ES2352736T3 - SELECTIVE AGONISTS AND ANTAGONISTS OF THE SOMATOSTATIN 1 AND / OR 4 RECEIVER. - Google Patents

Abstract

The use of a compound of Formula I, ** (See formula) ** in which Q is 1) H, 2) aryl, 3) heteroaryl or 10 4) a group of formula ** (See formula) ** in which aryl and heteroaryl are unsubstituted or substituted with 1 to 4 substituents selected from Ra; A is 1) H, 2) (C1-C6) alkyl or 3) (C3-C5) cycloalkyl; B is independently selected from 1) H, 2) halogen or 3) (C1-C6) alkyl; or the symbols B together can form a double or triple bond between the atoms to which they are attached; D is aryl or heteroaryl, which may be unsubstituted or substituted with one to four groups selected from Rd; R1 is 1) H, 2) (C1-C6) alkyl or 3) (C3-C7) cycloalkyl; each R2 is independently selected from 1) H, 2) (C1-C6) alkyl, 3) (C2-C6) alkenyl, 4) (C2-C6) alkynyl, 5) cycloalkyl (C3-C7), 6) cycloalkyl ( C3-C7) (C1-C6) alkyl, 7) -NH2 or 8) -C (= NRb) NRbRb; in which the symbols Rb together with the atoms to which they are attached can also form an unsaturated or saturated ring of 5 to 6 members; or R2 and R2, together with the nitrogen to which they are attached, can form a 5- to 7-membered ring containing 1 to 3 heteroatoms selected from N, O and S, in which the formed ring may be saturated or unsaturated; R3 is 1) H, 2) (C1-C6) alkyl, 3) (C2-C6) alkenyl, 4) (C2-C6) alkynyl or 5) (C3-C7) cycloalkyl; R4 is 1) H, 2) (C1-C6) alkyl, 3) (C2-C6) alkenyl, 4) (C2-C6) alkynyl, 5) Cy, 6) Cy (C1-C6) alkyl, 7) Cy-alkenyl (C2-C6) or 8) Cy-alkynyl (C2-C6); wherein the alkyl, alkenyl, alkynyl and Cy are each optionally substituted with one to two substituents selected from Rd; R5 is 1) H, 2) (C1-C6) alkyl, 3) (C2-C6) alkenyl, 4) (C2-C6) alkynyl, 5) aryl, 6) aryl (C1-C6) alkyl, 7) heteroaryl, 8) heteroaryl (C1-C6) alkyl or 9) - (CH2) kC (O) NHRb; wherein the aryl and heteroaryl are each optionally substituted with one to two substituents selected from Rd; or R4 and R5, together with the atom to which they are attached, form a 3 to 7 member ring containing 0 to 2 heteroatoms selected from N, O and S, in which said ring may be substituted with one to three selected substituents of Rd; or said ring may be fused to the aryl or heteroaryl which may be substituted with one to three substituents selected from Rd; Ra is independently 1) H, 2) halogen, 3) -ORb, 4) (C1-C6) alkyl or 5) -CF3; Rb is independently 1) hydrogen, 2) (C1-C6) alkyl, 3) (C2-C6) alkenyl, 4) (C2-C6) alkynyl, 5) Cy or 6) Cy (C1-C4) alkyl; Rd is independently 1) a group selected from Rc, 2) (C1-C6) alkyl, 3) (C2-C6) alkenyl, 4) (C2-C6) alkynyl, 5) aryl, 6) aryl-C1-alkyl C6), 7) heteroaryl (C1-C6) alkyl, 8) (C3-C7) cycloalkyl or 9) heterocyclyl; wherein the alkyl, alkenyl, alkynyl, aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from Rc; Rc is independently 1) a group selected from Ra, 2) -NO2, 3) -SRb, 4) -NRbRb, 5) -CN or 6) -NRbC (O) Rb; k is an integer 0 or 1; n is an integer from 0 to 3; and Cy is cycloalkyl, heterocyclyl, aryl or heteroaryl; or a pharmaceutically acceptable salt or ester thereof, for the preparation of a medicament for the treatment of a disease or condition in mammals in which interaction with the subtypes of somatostatin 1 and / or 4 receptors is indicated.

