evaporator, diluted with water (350 ml) and extracted with EtOAc (4 × 80 ml). The combined organic extract was washed with 1N aqueous HCl (3 × 60 ml), saturated aqueous NaHCO ₃ (2 × 50 ml), brine (45 ml) and then dried with anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated on a rotary evaporator, evaporated together with ether (50 ml) and dried in vacuo to give 3.

p-TSA • H-fR (NO ₂ ) -OMe (27)

TFA (6 ml) was added to a solution of Boc-fR (NO ₂ ) -OMe (26) (1.49 g, 3.1 mmol) in DCM (20 ml) at 0 ° C. After stirring at 0 ° C for The reaction mixture was stirred for 30 minutes at room temperature for 5 hours. The solvent was removed in vacuo, the residue was evaporated together with ether (25 ml) and the resulting residue was dissolved in methanol (25 ml). P-Toluenesulfonic acid monohydrate (0.6 g, 3.1 mmol) was added, the mixture was stirred for 5 minutes. at room temperature, volatiles were removed in vacuo and the residue was coevaporated with ether (2 × 25 ml) to give 27.

Boc-YfR (NO ₂ ) -OMe (28)

p-TSA • H-fR (NO ₂ ) -OMe (27, 3.46 g, 6 mmol), Boc-Y-OH (1.72 g, 6.12 mmol), HOBt (0.83 g, 6 , 18 mmol), TEA (1.6 ml, 12 mmol) and DMF (25 ml, anhydrous) were mixed and cooled at 0 ° C. and EDCI (1.1 g, 6.3 mmol) was added with stirring. After

stirring at room temperature for 16 hours, the mixture was concentrated on a rotary evaporator, diluted with water (110 ml) and extracted with EtOAc (4 × 23 ml). The combined organic extract was washed with 1N aqueous HCl (3 × 20 ml), saturated aqueous NaHCO ₃ (2 × 25 ml), brine (25 ml) and then dried with anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated on a rotary evaporator, obtaining 28.

Boc-YfR (NO ₂ ) -OH (29)

A mixture of Boc-YfR (NO ₂ ) -OCH ₃ (28, 2.64 g, 4.1 mmol), LiOH (0.113 g, 4.72 mmol), water (0.4 ml) and MeOH (10 ml) was stirred at room temperature for 6 hours. After removal of the solvent, the residue is dissolved in a minimum amount of water. Add 1N HCl (approximately 4.7 ml) to neutralize the mixture to pH 5-6. The solid is filtered off and dried in vacuo to yield 29.

Boc-YfR (NO ₂ ) W-NH ₂ (30)

Boc-YfR (NO ₂ ) -OH (29, 0.99 g, 1.56 mmol), HW-NH ₂ · HCl (0.43 g, 1.8 mmol), HOBt (0.25 g, 1, 84 mmol), TEA (0.55 ml, 3.9 mmol) and DMF (20 ml, anhydrous) were mixed and cooled at 0 ° C. and EDCI (0.36 g, 1.87 mmol) was added with stirring. After stirring at room temperature for 16 hours, the mixture was concentrated on a rotary evaporator, diluted with water (120 ml) and extracted with EtOAc (4 × 25 ml). The combined organic extract was washed with 1N aqueous HCl (3 × 20 ml), saturated aqueous NaHCO ₃ (2 × 25 ml), brine (20 ml) and then dried with anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated on a rotary evaporator, coevaporated with ether (20 ml) and

dried in vacuo to give 30.

H-YfR (NO ₂ ) -Trp-NH ₂ (31)

TFA (2 ml) was added to a solution of peptide 30 (0.95 g, 1.16 mmol) in DCM (6 ml) at 0 ° C. After stirring at 0 ° C for 30 minutes, the reaction mixture was stirred at room temperature for 5 hours. The solvent was removed on a rotary evaporator and the resulting residue was purified by preparative HPLC to obtain 31.

H-YfRW-NH ₂ (32)

Peptide 31 (0.25 g, 0.35 mmol), 5% Pd / BaSO ₄ (0.25 g, unreduced) and MeOH (15 mL) were combined and hydrogenated at a hydrogen pressure of 40 lbs / ⁱⁿ² (276 kPa) at room temperature for 48 h. After filtration, the filtrate was concentrated on a rotary evaporator and the residue was purified by preparative HPLC to obtain H-YfRW-NH ₂ (32).

Bc-YfR (NO ₂ ) W-NH ₂ (33)

Using the method of obtaining 28 followed by purification by preparative HPLC, 33 are obtained from H-YfR (NO ₂ ) W-NH ₂ (31, 0.26 g, 0.37 mmol), butyric acid (0.037 g, 0.42 mmol), HOBt (0.059 g, 0.43 mmol), TEA (0.1 ml, 0.74 mmol), EDCI (0.084 g, 0.44 mmol) and DMF (12 ml).

Bc-YfRW-NH ₂ (34)

Following Production Method 32, 34 of 33 (0.16 g, 0.2 mmol), 5% Pd / BaSO ₄ (0.15 g, unreduced), MeOH (12 ml) and TFA (0.1 ml) were obtained.

CH ₃ (CH ₂ ) ₈ CO-YfR (NO ₂ ) W-NH ₂ (35)

Using the method of obtaining 28 with subsequent purification

preparative HPLC, 35 of H-YfR (NO ₂ ) W-NH ₂ (31, 0.26 g, 0.36 mmol), decanoic acid (0.071 g, 0.41 mmol), HOBt (0.057 g, 0, 42 mmol), TEA (0.1 ml, 0.73 mmol), EDCI (0.083 g, 0.43 mmol) and DMF (12 ml).

CH ₃ (CH ₂ ) ₈ CO-YfRW-NH ₂ (36)

Preparation 31 was followed and 36 of 35 (0.2 g, 0.23 mmol), 5% Pd / BaSO ₄ (0.18 g, unreduced), MeOH (12 ml) and TFA (0.1 ml) were obtained.

Boc-YfR (NO ₂ ) -tryptamide (37)

The preparation procedure 30 is used and 37 is obtained from Boc-YfR (NO ₂ ) -OH (29, 0.95 g, 1.5 mmol), tryptamide (0.276 g, 1.73 mmol), HOBt (0.239 g, 1.77 mmol), TEA (0.5 ml, 3.6 mmol), EDCI (0.34 g, 1.8 mmol) and DMF (18 ml).

H-YfR (NO ₂ ) -tryptamide (38)

Peptide 30 (0.98 g, 1.27 mmol) in DCM (6 ml) and a solution of anisole-TFA-DCM (1: 8: 9, 6 ml) were mixed at 0 ° C and stirred under ice cooling for 20 minutes . The mixture was then stirred at room temperature overnight. The solvent was removed and the resulting residue was coevaporated with ether (2 × 25 ml) to give crude 38.

Bc-YfR (NO ₂ ) -tryptamide (39)

Using the procedure for obtaining 28 followed by purification by preparative HPLC, 39 of 38 (0.28 g, 0.41 mmol), butyric acid (0.042 g, 0.47 mmol), HOBt (0.066 g, 0.49 mmol), TEA are obtained (0.12 ml, 0.83 mmol), EDCI (0.094 g, 0.49 mmol) and DMF (10 ml).

Bc-YfR (NO ₂ ) -tryptamide (40)

Preparation 32 was followed and 40 of 39 (0.19 g, 0.25 mmol), 5% Pd / BaSO ₄ (0.18 g, unreduced), MeOH (12 ml) and TFA (0.1 ml) were obtained.

CH ₃ (CH ₂ ) ₈ CO-YfR (NO ₂ ) -tryptamide (41)

Using the procedure for obtaining 28 followed by purification by preparative HPLC, 41 of 38 (0.27 g, 0.4 mmol), decanoic acid (0.081 g, 0.47 mmol), HOBt (0.065 g, 0.48 mmol), TEA are obtained (0.11 ml, 0.81 mmol), EDCI (0.093 g, 0.49 mmol) and DMF (12 ml).

CH ₃ (CH ₂ ) ₈ CO-YfRW-tryptamide (42)

Preparation 32 was followed and 42 of 41 (0.21 g, 0.25 mmol), 5% Pd / BaSO ₄ (0.18 g, unreduced), MeOH (12 ml) and TFA (0.1 ml) were obtained.

Examples 76-81

Synthesis of Ac-YfRW-OMe (47), Ac-YfRW-NHCH ₃ (49), AcYfRWSar-NH ₂ (50), 3- (4-OH-Ph) propanoyl-fRW-NHCH ₃ (53), 3- ( 4-OH-Ph) propanoyl-fRW-NH (CH ₂ ) ₂ OH (54) and 3- (4-OH-Ph) propanoyl-fRW-NH (CH ₂ ) ₂ OH (55)

The compounds of these examples receive in accordance with the presented scheme V:

Boc-fR (NO ₂ ) -OH (43)

Preparation 29 was followed and 43 was obtained from Boc-fR (NO ₂ ) -OMe (26, 2.8 g, 5.8 mmol), LiOH (0.27 g, 11 mmol) and MeOH (15 ml).

Boc-fR (NO ₂ ) W-OMe (44)

The preparation procedure was 26 and 44 were obtained from Boc-fR (NO ₂ ) -OH (43, 4.22 g, 9.06 mmol), HW-OMe · l (2.65 g, 10.4 mmol), HOBt ( 1.44 g, 10.7 mmol), TEA (3.15 ml, 22.6 mmol), EDCI (2.08 g, 10.9 mmol) and DMF (55 ml).

H-fR (NO ₂ ) W-OMe (45)

TFA (12 ml) was added to a solution of 44 (5 g, 7.5 mmol) in DCM (30 ml) at 0 ° C. After stirring at 0 ° C for 1 h, the reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo, the residue was coevaporated with ether (2 × 35 ml), and the product was dried in vacuo to give crude 45.

Ac-YfR (NO ₂ ) W-OMe (46)

The preparation procedure 28 was followed and crude 46 was obtained from H-fR (NO ₂ ) W-OMe (45, 3.3 g, 5.8 mmol), Ac-Y-OH (1.5 g, 6.7 mmol), HOBt (0.93 g, 6.9 mmol), TEA (1.7 ml, 12.2 mmol), EDCI (1.34 g, 7 mmol) and DMF (25 ml).

Ac-YfRW-OMe (47)

Preparation 32 is followed and 47 of 46 (0.2 g, 0.26 mmol), 5% Pd / BaSO ₄ (0.19 g, unreduced), MeOH (15 ml) and TFA (0.1 ml) are obtained.

Ac-YfR (NO ₂ ) W-OH (48)

Using the procedure for obtaining 29 followed by purification by preparative HPLC and get 48 of Ac-YfR (NO ₂ ) W-OMe (46, 0.96 g, 1.25 mmol), LiOH (0.063 g, 2.6 mmol), water ( 0.4 ml) and MeOH (6 ml).

Ac-YfRW-NHCH ₃ (49)

The procedure for obtaining 30 is followed, with the exception of the coevaporation step, and the reaction product Ac-YfR (NO ₂ ) W-OH (48, 0.3 g, 0.39 mmol), methylamine (0.014 g, 0.45 mmol) is obtained, HOBt (0.058 g, 0.43 mmol), TEA (0.092 ml, 0.91 mmol), EDCI (0.089 g, 0.47 mmol) and DMF (12 ml). The indicated product was purified by preparative HPLC and then hydrogenated using the procedure of 32 in the presence of 5% Pd / BaSO ₄ (0.17 g, unreduced) in MeOH (12 ml) to obtain 49.

Ac-YfRWSar-NH ₂ (50)

The procedure for obtaining 30 is followed, with the exception of the stage of co-evaporation, and the reaction product Ac-YfR (NO ₂ ) W-OH (19, 0.3 g, 0.39 mmol), sarcosinamide · HCl (0.05 g, 0, 4 mmol), HOBt (0.058 g, 0.43 mmol), TEA (0.092 ml, 0.91 mmol), EDCI (0.089 g, 0.47 mmol) and DMF (12 ml). The product was purified by preparative HPLC and then hydrogenated using Production Method 32 in the presence of 5% Pd / BaSO ₄ (0.18 g, unreduced) in MeOH (12 ml) to give 50.

3- (4-OH-Ph) propanoyl-fRW-OCH ₃ (51)

Using a preparation procedure of 26 followed by purification by preparative HPLC, 51 of H-fR (NO ₂ ) W-OCH ₃ 45 (2.1 g, 3.7 mmol), 3- (4-hydroxyphenyl) propanoic acid (0.71) are obtained g, 4.3 mmol), HOBt (0.59 g, 4.4 mmol), TEA (1.1 ml, 0.91 mmol), EDCI (0.85 g, 4.5 mmol) and DMF (25 ml).

3- (4-OH-Ph) propanoyl-fRW-OH (52)

Following the procedure for obtaining compound 29, 52 of 51 (1.15 g, 1.61 mmol), LiOH (0.081 g, 3.38 mmol), water (0.4 ml) were obtained

and MeOH (8 ml).

3- (4-OH-Ph) propanoyl-fRW-NHCH ₃ (53)

Following the procedure for the preparation of compound 30, an interaction product of 52 (0.3 g, 0.42 mmol), methylamine (0.015 g, 0.49 mmol), HOBt (0.064 g, 0.47 mmol), TEA (0.14 ml) was obtained. , 0.98 mmol), EDCI (0.098 g, 0.51 mmol) and DMF (12 ml). This product was purified by preparative HPLC and hydrogenated according to the procedure used to obtain 32 in the presence of 5% Pd / BaSO ₄ (0.16 g) and MeOH (12 ml), obtaining 53.

3- (4-OH-Ph) propanoyl-fRW-NHCH ₂ CH ₂ OH (54)

Following the procedure for the preparation of compound 30, an interaction product of 52 (0.3 g, 0.42 mmol), ethanolamine (0.031 g, 0.51 mmol), HOBt (0.066 g, 0.49 mmol), TEA (0.14 ml) was obtained. , 1 mmol), EDCI (0.1 g, 0.52 mmol) and DMF (12 ml). The specified product was purified by preparative HPLC and hydrogenated according to the procedure used to obtain compound 32 in the presence of 5% Pd / BaSO ₄ (0.18 g) and MeOH (12 ml), obtaining 54.

3- (4-OH-Ph) propanoyl-fRWSar-NH ₂ (55)

Following the procedure for obtaining compound 30, the product of interaction 52 (0.3 g, 0.42 mmol), sarcosinamide · l (0.061 g, 0.49 mmol), HOBt (0.068 g, 0.5 mmol), TEA (0, 15 ml, 1.1 mmol), EDCI (0.098 g, 0.51 mmol) and DMF (12 ml). The specified product was purified by preparative HPLC and hydrogenated according to the procedure used to obtain compound 32 in the presence of 5% Pd / BaSO ₄ (0.18 g) and MeOH (12 ml), obtaining 55.

Examples 82-84

Synthesis of Bc-YfRW-NHCH ₃ (63), Bc-YfRW-NH (CH ₂ ) ₂ OH (64) and BcYfRW-N (CH ₃ ) (CH ₂ ) ₂ OH (65)

The compounds of these examples receive in accordance with the presented scheme VI:

Boc-YfRW-OCH ₃ (56)

Compound 28 was prepared according to the procedure and 2.1 g (95%) of 56 was obtained from Boc-YfR (NO ₂ ) -OH (29, 1.7 g, 2.6 mmol), HW-OCH ₃ · l (0.68 g, 2.7 mmol), HOBt (0.42 g, 3.1 mmol), TEA (0.8 ml, 5.8 mmol), EDCI (0.63 g, 3.3 mmol) and DMF (25 ml).

H-YfRW-OCH ₃ (57)

Following the procedure for the preparation of compound 38, 57 of 56 (2.1 g, 2.5 mmol) and anisole-TFA-DCM solution (1: 8: 9, 18 ml) were obtained.

Bc-YfRW-OCH ₃ (58)

Following the procedure for the preparation of compound 28, the crude reaction product of H-YfR (NO ₂ ) W-OCH ₃ (57, 1.21 g, 1.65 mmol), butyric acid (0.18 g, 2 mmol), HOBt (0 26 g, 1.95 mmol), TEA (0.57 ml, 4.1 mmol), EDCI (0.394 g, 2.06 mmol) and DMF (25 ml). The indicated product was purified by preparative HPLC to obtain 58.

Bc-YfRW-OH (59)

Following the procedure for preparing compound 29, 59 of 58 (0.1 g, 0.13 mmol), LiOH (0.004 g, 0.15 mmol), water (0.2 ml) and MeOH (2 ml) were obtained.

Bc-YfRW-NHCH ₃ (63)

Following the procedure for obtaining compound 28, an interaction product of 60 from 59 (0.1 g, 0.125 mmol), methylamine (0.006 ml, 0.15 mmol), HOBt (0.02 g, 0.15 mmol), TEA (0, 04 ml, 0.3 mmol), EDCI (0.03 g, 0.16 mmol) and DMF (3 ml). The specified product is hydrogenated according to the procedure used to obtain compound 32, in the presence of 5% Pd / BaSO ₄ (0.1 g, unreduced) in MeOH (6 ml), getting 63.

Bc-YfR (NO ₂ ) W- NH (CH ₂ ) ₂ OH (61)

Using the procedure for preparing compound 28, followed by purification by HPLC, 61 of 59 (1.3 g, 1.65 mmol), ethanolamine (0.12 ml, 1.9 mmol), HOBt (0.263 g, 1.95 mmol) were obtained. TEA (0.55 ml, 4 mmol), EDCI (0.38 g, 2 mmol) and DMF (20 ml).

Bc-YfRW- NH (CH ₂ ) ₂ OH (64)

Follow the procedure for obtaining compound 32 and obtain 64 in the form of a solid from 61 (0.22 g, 0.26 mmol), 5% Pd / BaSO ₄

(0.2 g, unreduced), MeOH (12 ml) and TFA (0.1 ml).

Bc-YfR (NO ₂ ) WN (CH ₃ ) (CH ₂ ) ₂ OH (62)

Using the procedure for preparing compound 28, followed by purification by HPLC, 62 of 59 (0.26 g, 0.33 mmol), N-methylethanolamine (0.032 ml, 0.4 mmol), HOBt (0.053 g, 0.39 mmol) are obtained. TEA (0.11 ml, 0.83 mmol), EDCI (0.076 g, 0.4 mmol) and DMF (10 ml).

Bc-YfRW-N (CH ₃ ) (CH ₂ ) ₂ OH (65)

Compound 32 was prepared according to the procedure and 65 of 62 (0.16 g, 0.19 mmol), 5% Pd / BaSO ₄ (0.19 g, unreduced), MeOH (10 ml) and TFA (0.1 ml) were obtained. .

Example 85

Synthesis of 3- (4-OHPh) propanoyl-YfRW-NH ₂ (69)

The compound of this example is obtained in accordance with the presented scheme VII:

3- (4-OHPh) propanoyl-fR (NO ₂ ) -OCH ₃ (66)

Using the procedure for preparing compound 28 followed by purification by preparative HPLC, 66 of 27 (1.5 g, 2.6

mmol), 3- (4-hydroxyphenyl) propanoic acid (0.48 g, 2.9 mmol), HOBt (0.43 g, 3.2 mmol), TEA (0.91 ml, 6.6 mmol), EDCI (0.63 g, 3.3 mmol) and DMF (28 ml).

3- (4-OHPh) propanoyl-fR (NO ₂ ) -OH (67)

Following the procedure for preparing compound 29, 67 of 66 (0.33 g, 0.63 mmol), LiOH (0.029 g, 1.2 mmol), water (0.4 ml) and MeOH (5 ml) were obtained.

3- (4-OHPh) propanoyl-fR (NO ₂ ) W-NH ₂ (68)

Using the procedure for preparing compound 28 followed by purification by preparative HPLC, 68 of 67 (0.32 g, 0.62 mmol), HW-NH ₂ · l (0.16 g, 0.68 mmol), HOBt (0.1 g, 0.73 mmol), TEA (0.2 ml, 1.6 mmol), EDCI (0.14 g, 0.75 mmol) and DMF (13 ml).

3- (4-OHPh) propanoyl-fRW-NH ₂ (69)

Compound 32 was prepared in the following manner and 69 of 68 (0.14 g, 0.2 mmol), 5% Pd / BaSO ₄ (0.12 g, unreduced), MeOH (9 ml) and TFA (0.1 ml) were obtained. .