Description

Field of the Invention

The present invention relates to peptidomimetic molecules based on (hetero) arylsulfonylamino, which are useful for the preparation of a medicament for the treatment or diagnosis of medical disorders related to somatostatin 1 and / or 4 receptor subtypes.

Background of the Invention

Somatostatin is a cyclic peptide found endogenously in two shorter is identical in sequence to the C-terminal half of the sst-28. Somatos
main forms consisting of 14 (sst-14) or 28 (sst-28) amino acids. The sst-14 tatina is produced in a generalized way in the organism, and acts both in a sis way

Thematic as local to inhibit the secretion of various hormones, growth factors and neurotransmitters. The biological effects of somatostatin are mediated by a family of G-protein coupled receptors, of which five subtypes (SSTR1-5) have been cloned in humans (Reisine and Bell 1995; Patel 1999). The affinities of the two endogenous forms of somatostatin towards the five subtypes are relatively similar (it has been reported that sst-28 has a moderate preference for SSTR5). However, the five subtypes are expressed differentially in different tissues, and also show differences in their interaction with several signaling pathways. Thus, the pleiotropic physiological responses mediated by somatostatin are a reflection of its wide distribution and the existence of multiple receptor subtypes.

Based on its sequence similarity and its affinity towards several somatostatin octapeptide and hexapeptide analogs, the family of five somatostatin receptor subtypes can be divided into two subfamilies: a subfamily consisting of SSTR2, SSTR3 and SSTR5 and another subfamily consisting of SSTR1 and SSTR4. The first has a high affinity, and the second a rather low affinity towards the hexapeptide and octapeptide analogs mentioned above (Hoyer et al. 1995). Due to the availability of selective and high affinity ligands, the physiology of the SSTR2,3,5 subfamily has been more thoroughly characterized, and it seems that the "classic" effects of somatostatin, such as the very potent inhibition of growth hormone, insulin, glucagon and gastric juice release,

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they are mediated primarily or exclusively through the members of this subfamily.

Although physiology and pathophysiology of the SSTR1 and SSTR4 subtypes are less understood, there have been several findings on the role of these subtypes described in scientific publications and in the patent literature. The US document

6,124,256 reported that, given its location in the vascular wall and its time-related induction during the proliferative stage, SSTR1 and / or SSTR4 may be the optimal subtypes to prevent fibroproliferative vasculopathy through a therapy based on the receptors of somatostatin According to this, Curtis et al. (2000) have described that SSTR1 and SSTR4 represent the predominant subtypes expressed in human blood vessels, and have proposed the use of selective agonists of SSTR1 or SSTR4 for the treatment of proliferative diseases mediated by endothelial cells. Aavik et al. (2002) have shown that a supposed analogue of selective peptide somatostatin (CH-275) of SSTR1 and SSTR4 is able to prevent intimal hyperplasia after a carotid denudation injury in rats. Together, these findings may explain why two somatostatin, octreotide and lanreotide peptide analogs, which have very high preferences for the SSTR2 and SSTR5 subtypes, but which have rather low affinities for the SSTR1 or SSTR4 subtypes, were not able to show efficacy in clinical trials aimed at preventing restenosis after percutaneous transluminal angioplasty (Eriksen et al. 1995; van Essen et al. 1995).

Due to the fact that activation of SSTR1 causes antiproliferative effects, a selective agonist of SSTR1 may be useful for the treatment of tumors harboring SSTR1. For example, it has been described that SSTR1 receptors are expressed in prostate cancer (Sinisi et al. 1997; Reubi et al. 1997; Reubi et al. 2001), but not in normal prostate tissue. Regardless of its functional properties as an agonist or antagonist, any selective ligand of SSTR1 may be useful for the diagnosis of prostate tumors or tumors in other tissues that express the SSTR1 subtype.

WO97 / 03054 and US 6,221,870 describe that selective SSTR1 antagonists derived from benzo [g] quinoline (WO097 / 03054) or ergoline (US 6,221,870) decrease aggressive behavior in mice and, based on This observation suggests that such compounds are useful for the treatment of depression, anxiety, affective disorders and attention deficit hyperactivity disorders.