Example 86

Synthesis of Ac-YfR-Tryptamide (73)

The compound of this example is obtained in accordance with the presented scheme VIII:

Ac-YfR (NO ₂ ) -OCH ₃ (70)

Using the procedure for preparing Compound 28, followed by purification by preparative HPLC, 70 of 27 (0.36 g, 0.63 mmol), Ac-Y-OH (0.14 g, 0.63 mmol), HOBt (0.1 g) were obtained. 0.74 mmol), TEA (0.17 ml, 1.2 mmol), EDCI (0.14 g, 0.76 mmol) and DMF (12 ml).

Ac-YfR (NO ₂ ) -OH (71)

Following the procedure for obtaining compound 29 with an additional step of coevaporation from THF (5 ml), a mixture of 71 and two equivalents of LiCl from 70 (0.08 g, 0.14 mmol), LiOH (0.007 g, 0.28 mmol), water (0.2 ml) and MeOH (4 ml).

Ac-YfR-Tryptamide (73)

Following the procedure for obtaining compound 28, the crude reaction product 72 was obtained from a mixture of Ac-YfR (NO ₂ ) -OH / 2LiCl (71, 0.091 g, 0.136 mmol), tryptamine (0.025 ml, 0.15 mmol), HOBt (0.021 g, 0.15 mmol), TEA (0.1 ml, 0.7 mmol), EDCI (0.03 g, 0.16 mmol) and DMF (6 ml). The specified product is hydrogenated according to the procedure used to obtain compound 32,

in the presence of 5% Pd / BaSO ₄ (0.2 g, unreduced) and MeOH (8 ml) to give 73 as a solid.

Example 87

Synthesis of Hydrocinnamoyl-fRW-NH ₂ (77)

The compound of this example is obtained in accordance with the presented scheme IX:

Hydrocinnamoyl-fR (NO ₂ ) -OCH ₃ (74)

Following the procedure for obtaining compound 28, 74 of 27 (0.25 g, 0.43 mmol), hydrocinnamic acid (0.068 g, 0.45 mmol), HOBt (0.068 g, 0.5 mmol), TEA (0.16 ml, 1.1 mmol), EDCI (0.097 g, 0.51 mmol) and DMF (20 ml).

Hydrocinnamoyl-fW (NO ₂ ) -OH (75)

Following the procedure for preparing compound 29, 75 of 74 (0.22 g, 0.43 mmol), LiOH (0.014 g, 0.56 mmol), water (0.3 ml) and MeOH (8 ml) were obtained.

Hydrocinnamoyl-fRW-NH ₂ (77)

Following the procedure for the preparation of compound 28, a crude reaction product of 76/75 (0.2 g, 0.4 mmol) was obtained.

HW-NH ₂ · l (0.1 g, 0.42 mmol), HOBt (0.068 g, 0.5 mmol), TEA (0.14 ml, 1 mmol), EDCI (0.1 g, 0.52 mmol) and DMF (12 ml). The specified product is hydrogenated according to the procedure used to obtain compound 32, in the presence of 5% Pd / BaSO ₄ (0.2 g, unreduced) and MeOH (10 ml), to obtain 77.

Example 88

Synthesis of 3- (4-OHPh) propanoyl- (4-Ff) RW-NH ₂ (82)

The compound of this example is obtained in accordance with the presented scheme X:

Boc- (4-Ff) R (NO ₂ ) -OMe (78)

Following the procedure for preparing compound 26, 78 from Boc- (4-Ff) -OH (1.5 g, 5.3 mmol), HR (NO ₂ ) -Ome · HCl (1.46 g, 5.4 mmol) are obtained HOBt (0.87 g, 6.4 mmol), TEA (1.86 ml, 13.3 mmol), EDCI (1.33 g, 6.9 mmol) and DMF (35 ml).

H- (4-Ff) R (NO ₂ ) -OMe (79)

TFA (4 ml) was added to a solution of 78 (2.48 g, 5 mmol) in DCM (20 ml) at 0 ° C. The mixture was stirred under ice cooling for 30 minutes. and then stirred at room temperature

throughout the night. The solvent was removed, the residue was evaporated together with ether (2 × 30 ml), and the obtained residue was dried in vacuo to obtain 79 as a solid.

3- (4-OHPh) propanoyl- (4-Ff) R (NO ₂ ) -OMe (80)

Following the procedure for preparing compound 26, 80 of 79 (2 g, 5 mmol), 3- (4-hydroxyphenyl) propanoic acid (0.92 g, 5.5 mmol), HOBt (0.8 g, 5.9 mmol) were obtained. ), TEA (1.7 ml, 12.6 mmol), EDCI (1.15 g, 6 mmol) and DMF (25 ml).

3- (4-OHPh) propanoyl- (4-Ff) R (NO ₂ ) -OH (81)

Following the procedure for preparing compound 29, 81 of 80 (0.75 g, 1.4 mmol), LiOH (0.065 g, 2.7 mmol), water (0.4 ml) and MeOH (8 ml) were obtained.

3- (4-OHPh) propanoyl- (4-Ff) R (NO ₂ ) W-NH ₂ (82)

Using the procedure for the preparation of compound 30 followed by purification by preparative HPLC, an interaction product of 81 (0.4 g, 0.75 mmol), HW-NH ₂ · HCl (0.2 g, 0.82 mmol), HOBt (0, 12 g, 0.9 mmol), TEA (0.26 ml, 1.9 mmol), EDCI (0.17 g, 0.9 mmol) and DMF (20 ml). The specified product is hydrogenated according to the procedure used to obtain compound 32, in the presence of 5% Pd / BaSO ₄ (0.25 g, unreduced) and MeOH (15 ml), to obtain 82.

Examples 89-91

Synthesis of 3- (4-OHPh) propanoyl-fR-tryptamide (88), 3- (2-OHPh) propanoyl-fR-tryptamide (89) and hydrocinnamoyl-fR-tryptamide (90)

The compounds of these examples receive in accordance with the presented scheme XI:

Boc-fR (NO ₂ ) -tryptamide (83)

Boc-fR (NO ₂ ) -OH (43, 507.9 mg, 1.09 mmol), tryptamine (172.9 mg, 1.08 mmol), HOBt (163.3 g, 1.08 mmol), TEA (0.16 ml, 0.12 mmol) and DMF (6 ml, anhydrous) are mixed, cooled at 0 ° C. and EDCI (226.9 mg, 1.18 mmol) is added with stirring. After stirring at 0 ° C for 45 minutes, the ice bath was removed, the mixture was heated and stirred at room temperature for 14.5 hours. The mixture was diluted with EtOAc (20 ml) and washed with 2N aqueous HCl (3 × 5 ml), aqueous acidic the layer was extracted again with EtOAc (1 × 10 ml) and the combined EtOAc layers were washed with 1M NaHCO ₃ (3 × 5 ml) and brine (10 ml). Then, the organic extract was dried with anhydrous Na ₂ SO ₄ , the moisture absorber was removed by filtration, and the filtrate was concentrated on a rotary evaporator. The resulting solid was dried in vacuo to yield 83.

p-TSA • H-fR (NO ₂ ) -tryptamide (84)

TFA (3 ml) was added to a solution of Boc-fR (NO ₂ ) -tryptamide (83)

(0.58 g, 0.95 mmol) in DCM (6 ml) at 0 ° C. After stirring at 0 ° C for 30 minutes the reaction mixture was stirred at room temperature for 1.25 hours. p-Toluenesulfonic acid monohydrate (176.2 mg, 0.93 mmol) was added and the volatiles were removed on a rotary evaporator to give a brown oil. The oil is triturated with ether (10 ml) and the residue dried in vacuo to give 84.

3- (4-OHPh) propanoyl-fR (NO ₂ ) -tryptamide (85)

p-TSA • H-fR (NO ₂ ) -tryptamide (84, 149.9 mg, 220 μmol), 3- (4-hydroxyphenyl) propanoic acid (39.6 mg, 238 μmol), HOBt (33.7 mg , 233 μmol), NMM (0.37 ml, 337 μmol) and DMF (1.5 ml, anhydrous) were mixed, cooled at 0 ° C and EDCI (44.6 mg, 233 μmol) was added with stirring. After stirring at 0 ° C for 1.3 hours, the ice bath was removed, the mixture was heated and stirred at room temperature for 100 hours. The mixture was diluted with EtOAc (20 ml) and washed with 2N aqueous HCl (3 × 5 ml), aqueous acidic the layer was extracted again with EtOAc (1 × 10 ml) and the combined EtOAc layers were washed with 1M NaHCO ₃ (3 × 5 ml) and brine (10 ml). Then, the organic extract was dried with anhydrous Na ₂ SO ₄ , the moisture absorber was removed by filtration, and the filtrate was concentrated on a rotary evaporator to obtain 85.

3- (2-OHPh) propanoyl-fR (NO ₂ ) -tryptamide (86)

Following the procedure used to prepare compound 85, the crude reaction product was obtained 84 (151.7 mg, 223 μmol), 3- (2-hydroxyphenyl) propanoic acid (39.2 mg, 236 μmol), HOBt (35.3 mg, 231 μmol), NMM (0.40 ml, 364 μmol),

EDCI (45.0 mg, 235 μmol) and DMF (1.5 ml, anhydrous). Then, the resulting material was purified by preparative HPLC (C ₄ ) to obtain 86.

Hydrocinnamoyl-fR (NO ₂ ) -tryptamide (87)

Following the procedure used to obtain compound 85, 87 of 84 (150.6 mg, 221 μmol), hydrocinnamic acid (35.6 mg, 237 μmol), HOBt (34.4 mg, 225 μmol), NMM (0, 37 ml, 337 μmol), EDCI (45.1 mg, 235 μmol) and DMF (1.5 ml, anhydrous).

3- (4-OHPh) propanoyl-fR-tryptamide (88)

Following the procedure used to prepare compound 32, 88 of 95 mg (145 μmol) 85 and 5% Pd-BaSO ₄ (68 mg, unreduced) are obtained.

3- (2-OHPh) propanoyl-fR-tryptamide (89)

Following the procedure used to prepare compound 32, except that the resulting product was lyophilized from acetonitrile-water and not purified by HPLC, 89 of 33.7 mg (51 μmol) 86 and 5% Pd-BaSO ₄ (31 mg) were obtained. unrestored).

Hydrocinnamoyl-fR-tryptamide (90)

Following the procedure used to prepare compound 32, 90 of 106 mg (165 μmol) 87 and Pd-BaSO ₄ (63 mg, unreduced) are obtained.

Example 92

Synthesis of 3- (4-OHPh) propanoyl-Me-fR-tryptamide (95)

The compound of this example receive in accordance with the presented scheme XII:

Boc-Me-fR (NO ₂ ) -OMe (91)

Boc-Me-f-OH (1,0008 g, 3.6 mmol), HR (NO ₂ ) -OMe • HCl (0.9659 g, 3.6 mmol), HOBt (0.5515 g, 3.6 mmol), TEA (0.525 ml, 3.8 mmol) and DMF (20 ml, anhydrous) are mixed, cooled at 0 ° C. and EDCI (0.7211 g, 3.8 mmol) is added with stirring. After stirring at 0 ° C for 1 h, the ice bath was removed, the mixture was heated and stirred at room temperature for 23 h. The mixture was diluted with EtOAc (20 ml) and washed with 2N aqueous HCl (3 × 8 ml), aqueous acidic layer extracted again with EtOAc (1 × 10 ml) and the combined EtOAc layers were washed with 1M NaHCO ₃ (3 × 8 ml) and brine (10 ml). Then, the organic extract was dried with anhydrous Na ₂ SO ₄ , the moisture absorber was removed by filtration, and the filtrate was concentrated on a rotary evaporator to obtain 91.

p-TSA • H-Me-fR (NO ₂ ) -OMe (92)

Following the procedure for preparing compound 84, 92 was obtained in the form of a hydrated p-TSA salt from 91 (0.4989 g, 1.0 mmol).

3- (4-OHPh) propanoyl-Me-fR (NO ₂ ) -OMe (93)

p-TSA • H-Me-fR (NO ₂ ) -OMe (92, 282.8 mg, 500 μmol), 3- (4-hydroxyphenyl) propanoic acid (85.7 mg, 516 μmol), HOBt

(77.4 mg, 505 μmol), NMM (0.60 ml, 546 μmol) and DMF (3 ml, anhydrous) are mixed, cooled at 0 ° C. and EDCI (101.9 mg, 532 μmol) is added with stirring. After stirring at 0 ° C for 1.3 hours, the ice bath was removed, the mixture was heated and stirred at room temperature for 24 hours. More EDCI (41.2 mg, 215 μmol) was added, the mixture was stirred at room temperature for 64 h, EDCI (29.9 mg, 156 μmol) was added again with a small amount of NMM (0.60 ml, 546 μmol) and the mixture was heated at 50 ° C. for 8 hours. Then the mixture was left at room temperature for 21 hours and treated by the method for producing compound 91 to obtain 93.

3- (4-OHPh) propanoyl-Me-fR (NO ₂ ) -OH (94)

A mixture of 3- (4-OHPh) propanoyl-Me-fR (NO ₂ ) -OMe (93, 96.3 mg, 177 μmol), LiOH monohydrate (21.3 mg, 508 μmol) in a mixture of THF-MeOH-water ( 6 ml, 4: 1: 1) was stirred at room temperature for 1 h. 6% aqueous KHSO ₄ (1.3 ml) was added and the volatiles were removed on a rotary evaporator. Water (1.4 ml) was added to the wet residue, the pH was adjusted to ~ 2 with a few additional drops of 6% aqueous KHSO _4, and the aqueous mixture was extracted with EtOAc (3 × 2 ml). The combined organic layers were washed with water and brine and dried over anhydrous Na ₂ SO ₄ . The used moisture absorber was removed by filtration, and the filtrate was concentrated on a rotary evaporator to obtain 94.

3- (4-OHPh) propanoyl-Me-fR-tryptamide (95)

3- (4-OHPh) propanoyl-Me-fR (NO ₂ ) -OH (94, 77.0 mg, 146 μmol),

tryptamine (23.9 mg, 149 μmol), HOBt (25.1 mg, 164 μmol), NMM (0.17 ml, 155 μmol) and DMF (5 ml, anhydrous) are mixed, cooled at 0 ° C and with stirring add EDCI (32.4 mg, 169 μmol). After stirring at 0 ° C for 1.5 hours, the ice bath was removed, the mixture was heated and stirred at room temperature for 4 hours. The mixture was subjected to the procedure for preparing compound 85 to obtain a crude reaction product, which was purified by preparative HPLC (C ₄ ) The purified product was dissolved in a mixture of 10% acetic acid-MeOH (20 mL) and hydrogenated at a hydrogen pressure of 40 lbs / ⁱⁿ² (276 kPa) at room temperature for 15 h using 5% Pd-BaSO ₄ (31.3 mg , unreduced) as a catalyst. The catalyst was removed by filtration through celite, the volatiles were removed in vacuo, the residue was redissolved in 10% acetonitrile-water (15 ml), and the mixture was frozen and lyophilized to give 95.

Example 93

Synthesis of [1-carbamoyl-2- (1H-indol-3-yl) ethyl] amide 5- [2-acetylamino-3- (4-chlorophenyl) propionylamino] -4-oxo-6-phenyl-2- (2- pyridin-2-yl-ethyl) hexanoic acid (103)

The compound of this example is obtained in accordance with the presented schemes XIII and XIV:

(R) -3- (tert-butoxycarbonylamino) -1-diazo-4-phenylbutan-2-one (96)

To a solution of Boc-f-OH (5.30 g, 20 mmol) in anhydrous THF (100 ml) was added TEA (2.02 g, 20 mmol) and ethyl chloroformate (2.16 g, 20 mmol) at –15 ° C. in an argon atmosphere. The mixture was stirred at -15 ° C for 30 minutes and then heated to 0 ° C. A solution of diazomethane in ether [100 ml, obtained from Me (NO) NCONH ₂ (4.0 g, 40 mmol) and 50% aqueous was added. KOH (20 ml)]. The mixture was warmed and stirred at room temperature for 3 hours. The mixture was washed with saturated aqueous NaHCO ₃ (30 ml), saturated aqueous ammonium chloride (30 ml) and saturated brine (2 × 30 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated on a rotary evaporator. The residue was crystallized from hexanes-EtOAc at 5 ° C to give the desired product. The mother liquor was concentrated and purified by chromatography (hexanes-EtOAc, 80:20) to obtain an additional amount of the desired product.

(R) -3- (tert-butoxycarbonylamino) -1-chloro-4-phenylbutan-2-one (97)

To a solution of diazoketone (96, 115 mg, 0.4 mmol) in ether (3 ml) was added a mixture of 4N HCl / 1,4-dioxane (0.11 ml, 0.44 mmol, obtained by diluting conc. HCl 1,4- dioxane) dropwise at 0 ° C. The resulting mixture was stirred at 0 ° C for 30 minutes. A few drops of TEA were added to neutralize the solution, and the mixture was diluted with EtOAc (20 ml), washed with saturated aqueous NaHCO ₃ (10 ml) and brine (3 × 10 ml). The organic layer was dried over Na ₂ SO ₄ and the solvents were evaporated. The residue was purified by chromatography (hexanes-EtOAc, 90:10) to obtain 108 mg (92%) of a colorless solid: mp: 101-102 ° C; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.43 (s, 9H), 3.03, 3.10 (ABX, J _AB = 13.8 Hz, J _AX = 7.1 Hz, J _BX = 6 , 8 Hz, 2H), 4.00, 4.19 (AB, J _AB = 16.2 Hz, 2H), 4.70 (m, 1H), 5.04 (wide d, J = 6.8 Hz 1H), 7.18-7.37 (m, 5H).

Methyl 2-methoxycarbonyl-4- (2’-pyridinyl) butanoate (98)

To freshly prepared NaOMe [from 2.3 g (0.1 mol) sodium] in MeOH (25 ml), dimethyl malonate (32 g, 0.24 mmol) is added. A solution of 2-vinylpyridine (10.5 g, 0.1 mol) in MeOH (15 ml) was added dropwise over 40 minutes to a solution of NaOMe under reflux. The resulting mixture was refluxed for 2.5 hours. MeOH was removed under reduced pressure, the residue was treated with 2N HCl (150 ml), then extracted with ether (2 × 60 ml) to remove excess dimethyl malonate. The aqueous phase was made basic with 2N NaOH and extracted with ether (3 × 100 ml). The combined organic phases are washed with brine (3 × 60 ml) and dried over Na ₂ SO ₄ . The filtrate is concentrated under reduced pressure, then a large

part of the excess 2-vinylpyridine is removed in vacuo. The residue was purified by chromatography (hexanes-EtOAc, 60:40 to 50:50 to 30:70) to obtain the desired product.

Methyl (R) -5- (tert-butoxycarbonylamino) -2-methoxycarbonyl-6-phenyl-2- [2 ’- (2" -pyridinyl) ethyl] -4-oxohexanoate (99)

To a solution of α-chloroketone (97, 150 mg, 0.5 mmol) in anhydrous 1,2-dimethoxyethane (3.0 ml) was added NaI (75 mg, 0.5 mmol) and the mixture was stirred under argon for 15 min. (Mixture A). To a solution of diester (98, 142 mg, 0.6 mmol) in anhydrous 1,2-dimethoxyethane (3.0 ml) was added freshly prepared NaOMe (32 mg, 0.6 mmol) and the mixture was stirred under argon for 15 min ( Mixture B). Mixture B was added to mixture A and the resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc (30 ml) and washed with brine (2 × 10 ml). The organic layer was dried over Na ₂ SO ₄ , the solvents were removed on a rotary evaporator and the residue was purified by chromatography (hexanes-i-PrOH, 80:20) to give 99.

(2RS, 5R) -5- (tert-butoxycarbonylamino) -6-phenyl-2- [2 ’- (2" -pyridinyl) ethyl] -4-oxohexanoic acid (100)

To a solution of diester (99, 165 mg) in MeOH (10 ml) was added 5N NaOH (1.0 ml) and the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated on a rotary evaporator and the residue was dissolved in water (10 ml). and acidified with 3N HCl to pH = 3. The mixture was extracted with DCM (3 × 10 ml) and the combined organic phases were washed with brine (10 ml) and dried over Na ₂ SO ₄ . The solvents are removed on a rotary evaporator to give diacid. The crude diacid is suspended in toluene

(10 ml) and the mixture was refluxed under argon for 3 hours. The solvent was evaporated and the residue was purified by chromatography (DCM-MeOH, 98: 2 to 95: 5) to obtain a mixture of two diastereomers that could be separated by preparative HPLC.