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According to Bito et al. (1994), the SSTR4 subtype is expressed at high levels in the rat hippocampus, where somatostatin has been reported to play an important role in the regulation of membrane conductance. Because the hippocampus is a brain structure closely associated with learning and memory, as well as mental disorders such as depression and schizophrenia, the prominent role of the SSTR4 subtype in the hippocampus suggests that selective agonists or antagonists of SSTR4 with Ability to cross the blood brain barrier may have therapeutic potential.

Through the use of in situ hybridization, Mori et al. (1997) have shown that in the eye of rats the expression of SSTR4 predominates in the epithelium of the posterior iris and in the ciliary body. In addition, the authors have observed that somatostatin lowers intraocular pressure (IOP) and, based on these observations, they have proposed that selective SSTR4 ligands may be useful as anti-glaucoma agents.

Somatostatin has a very short biological half-life, and is therefore unsuitable for therapeutic use. Several shorter analogs of somatostatin hexa- and octapeptides with improved biological stability have been identified (eg, US Pat. Nos. 4,485,101, US 5,409,894 or WO97 / 47317). However, these abbreviated peptide analogs are very predisposed in favor of the SSTR2,3,5 subfamily and do not show any significant interaction with the SSTR1 or SSTR4 subtypes. In contrast, WO97 / 14715 and Rivier et al. (2001) describe a group of undecapeptide agonists with preference towards SSTR1. However, in addition to their often rather short biological half-lives, peptides also possess other problematic properties that make them unsatisfactory as medications. For example, peptides have a very limited ability to penetrate through membranes. This is one of the reasons why in most cases it is impossible to apply the peptides orally, and why the peptides generally do not reach the central nervous system.

In recent years, several non-peptide somatostatin agonists have been identified. In addition to the selective SSTR1 antagonists already mentioned reported in WO97 / 03054 and US 6,221,870, WO97 / 43278 describes several thiourea-based compounds that preferentially interact with the SSTR4 subtype of somatostatin and H3 of histamine. US documents

6,329,389 and US 6,352,982 provide selective SSTR4 compounds centered around tetrahydroquinoline or 4,1-benzoxazepine structures. Rohrer et al. (1998) have been able to identify selective subtype agonists for each

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of the five subtypes of somatostatin receptors using a combinatorial chemistry strategy, which incorporated the generally accepted hypothesis about the structure-activity relationship of active compounds in somatostatin receptors that amino acid residues 8 and 9 of sst-14 (which consist of a tryptophan and a lysine) are essential for proper ligand-receptor interaction.

The present invention describes a new class of somatostatin receptor ligands in the form of sulfonamidopeptidomimetic molecules. These compounds are related in part to the sulfonamido-peptidomimetic molecules, which have been presented in Brussaard et al. (1989), WO02 / 24192 and WO03 / 026575 in the context of another family of G-protein coupled receptors, specifically the FF neuropeptide receptor. Sulfonamide derivatives of monocyclic or bicyclic amino acids have also been described in US documents.

6,271,252 and US 6,221,888 as antagonists of cell adhesion molecules (CAM) that inhibit leukocyte adhesion and pathologies mediated by leukocyte adhesion.

Summary of the Invention

The present invention relates to non-peptide compounds that possess a high degree of selectivity towards the two receptor subtypes of the SSTR1 / SSTR4 somatostatin receptor subfamily. Those skilled in the art will appreciate that, based on their agonism or antagonism in an SSTR1 or SSTR4 receptor, a wide variety of therapeutic, prophylactic and diagnostic applications can be achieved from the compounds of this invention:

one.

The compounds of the invention are useful for the preparation of a medicament for the prevention or treatment of diseases or symptoms of anxiety, depression, schizophrenia, epilepsy, attention deficit hyperactivity disorders and neurodegenerative diseases such as dementia, Alzheimer's disease and Parkinson's disease The treatment of affective disorders includes bipolar disorders, eg manic-depressive psychosis, extreme psychotic states, eg, mania and excessive mood swings for which behavior stabilization is sought. The treatment of anxiety states includes generalized anxiety as well as social anxiety, agoraphobia and those behavioral states characterized by social withdrawal, eg negative symptoms.