{1-benzyl-4- [1-carbamoyl-2- (1H-indol-3-yl) ethylcarbamoyl] -2-oxo-6-pyridin-2-ylhexyl} carbamic acid tert-butyl ester (101)

Mix acid 100 (44 mg, 0.1 mmol), HW-NH ₂ · l (26 mg, 0.11 mmol), HOBt (16 mg, 0.12 mmol), TEA (24 mg, 0.24 mmol) EDCI (24 mg, 0.12 mmol) and DMF (1 ml, anhydrous). The mixture was stirred at room temperature overnight, then poured into water (10 ml) and extracted with EtOAc (4 × 9 ml). The combined extract was washed with 1N HCl (2 × 8 ml), saturated NaHCO ₃ (1 × 8 ml), brine (8 ml), then dried with anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated on a rotary evaporator to obtain 101.

[1-Carbamoyl-2- (1H-indol-3-yl) ethyl] 5-amino-4-oxo-6-phenyl-2- (2-pyridin-2-yl-ethyl) hexanoic acid amide (102)

Peptide 101 (97 mg, 0.16 mmol) was mixed with a solution (1 ml) of anisole-TFA-DCM (1: 8: 9). The mixture was stirred at room temperature overnight. After solvent removal

the resulting residue was coevaporated with ether (2 x 8 ml) to give 0.81 g (99%) of 102.

Ac- (4-Cl-F) -OH

A mixture of Boc- (4-Cl-F) -OH (54 mg, 0.18 mmol), DCM (0.5 ml) and TFA (0.5 ml) was stirred at room temperature for 2 hours. After removing the solvent, the resulting the residue was mixed with DCM (1 ml), acetic anhydride (17 mg, 0.2 mmol) and TEA (40 mg, 0.4 mmol). The mixture was stirred at room temperature overnight, then concentrated on a rotary evaporator to give Ac- (4-Cl-F) -OH.

[1-Carbamoyl-2- (1H-indol-3-yl) ethyl] amide 5- [2-acetylamino-3- (4-chlorophenyl) propionylamino] -4-oxo-6-phenyl-2- (2-pyridine -2-yl-ethyl) hexanoic acid (103)

EDCI (36 mg, 0.19 mmol) is added to the mixture of peptide 102 (81 mg, 16 mmol), Ac- (4-Cl-F) -OH (41 mg, 0.17 mmol), HOBt (24 mg, 0 , 18 mmol), TEA (35 mg, 0.35 mmol) and DMF (2 ml, anhydrous) at 0 ° C. The reaction mixture was stirred at room temperature overnight and then worked up according to the procedure for obtaining compound 101. The crude product was purified by preparative HPLC, receiving 103.

Example 94

Synthesis of N- {3- [9-benzyl-12- (4-chlorobenzyl) -3- (1H-indol-3-ylmethyl-2,5,8,14-tetraoxo-1,4,7,13-tetraazacyclotetracos- 6-yl] propyl} guanidine (110)

The specified example is obtained in accordance with the presented scheme XV:

Boc-R (Pbf) W-OMe (104)

NMM (0.48 ml, 4.4 mmol) was added to a mixture of Boc-R (Pbf) -OH (1.053 g, 2.0 mmol), HW-OMe • HCl (0.509 g, 2.0 mmol), HOBt ( 0.270 g, 2.0 mmol), EDCI (0.422 g, 2.2 mmol) in DMF (10 ml) at 0 ° C and the resulting mixture was stirred at 0 ° C for 1 h, and then at room temperature for 4 h. The reaction mixture was diluted with EtOAc (100 ml) and washed successively with water (2 × 10 ml), 1N HCl (2 × 10 ml), saturated NaHCO ₃ (2 × 10 ml) and brine (2 × 10 ml). The organic layer was dried over MgSO ₄ , the desiccant was removed by filtration, and the filtrate was concentrated on a rotary evaporator to give 1.454 g (100%) of the crude product 104.

p-TSA • H-R (Pbf) W-OMe (105)

Solution 104 (1.454 g, 2.0 mmol) in TFA-DCM-water mixture

(10: 40: 0.5, 20 ml) and DCM (20 ml) were stirred at room temperature for 6 hours. P-Toluenesulfonic acid monohydrate (0.380 g, 2.0 mmol) was added and the mixture was stirred for 10 minutes at room temperature. temperature. The solvent was removed on a rotary evaporator and the residue was triturated with ether-hexane (1: 1, 100 ml) to give 1.598 g (99.9%) of crude 105.

Boc- (Carba-4-Cl-Ff) -R (Pbf) W-OMe (106)

EDCI (105.5 mg, 0.55 mmol) and NMM (0.12 ml, 1.1 mmol) are added to the thoroughly mixed mixture of 5 (216 mg, 0.5 mmol), 105 (399.5 mg, 0, 5 mmol) and HOBt (67.6 mg, 0.5 mmol) in DMF (9 ml) at 0 ° C. The resulting mixture was stirred at 0 ° C for 1 h and then at room temperature for 5 h. Mixture treated by the procedure for preparing compound 104 to obtain 508 mg (98%) of 106.

p-TSA • H- (carba-4-Cl-Ff) -R (Pbf) W-OMe (107)

A solution of 106 (508 mg, 488 μmol) in a TFA-DCM-water mixture (10: 90: 0.5, 15 ml) was stirred at room temperature for 17 hours. An HPLC analysis indicated that the reaction was not yet complete, therefore, another TFA-DCM-water mixture (10: 90: 0.5, 10 ml) and water (1 ml) were added and the resulting mixture was stirred at room temperature for 7 days. p-Toluenesulfonic acid monohydrate (92.8 mg, 488 μmol) and the mixture was stirred for 10 min at room temperature. The solvent was removed on a rotary evaporator and the residue was triturated with ether (25 ml) to give crude 107.

Fmoc-11-Aun- (Carba-4-Cl-Ff) -R (Pbf) W-OMe (108)

Follow the procedure for obtaining compounds 104 and get

crude 108 of Fmoc-11-Aun-OH (207 mg, 488 μmol), 107 (543 mg, 488 μmol), HOBt (66.0 mg, 488 μmol), EDCI (103.0 mg, 537 μmol) and NMM (0.118 ml, 1.07 mmol).

[11-Aun- (carba-4-Cl-Ff) -R (Pbf) W] (109)

1N NaOH (2.2 ml, 2.2 mmol) was added to a solution of 108 (520 mg, 387 μmol) in a mixture of THF-MeOH (1: 1) at room temperature and the resulting mixture was stirred at room temperature for 2 hours. Mixture acidify with 1N HCl to pH ~ 3 and partition between EtOAc (100 ml) and water (20 ml). Then the aqueous phase was extracted with EtOAc (2 × 20 ml), the combined organic phase was washed with brine (20 ml) and dried over MgSO ₄ . The moisture desiccant is removed by filtration, the filtrate is concentrated on a rotary evaporator and the residue is triturated with ether (20 ml) to obtain the crude amino acid to be cyclized. Add NMM (47 μl, 460 μmol) to a mixture of the above crude amino acid (430 mg, 387 μmol), HOBt (53 mg, 387 μmol) and EDCI (82.5 mg, 430 μmol) in DMF at 0 ° C. the mixture was stirred at 0 ° C for 1 h, and then at room temperature for 14 h. The mixture was worked up according to the procedure for the preparation of compound 104, and purified by preparative HPLC to obtain 109.

[11-Aun- (carba-4-Cl-Ff) -RW] (110)

A mixture of 109 (42 mg, 39 μmol) in a TFA-DCM-water mixture (10: 10: 0.5; 5 ml) was stirred at room temperature for 20 hours, the volatiles were removed on a rotary evaporator and the residue was purified by preparative HPLC. The product containing fractions are combined, concentrated, frozen and lyophilized to give

110 as a TFA salt.

Examples 95-99

The combination method (CP) for the formation of a peptide bond, carried out in solution:

The amine component (1 equivalent), the acid component (1 equivalent) and HOBt (2 equivalents) are dissolved in DMF (2 ml / mmol of substrate). The solution is treated with N-methylmorpholine (3-4 equivalents), EDCI (1.2 equivalents) and stirred at room temperature until the formation of the product is completed (usually 1-5 hours). The product precipitates after adding water (6-10 ml / ml DMF) to the reaction mixture, and it is separated from the liquid by filtration or decantation.

A. Synthesis of the skeleton of the dipeptide Boc-DPhe-Arg (NO ₂ ) OH (A-2)

A-1. Boc-DPhe-Arg (NO ₂ ) OMe

Reactant / Reagent MM: Moth: Number: Units: Boc-d-phe 265.31 0.05 13.26 g DMF fifty ml EDCI 191.17 0.06 11.5 g H-Arg (OMe) HCl 260.69 0.05 13.48 g Hobt 135.13 0.1 13.5 g NMM 101.14 0.15 16.5 ml

To form a peptide bond, a coupling method (CP) in solution is used.

A-2. Boc-DPhe-Arg (NO ₂ ) OH

Reactant / Reagent MM: Moth: Number: Units: Boc-DPhe-Arg (NO ₂ ) OMe 480.23 0.01 4.8 g Lioh 23.95 0,023 0.55 g Thf twenty ml Water 10 ml

A solution of Boc-DPhe-Arg (NO ₂ ) OMe in THF was cooled in an ice bath and treated at 0 ° C. with an aqueous LiOH solution. The reaction mixture was stirred in an ice bath for 4 hours. The solvents are evaporated to a small residual volume, which is treated with 1N HCl (approximately 25 ml) to a pH of 2-3. The product is extracted with ethyl acetate, washed with a mixture of water / brine, dried with anhydrous magnesium sulfate; the solvent was evaporated to dryness to give the title compound.

B. Synthesis of amino-terminal groups

B-1. 3- (4-Benzyloxyphenyl) propionic acid

Reactant / Reagent MM: Moth: Number: Units: p-hydroxypropionic acid 166.17 0.0468 7.78 g benzyl bromide 171.03 0,048 8.17 g NaOH, 1N one hundred ml EtOH 150 ml

Use the methodology described in JACS 1955, 77, p. 4887-4892. The product precipitates after the reaction mixture is acidified to pH 2-3.

B-2. 3- (4-Benzyloxyphenyl) propionyl chloride

Reactant / Reagent MM: Moth: Number: Units: 3- (4-benzyloxyphenyl) propionic acid 256.11 0,038 9.73 g PCl ₅ , 95% 208.24 0.0418 9.15 g toluene 400 ml

Solid PCl _{5 was} added to a solution of 3- (4-benzyloxyphenyl) propionic acid in toluene over 1 hour. The reaction mixture was stirred at room temperature for 3 hours and the solvent was evaporated. The residue was stirred with hexanes overnight to give a crystalline solid, which was filtered and dried in vacuo.

B-3. 4- (S) -Benzyl-3- [3- (4-benzyloxyphenyl) propionyl] oxazolidin-2-one

Reactant / Reagent MM: Moth: Number: Units: benzyloxyphenylpropanoyl chloride 274.74 0.005 1.37 g (S) - (-) - 4-benzyloxazolidinone 177.2 0.005 0.89 g t-BuLi 1.7 in Pentane 0.0051 3 ml THF, anhydrous 6 ml THF, anhydrous 6 ml

The procedure described in Tetrahedron 52 (43), 1996, p. 137333-13738 is used. The Li- (S) - (-) - 4-benzyloxazazolidinone salt is prepared at a temperature of –65 ° C to –72 ° C. A solution of decanoyl chloride in THF is cooled to –72 ° C and treated with a solution of Li- (S) - (-) -4-benzyloxazolidinone at the same temperature. The reaction mixture was stirred at a temperature of –70 ° C to –75 ° C for 1 hour and overnight at room temperature, treated with a solution of NH ₄ Cl and extracted with ethyl acetate. The organic layer was washed with water / brine, dried with MgSO ₄ and evaporated. The residue was purified on a silica column using a solution of hexane / ethyl acetate 7/3 as the eluent to give the title compound.

B-4. 4- (S) -Benzyl-3- [2- (4-benzyloxybenzyl) pent-4-enoyl] oxazolidin-2-one

Reactant / Reagent MM: Moth: Number: Units: 4- (S) -Benzyl-3- [3- (4-benzyloxyphenyl) propionyl] oxazolidin-2-one 415.48 0.003 1.24 g Allyl bromide, d = 1,398 120.98 0.006 0.52 ml Thf thirty ml NaHMDS, 0.6M to THF 0.003 5 ml

NaHMDS is added to a solution of 4- (S) -benzyl-3- [3- (4-benzyloxyphenyl) propionyl] oxazolidin-2-one in THF at a temperature of –70 ° C to –75 ° C over 15 minutes. The mixture is stirred for 1 hour and treated with allyl bromide at -70 ° C. Stirring is continued at the same temperature for 1 hour. The reaction mixture was allowed to warm to 0 ° C for 3 hours and quenched with 10% NH ₄ Cl. The product was extracted with ethyl acetate, washed with water / brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated and the crude product was purified on a silica column using a 4: 1 hexane / ethyl acetate mixture to obtain the title compound.

B-5. 2- (4-Benzyloxybenzyl) pent-4-enoic acid

Reactant / Reagent MM: Moth: Number: Units: Amide 455.54 0.004 1.85 g H ₂ O ₂ , 30% 0.016 1.82 ml Lioh 23.95 0.008 0.19 g Thf 10 ml

The procedure described in JOC 1992, 57 (10), 2888-2902 (p. 2894) is used.

B-6. 4- (4- (S) -Benzyl-2-oxooxazolidin-3-yl) -3- (4-benzyloxybenzyl) -4-oxobutyronitrile

To obtain B-6 using a technique similar to that used to obtain B-4.

B-7. 4-amino-2- (4-hydroxybenzyl) butyric acid ethyl ester hydrochloride

2-cyanomethyl-3-phenylpropionic acid (8.16 g, 43 mmol) in ethanol solution (75 ml) and concentrated HCl (10 ml) was hydrogenated overnight at 40 lb / ⁱⁿ² (276 kPa) in the presence of 10% Pd / C. The catalyst is removed by filtration; the filtrate was concentrated under reduced pressure to dryness to give the title compound.

B-8. 3- (4-Benzyloxyphenyl) -2-decanoylaminopropionic acid methyl ester

Reactant / Reagent MM: Moth: Number: Units: H-Tyr (Bzl) -OMe HCl 321.8 0.003 0.965 g decanoyl chloride, 98% d = 0.919 190.71 0.006 1.27 ml TEA, d = 0.726 101.19 0.016 2.2 ml DCM fifteen ml

TEA was added to a solution of the remaining reactants in DCM at a temperature of from –2 ° C to + 3 ° C. The reaction mixture was stirred at room temperature for 4 hours and diluted with 0.1N HCl. The product was extracted with DCM, washed with water, dried with MgSO ₄ and the solvent was evaporated under reduced pressure. The residue was crystallized from hexanes to give the title compound.

B-9. 3- (4-Benzyloxyphenyl) -2-decanoylaminopropionic acid

Reactant / Reagent: MM: Moth: Number: Units: Ester 439.59 0,00223 0.98 g 1N NaOH 0.0023 2,3 ml Thf 4.3 ml Water 0.7 ml

The reactants are stirred at room temperature for 5 hours. The solvents are evaporated under reduced pressure; the residue is diluted with water and acidified to a pH of about 2. The resulting product precipitate is filtered off, washed with water until the filtrate reaches about 6, and dried in vacuum overnight.

C. Synthesis of carboxyl end groups

C-1. N ¹ -Benzyl-3- (1H-indol-3-yl) -N ^1- methylpropan-1,2-diamine

A 2M solution of the BH ₃ · Me ₂ S complex in THF (40 ml) was added to a solution of the amide substrate (4.5 g, 8.4 mmol) in anhydrous THF (50 ml). The reaction mixture is heated at 75 ° C, while slowly distilled off liquid is collected through a refrigerator. After 2 hours, a new portion of a 2M solution of the BH ₃ · Me ₂ S complex in THF (10 ml) was added and heating was continued with simultaneous distillation for another 3 hours. The reaction mixture was cooled to room temperature and carefully treated with MeOH until gas evolution ceased, and 3N NaOH. The crude product was extracted with ethyl acetate and purified on a silica column using a solution of 1.5% MeOH in AcOEt and then a solution of EtOAc / DCM / MeOH / Et ₃ N 4/5 / 0.5 / 0.3 to give the title compound.

C-2. N ¹ -Benzyl-N ¹ -hexyl-3- (1H-indol-3-yl) propan-1,2-diamine

To obtain C-2 using a technique similar to that used to obtain C-1.

C-3. N ¹ -Hexyl-3- (1H-indol-3-yl) -N ^1- methylpropan-1,2-diamine

To obtain C-3 using a technique similar to that used to obtain C-1.

D. Assembly of tetrapeptide mimetics

D-1. (1- {4-nitroguanidino-1- [2- (hexylmethylamino) -1- (1H-indol-3-ylmethyl) ethylcarbamoyl] butylcarbamoyl} -2-phenylethyl) carbamic acid tert-butyl ester

Reactant / Reagent: MM: Moth: Number: Units: dipeptide 466.49 0,0005 0.233 g N ¹ -Hexyl-3- (1H-indol-3-yl) -N ^1- methylpropan-1,2-diamine 287.24 0,0005 0.143 g Hobt 135.12 0.001 0.135 g NMM, d = 0.92 101.14 0.0015 0.17 ml EDCI 191.17 0,0006 0.114 g DMF one ml

To form a peptide bond, a coupling method (CP) in solution is used. The crude product was purified on a silica column using hexane / ethyl acetate 6/1 to obtain the title compound.

To obtain the following compounds D-2, D-3, D-4 and D-5, a procedure similar to that used to obtain D-l was used.

D-2. 2- [2- (2-tert-Butoxycarbonylamino-3-phenylpropionylamino) -5-nitroguanidinopentanoylamino] -3- (1H-indol-3-yl) propionic acid methyl ester

D-3. (1- {1- [2- (Benzylhexylamino) -1- (1H-indol-3-ylmethyl) ethylcarbamoyl] -4-nitroguanidinobutylcarbamoyl} -2-phenylethyl) carbamic acid tert-butyl ester

D-4. (1- {4-nitroguanidino-1- [2- (1H-indol-3-yl) -1- (methylpropylcarbamoyl) ethylcarbamoyl] butylcarbamoyl} -2-phenylethyl) carbamic acid tert-butyl ester

D-5. (1- {1- [1- (carbamoylmethylmethylcarbamoyl) -2- (1H-indol-3-yl) ethylcarbamoyl] -4-nitroguanidinobutylcarbamoyl} -2-phenylethyl) carbamic acid tert-butyl ester

D-6. [2- (Hexylmethylamino) -1- (1H-indol-3-ylmethyl) ethyl] 2- (2-amino-3-phenylpropionylamino) -5-nitroguanidinopentanoic acid amide

Reactant / Reagent: MM: Moth: Number: Units: tripeptide 0.15 g TFA / DCM / H ₂ O (1/2 / 0.1) 2 ml

The reaction mixture was stirred at room temperature for 4 hours and diluted with 1,2-dichloroethane. The solvents are evaporated under reduced pressure; the residue was dried in vacuo overnight.

D-7. (1- {4-nitroguanidino-1- [2- (hexylmethylamino) -1- (1H-indol-3-ylmethyl) ethylcarbamoyl] butylcarbamoyl} -2-phenylethyl) amide 2- (4-benzyloxybenzyl) pent-4-eno acid

Reactant / Reagent: MM: Moth: Number: Units: Amide bond formation 749.82 0,000226 0.17 g acid 296.36 0,0003 0.09 g Hobt 135.12 0,0006 0.08 g NMM, d = 0.92 101.14 0.001 0.11 ml EDCI 191.17 0,00036 0,069 g DMF 0.7 ml

To form a peptide bond, a coupling method (CP) in solution is used. The crude product was purified by reverse phase preparative HPLC to give the title compound.