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2.

The compounds of the invention, depending on their agonist or antagonistic character over SSTR1 or SSTR4, are advantageous in diseases that involve a pathological vascular proliferation, eg angiogenesis, restenosis, smooth muscle proliferation, endothelial cell proliferation and formation of outbreaks of new blood vessels or conditions that require the activation of neovascularization. Angiogenic disease can be, for example, age-related macular degeneration or vascular proliferation associated with surgical procedures, eg angioplasty and AV shunts. Other possible uses are treatments of atherosclerosis, neovascularization of plaques, hypertrophic cardiomyopathy, myocardial angiogenesis, valvular disease, myocardial infarction, coronary collateral circulation, cerebral collateral circulation and ischemic limb angiogenesis.

3.

The compounds of the invention are also indicated for the preparation of a medicament for the treatment of diseases related to a pathological condition of the retina and / or the iris-ciliary body of mammals. Such conditions may be high intraocular pressure (IOP) and / or deep eye infections. Treatable diseases can be, for example, glaucoma, stromal keratitis, iritis, retinitis, cataracts and conjunctivitis. Other diseases related to the eye may include ocular and corneal angiogenic conditions, for example, corneal graft rejection, retrolental fibroplasia, Osler-Webber syndrome or rubeosis.

Four.

The compounds of the invention are also useful for the preparation of a medicament for the prevention or treatment of diseases or symptoms related to diabetic complications such as diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, Doan's syndrome and orthostatic hypotension.

5.

The compounds of the invention are useful for the preparation of a medicament for the treatment of various tumors such as, eg, adenoma cell proliferation, thyroid cancer, large intestine cancer, breast cancer, prostate cancer. , small cell lung cancer, non-small cell lung cancer, pancreatic cancer, stomach cancer, GI tumors, cholangiocarcinoma, liver cancer, bladder cancer, ovarian cancer, melanoma, osteosarcoma, chondrosarcoma, malignant pheochromocytoma, neuroblastoma, brain tumors, thymoma, paragangliomas , prostate carcinomas, sarcomas, gastroenteropancreatic tumors, gastric carcinomas, pheochromocytomas, ependymomas, tumors

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renal, leukemia, eg, basophilic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin's disease and non-Hodgkin's lymphoma.

6. The compounds of the invention can also be used for the formation of

images of healthy or diseased tissues and / or organs, such as brain, vessels or 5 tumors, which have SSTR1 and / or SSTR4 receptors.

7. The compounds of the invention are useful for targeting tumors with SSTR1 and / or SSTR4 receptors by using a compound of the invention conjugated with anti-neoplastic drugs directly or by using a suitable spacer molecule.

Finally, the compounds of the invention are useful for wound healing, ovulation, menstruation, placentation, peptic ulcers, psoriasis, rheumatoid arthritis and Crohn's disease.

Detailed description of the invention

The invention relates to the use of compounds having the general formula (I) and pharmaceutically acceptable salts and esters thereof for the preparation of a medicament for the treatment of a disease or condition in mammals in which it is indicated as useful. interaction with somatostatin 1 and / or 4 receptor subtypes,

image 1

twenty

in which

Q is 1) H, 2) aryl,

3) heteroaryl or 4) a group of formula

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image 1

wherein the aryl and heteroaryl may be unsubstituted or substituted with 1 to 4 substituents selected from Ra;

A is

1 HOUR,

2) (C1-C6) alkyl or

3) cycloalkyl (C3-C5);

B is independently selected from 1 HOUR, 2) halogen or 3) (C1-C6) alkyl;

or B and B together can form a double or triple bond between the atoms to which they are attached; D is aryl or heteroaryl, which may be unsubstituted or substituted with one to four groups selected from Rd; R1 is