Example 95

Synthesis of (1- {4-guanidino-1- [2- (hexylmethylamino) -1- (1H-indol-3-ylmethyl) ethylcarbamoyl] butylcarbamoyl} -2-phenylethyl) amide 2- (4-hydroxybenzyl) pentanoic acid

Reactant / Reagent: MM: Moth: Number: Units: Starting material (D-7) 913.15 0.1 g EtOH fifteen ml Pd (OH) ₂

The reaction mixture was hydrogenated at room temperature under 45 lbs / ⁱⁿ² (310 kPa) overnight. The catalyst is separated by filtration through celite. The solvent was evaporated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to give the title compound.

Example 96

Synthesis of [1- (1- {4-guanidino-1- [2- (hexylmethylamino) -1- (1H-indol-3-ylmethyl) ethylcarbamoyl] butylcarbamoyl} -2-phenylethylcarbamoyl) -2- (4-hydroxyphenyl) ethyl ] decanoic acid amide

Reactant / Reagent M.M .: Moth: Number: Units: acid 426.56 0,00023 0.1 g amine 635.8 0.00019 0.12 g Hobt 135.12 0,0005 0,07 g NMM, d = 0.92 101.14 0.001 0.11 ml EDCI 191.17 0,0003 0.06 g DMF one ml Pd (OH) ₂

To form a peptide bond, a coupling method (CP) in solution is used. Hydrogenation is performed in ethanol at 45 lb / ⁱⁿ² (310 kPa) for 48 hours. The catalyst is removed by filtration; the crude product was purified by reverse phase preparative HPLC to give the title compound.

To obtain the compound of Examples 97-99, a procedure similar to that used to obtain the compound of Example 95 was used.

Example 97

Synthesis of 2- (5-guanidino-2- {2- [2- (4-hydroxybenzyl) pentanoylamino] -3-phenylpropionylamino} pentanoylamino) -3- (1H-indol-3-yl) propionic methyl ester

acid

Example 98

Synthesis of (1- {1- [1- (Benzylmethylcarbamoyl) -2- (1H-indol-3-yl) ethylcarbamoyl] -4-guanidinobutylcarbamoyl} -2-phenylethyl) amide 2- (4-hydroxybenzyl) pentanoic acid

Example 99

Synthesis of [2- (1- {1- [1- (carbamoylmethylmethylcarbamoyl) -2- (1H-indol-3-yl) ethylcarbamoyl] -4-guanidinobutylcarbamoyl} -2-phenylethylcarbamoyl) -3- (4- hydroxyphenyl) propyl] carbamic acid

C. Solid-phase synthesis of peptides manually

The following peptides are synthesized manually using the chemistry of Fmoc and Rink amide resin as a solid support. Removal of the Fmoc protecting groups is achieved with 20% piperidine in DMF for 30 min followed by washing with DMF (3 × 35 ml), MeOH (3 × 35 ml) and DMF (3 × 35 ml). The color reaction with ninhydrin is used to control the completion of the reaction. The terminal amino group acetylation is carried out with a mixture of 5% Ac ₂ O / 0.25% NMM / 0.2% HOBt in DMF for 30 minutes, followed by extensive washing with DMF and DCM and short-term drying in vacuum. The crude product is cleaved from the resin and the protecting groups are removed using 93% TFA and 2.3% ethanedithiol in water for 3 hours at room temperature. After removing the resin by filtration and washing with 3% TFA (3 × 18 ml), the filtrate was extracted with ether (6 × 20 ml), frozen and lyophilized. The crude product is then dissolved in 30% aqueous acetic acid and the solution purified by preparative HPLC (particle size 10 μm, Vydac C ₁₈ , 10 × 250 mm, gradient elution with a mixture of 6-60% acetonitrile-water (0.1% TFA) for 1, 5 hours). The fractions containing the product are combined and lyophilized to obtain purified peptides.

Example 100

Synthesis of Ac-Y- (4-Py) ala-RW-NH ₂ • 2TFA

Fmoc-W (Boc) -OH and Fmoc-R (pbf) -OH (each in a 2-fold excess) are sequentially attached to the Rink amide resin (4.28 g, 3 mmol) using PyBOP (2-fold excess) and NMM (4x excess). After washing with DMF (3 × 35 ml), ether (4 × 35 ml) and drying in vacuo, an increase in mass is achieved. Resin

(1.17 g, 0.35 mmol) are suspended in DMF (10 ml), the Fmoc group is removed, PyBOP (0.6 g, 1.15 mmol), NMM (0.26 ml, 2.8 mmol) are added sequentially. and Fmoc- (4-Py) ala-OH (0.447 g, 1.15 mmol) and the mixture was shaken for 1 h. After removal of the Fmoc protecting group, the binding procedure with Fmoc-Y (t-Bu) -OH (0.528) was repeated. g, 1.1 mmol). The peptide is then deprotected, acetylated and cleaved from the resin to give the product.

Example 101

Synthesis of Ac-Y- (3-Py) ala-RW-NH ₂ • 2TFA

The title compound was prepared according to Example 100 except that Fmoc- (3-Py) ala-OH was used instead of Fmoc- (4-Py) ala-OH.

Example 102

Synthesis of Ac-Y- (2-Py) ala-RW-NH ₂ • 2TFA

The addition of Fmoc- (2-Py) ala-OH to a solution of PyBop and NMM in DMF leads to a very rapid decomposition of the amino acid. Therefore, the compound of this example was prepared using a modification of the procedure used for Example 100, in which NMM (88 μl, 0.8 mmol) was added to a solution of Fmoc- (2-Py) ala-OH (0.311 g, 0.8 mmol) and PyBrop (0.373 mg, 0.8 mmol). After 15 minutes, a second equivalent of NMM was added. After 100 minutes, any unreacted amino-ends are acetylated and then follow the remaining steps described in Example 100 to give the title compound.

Viii. Examples of compositions and method of treatment

Example A

An obese woman, weighing 130 kg, is subjected

treatment with the above method in order to achieve weight loss. In particular, once a day for a period of 6 months, the patient is administered, by intravenous injection, 15 ml of an aqueous solution, including:

Component Concentration (mg / ml) Connection Note one 5 Sodium bisulfate one Sodium chloride 7 Chlorobutanol 5 Lemon acid 10 Sterile water dost. how many. up to 1 ml Sodium hydroxide to bring to pH 5

At the end of the treatment period, the patient exhibits measurable weight loss.

Example B

An obese man weighing 150 kg is exposed to a program aimed at reducing body weight, which provides weight loss due to reduced obesity through combination therapy, including a limited diet and increased physical activity. In particular, once a day for a period of 6 months after weight loss, the patient is administered, by intravenous injection, 15 ml of an aqueous solution, including:

Component Concentration (mg / ml) Connection Note nine 5 Sodium bisulfate one Sodium chloride 7 Chlorobutanol 5 Lemon acid 10 Sterile water dost. how many. up to 1 ml Sodium hydroxide to bring to pH 5

At the end of the treatment period, the patient showed sustained weight loss and decreased obesity.

Example C

An obese man weighing 165 kg is exposed to a program aimed at reducing body weight, which provides weight loss through combination therapy, including a limited diet, the presence of increased physical activity and subcutaneous injection daily of 15 ml of an aqueous solution, including:

Component Concentration (mg / ml) Connection Note 88 5 Sodium bisulfate one Sodium chloride 7 Chlorobutanol 5 Lemon acid 10 Sterile water dost. how many. up to 1 ml Sodium hydroxide to bring to pH 5

Once the desired weight loss has been achieved,

Patient weight loss is maintained by continuing intravenous injection once a day for an additional period of 6 months. At the end of the treatment period, the patient showed sustained weight loss and decreased obesity.

Example D

An obese woman, weighing 140 kg, is treated in this way in order to achieve weight loss. In particular, it is treated with a subcutaneous implantable pump that delivers 0.1 mg / kg of the compound of Example 31 over a 24-hour period. The pump contains a solution of the compound dissolved in a solution of 50% propylene glycol and 50% sterile water. The pump is replaced monthly, and treatment is continued for a six-month period, at which time the patient exhibits weight loss and a decrease in obesity.

Example E

An obese man weighing 150 kg is treated with the indicated method in order to achieve weight loss. In particular, he is treated with an oral tablet, taken twice a day, containing 300 mg of the compound of Example 29. The treatment lasts for 12 months, at which time the patient shows weight loss and decreased obesity.

Claims (18)

1. The compound having a structure corresponding to formula (I):

Where (A) X is selected from hydrogen, OR ¹ , —NR ¹ R ^{1 ′} and –CHR ¹ R ^{1 ′} , where R ¹ and R ^{1 ′ are} independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, and acyl; (B) (1) each R ^{2 is} independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl; or (2) (a) R ² bonded to a carbon atom that is bonded to X and Z ¹ and the substituent R ⁵ may optionally combine to form a carbocyclic or heterocyclic ring that is fused to the phenyl ring J; or; (b) R ² bonded to a carbon atom that is bonded to an Ar ring can combine with R ⁷ to form a ring fused to an Ar ring; or (C) each of Z ¹ , Z ² and Z ^{3 is} independently selected from —N (R ^3e ) C (R ³ ) (R ^3a ) -; -C (R ³ ) (R ^3a ) N (R ^3e ) -; -C (O) N (R ^3d ) -; -N (R ^3d ) C (O) -; -C (R ³ ) (R ^3a ) C (R ^3b ) (R ^3c ) -; -SO ₂ N (R ^3d ) - and -N (R ^3d ) SO ₂ -; where each of R ³ , R ^3a , R ^3b and R ^3c , when present, is independently selected from hydrogen and (C ₁ -C ₆ ) alkyl; (2) R ^3d , when present, is selected from hydrogen and (C ₁ -C ₆ ) alkyl; (3) R ^3e , when present, is selected from hydrogen and (C ₁ -C ₆ ) alkyl; (D) p is 0, 1, 2, 3, 4 or 5; where, when p is greater than 0, each R ⁴ and R ^{4 ′ is} independently selected from hydrogen, (C ₁ -C ₆ ) alkyl and aryl; (E) R ⁵ represents 5 substituents (i.e., positions 2-6) in the phenyl ring J, where each R ^{5 is} independently selected from hydrogen, hydroxy, halogen, thiol, —OR ¹² , —N (R ¹² ) (R ^{12 '} ), (C ₁ -C ₆ ) alkyl, nitro, aryl; where each R ¹² and R ^{12 'is} independently selected from hydrogen and (C ₁ -C ₆ ) alkyl; or two R ⁵ substituents may optionally combine to form a carbocyclic or heterocyclic ring that is fused to the phenyl ring J; (F) q is 0, 1, 2, 3, 4, or 5; where when q is greater than 0, each R ⁶ and R ^{6 ′ is} independently selected from hydrogen and (C ₁ -C ₆ ) alkyl; (G) Ar represents an aryl or heteroaryl ring selected from the group consisting of phenyl, thiophene, furan, oxazole, thiazole, pyrrole and pyridine; (H) R ⁷ represents substituents on the Ar ring, where each R ^{7 is} selected from hydrogen, halogen, —NR ¹³ R ^{13 ′} , (C ₁ -C ₆ ) alkyl and nitro; where each R ¹³ and R ^{13 ′ is} independently selected from hydrogen and (C ₁ -C ₆ ) alkyl; (I) r is 0, 1, 2, 3, 4, 5, 6, or 7; where, when r is greater than 0, each R ⁸ and R ^{8 ′ is} independently selected from hydrogen and (C ₁ -C ₆ ) alkyl; (J) B is selected from —N (R ¹⁴ ) C (= NR ¹⁵ ) NR ¹⁶ R ¹⁷ , —NR ²⁰ R ²¹ , a heteroaryl ring containing at least one nitrogen atom in the ring, and a heterocycloalkyl ring containing, at least one nitrogen atom in the ring, where R ¹⁴ , R ¹⁵ R ¹⁶ , R ¹⁷ , R ²⁰ and R ^{21 are} independently selected from hydrogen (C ₁ -C ₆ ) alkyl; (K) s is 0, 1, 2, 3, 4 or 5; where, when s is greater than 0, each R ⁹ and R ^{9 ′ is} independently selected from hydrogen and (C ₁ -C ₆ ) alkyl; (L) R ^{10 is} selected from the group consisting of an optionally substituted bicyclic aryl ring and an optionally substituted bicyclic heteroaryl ring; (M) D is independently selected from hydrogen, amino, and —C (O) R ¹¹ ; where R ¹¹ selected from the group consisting of hydroxy; alkoxy; amino; alkylamino; —N (R ¹⁹ ) CH ₂ C (O) NH ₂ where R ¹⁹ is (C ₁ -C ₆ ) alkyl; -NHCH ₂ CH ₂ OH and -N (CH ₃ ) CH ₂ CH ₂ OH; or its optical isomer, diastereomer or enantiomer; its pharmaceutically acceptable salt, hydrate or its biohydrolyzable ester, amide or imide. 2. The compound according to claim 1, where X is selected from –NR ¹ R ^{1 ′} and –CHR ¹ R ^{1 ′} and where R ¹ represents hydrogen or (C ₁ -C ₆ ) alkyl and R ^{1 ′} represents acyl. 3. The compound according to claim 1 or 2, where each R ² represents hydrogen. 4. The compound according to any one of the preceding claims., Where Z ¹ , Z ² and Z ^{3 are} independently selected from —C (R ³ ) (R ^3a ) N (R ^3e ) -; -C (O) N (R ^3d ) -; —C (R ³ ) (R ^3a ) C (R ^3b ) (R ^3c ) - and —SO ₂ N (R ^3d ) -. 5. The compound according to claim 4, where each R ³ , R ^3a , R ^3b and R ^3c , if present, is independently selected from hydrogen and (C ₁ -C ₆ ) alkyl; R ^3d , if present, is selected from hydrogen and (C ₁ -C ₆ ) alkyl; R ^3e , if present, is selected from hydrogen and (C ₁ -C ₆ ) alkyl. 6. The compound according to claim 1, where p is 1 or 2. 7. The compound according to claim 1, where each R ⁴ , if present, is hydrogen, and each R ^{4 '} , if present, is hydrogen or (C ₁ -C ₆ ) alkyl. 8. The compound according to claim 1, where each R ⁵ independently selected from hydrogen; hydroxy; halogen; thiol and -N (R ¹² ) (R ^{12 '} ), where R ¹² and R ^12' each represents hydrogen or (C ₁ -C ₆ ) alkyl, preferably four of the substituents R ⁵ on ring J are hydrogen, preferably at position 4 the ring is a substituent other than hydrogen. 9. The compound according to any one of the preceding claims., Where q is 0, 1 or 2, preferably, where q is greater than 0, each R ⁶ represents hydrogen and each R ^{6 '} represents hydrogen or (C ₁ -C ₆ ) alkyl . 10. The compound according to claim 1, where Ar is selected from phenyl, thiophene and furan, preferably phenyl, and where the substituent at position 4 of the phenyl ring is selected from hydrogen, fluoro, chloro, bromo, iodo, nitro and (C ₁ -C ₆ ) alkyl, and in the remaining four positions, the substituents are hydrogen. 11. The compound according to any one of the preceding claims., Where r is 2, 3 or 5, and each R ⁸ and R ^{8 ′ is} independently selected from hydrogen and (C ₁ -C ₆ ) alkyl. 12. The compound according to any one of the preceding claims., Where B is selected from -N (R ¹⁴ ) C (= NR ¹⁵ ) NR ¹⁶ R ¹⁷ , a heteroaryl ring containing at least one nitrogen atom in the ring, and a heterocycloalkyl ring containing at least one nitrogen atom in the ring, preferably B represents —N (R ¹⁴ ) C (= NR ¹⁵ ) NR ¹⁶ R ¹⁷ , where R ¹⁴ , R ¹⁵ , R ¹⁶ and R ^{17 are} independently selected from hydrogen and (C ₁ -C ₆ ) alkyl. 13. The compound according to any one of the preceding claims., Where s is 1 or 2 and R ⁹ represents hydrogen and each R ^{9 '} represents hydrogen or (C ₁ -C ₆ ) alkyl. 14. The compound according to any one of the preceding claims., Where R ^{10 is} selected from 1-naphthyl, 2-naphthyl, indane, 1H-indene, benzocyclobutane, benzocyclobutene, indole, indoline, pyridine, dihydropyridine, octahydropyridine, benzothiophene, benzofuran, benzimide benzopyran, quinoline, quinolone and isoquinoline. 15. The compound according to any one of the preceding claims., Where D is selected from amino and -C (O) R ¹¹ . 16. A compound having a structure corresponding to formula (A):

Where (A) R ¹ and R ^{1 ′ are} independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl and acyl; (B) R ^{2 is} selected from the group consisting of hydrogen and (C ₁ -C ₆ ) alkyl; (C) Z ^{1 is} selected from —N (R ^3e ) C (R ³ ) (R ^3a ) -; -C (R ³ ) (R ^3a ) N (R ^3e ) -; -C (O) N (R ^3d ) -; -N (R ^3d ) C (O) -; -C (R ³ ) (R ^3a ) C (R ^3b ) (R ^3c ) -; -SO ₂ N (R ^3d ) -; -N (R ^3d ) SO ₂ -; Where (1) each of R ³ , R ^3a , R ^3b and R ^3c , if present, is independently selected from hydrogen and (C ₁ -C ₆ ) alkyl; (2) R ^3d , if present, is selected from hydrogen and (C ₁ -C ₆ ) alkyl; (3) R ^3e , if present, is selected from hydrogen and (C ₁ -C ₆ ) alkyl; (D) p is 1 or 2 and each R ⁴ and R ^{4 ′ is} independently selected from hydrogen, (C ₁ -C ₆ ) alkyl and aryl; (E) R ^{5 is} selected from hydrogen, hydroxy, chloro, fluoro, —N (R ¹² ) (R ^{12 ′} ), where R ¹² and R ^{12 ′ are} each independently selected from hydrogen and (C ₁ -C ₆ ) alkyl; (F) q is 0, 1 or 2; where, when q is greater than 0, each R ⁶ and R ^{6 ′ is} independently selected from hydrogen and (C ₁ -C ₆ ) alkyl; (G) R ^{7 is} selected from hydrogen, halogen, —NR ¹³ R ^{13 ′} , (C ₁ -C ₆ ) alkyl, nitro; where each R ¹³ and R ^{13 ′ is} independently selected from hydrogen and (C ₁ -C ₆ ) alkyl; (H) B is selected from —N (R ¹⁴ ) C (= NR ¹⁵ ) NR ¹⁶ R ¹⁷ , a heteroaryl ring containing at least one nitrogen atom in the ring, and a heterocycloalkyl ring containing at least one atom nitrogen in the ring; where R ¹⁴ , R ¹⁵ , R ¹⁶ and R ^{17 are} independently selected from hydrogen and (C ₁ -C ₆ ) alkyl; (I) R ¹⁰ represents an optionally substituted bicyclic ring selected from 1-naphthyl, 2-naphthyl, indane, 1H-indene, benzocyclobutane, benzocyclobutene, indole, indoline, pyrindine, dihydropyrindine, octahydropyrindine, benzothiophene, benzofuran, benzofuran, benzofuran, benzofuran, benzene quinolone and isoquinoline; (J) R ^{11 is} selected from the group consisting of amino; alkylamino; —N (R ¹⁹ ) CH ₂ C (O) NH ₂ where R ¹⁹ is (C ₁ -C ₆ ) alkyl; -NHCH ₂ CH ₂ OH; -N (CH ₃ ) CH ₂ CH ₂ OH; or its optical isomer, diastereomer or enantiomer; its pharmaceutically acceptable salt, hydrate or its biohydrolyzable ester, amide or imide. 17. A pharmaceutical composition having selectivity for MC-4 and / or MC-3 receptors, comprising (a) a safe and effective amount of a cyclic peptide analogue according to any one of the preceding claims. and (b) a pharmaceutically acceptable excipient. 18. The pharmaceutical composition according to 17, used to treat a disorder selected from the group consisting of insulin resistance, glucose intolerance, type II diabetes, coronary heart disease, high blood pressure, hypertension, dyslipidemia, cancer (for example, endometrial cancer, brain, ovarian cancer, breast cancer, prostate cancer, gall bladder cancer, colon cancer), menstrual abnormalities, hirsutism, infertility, gall bladder disease, limited lung damage, sleep apnea, gout, ost eoarthritis and thromboembolic disease in an animal subject, preferably the disease is a disorder associated with abnormalities in body weight selected from the group consisting of obesity, anorexia and cachexia.