1 HOUR, 2) (C1-C6) alkyl or 3) cycloalkyl (C3-C7);

each R2 is independently selected from 1 HOUR, 2) (C1-C6) alkyl, 3) alkenyl (C2-C6), 4) (C2-C6) alkynyl, 5) cycloalkyl (C3-C7), 6) cycloalkyl (C3-C7) alkyl (C1-C6), 7) -NH2 or 8) -C (= NRb) NRbRb;

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in which Rb and Rb, together with the atoms to which they are attached, can also form an unsaturated or saturated ring of 5 to 6 members; or R2 and R2, together with the nitrogen to which they are attached, form a 5 to 7 member ring containing 1 to 3 heteroatoms selected from N, O and S, in which the formed ring may be saturated or unsaturated; R3 is

1 HOUR, 2) (C1-C6) alkyl, 3) alkenyl (C2-C6), 4) (C2-C6) alkynyl or 5) cycloalkyl (C3-C7);

R4 is 1) H, 2) (C1-C6) alkyl, 3) (C2-C6) alkenyl, 4) (C2-C6) alkynyl, 5) Cy, 6) Cy (C1-C6) alkyl, 7) Cy-alkenyl (C2-C6) or 8) Cy-alkynyl (C2-C6);

wherein the alkyl, alkenyl, alkynyl and Cy are each optionally substituted with one to two substituents selected from Rd; R5 is

1 HOUR, 2) (C1-C6) alkyl, 3) alkenyl (C2-C6), 4) (C2-C6) alkynyl, 5) aryl, 6) aryl (C1-C6) alkyl, 7) heteroaryl, 8) heteroaryl (C1-C6) alkyl or 9) - (CH2) kC (O) NHRb;

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wherein the aryl and heteroaryl are each optionally substituted with one to two substituents selected from Rd; or R4 and R5, together with the atom to which they are attached, form a 3 to 7 member ring containing 0 to 2 heteroatoms selected from N, O and S, in which said ring may be substituted with one to three selected substituents of Rd; or said ring may be fused to the aryl or heteroaryl which may be substituted with one to three substituents selected from Rd; Ra is independently

1 HOUR, 2) halogen, 3) -ORb, 4) (C1-C6) alkyl or 5) -CF3;

Rb is independently 1) hydrogen, 2) (C1-C6) alkyl, 3) (C2-C6) alkenyl, 4) (C2-C6) alkynyl, 5) Cy or 6) Cy (C1-C4) alkyl;

Rd is independently 1) a group selected from Rc, 2) (C1-C6) alkyl, 3) (C2-C6) alkenyl, 4) (C2-C6) alkynyl, 5) aryl, 6) aryl-C1-alkyl C6), 7) heteroaryl (C1-C6) alkyl, 8) (C3-C7) cycloalkyl or 9) heterocyclyl; in which the alkyl, alkenyl, alkynyl, aryl and heteroaryl are each option

Nally substituted with one to four independently selected substituents

temente de Rc;

Rc is independently

1) a selected group of Ra,

2) -NO2,

3) -SRb,

4) -NRbRb,

5) -CN or

6) -NRbC (O) Rb;

k is an integer 0 or 1;

n is an integer from 0 to 3; Y

Cy is cycloalkyl, heterocyclyl, aryl or heteroaryl.

"Alkyl", as well as other groups having the prefix "alc", such as alkoxy, alkanoyl, means carbon chains that can be linear or branched, or combinations thereof. The size of the alkyl can be further specified by adding the number of carbons behind the group, eg (C1-C6) alkyl, (C1-C3) alkyl. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, neo-pentyl, hexyl, heptyl, octyl, nonyl.

"Alkenyl" means carbon chains that contain at least one carbon-carbon double bond, and which can be linear or branched, or combinations thereof. The alkenyl size can be further specified by adding the number of carbons behind the group, eg alkenyl (C2-C6), alkenyl (C2C8). Examples of alkenyl groups include vinyl, allyl, isopropenyl, 1-pentenyl, 2pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl.

"Alkynyl" means carbon chains that contain at least one carbon-carbon triple bond, and which may be linear or branched, or combinations thereof. The alkynyl size can be further specified by adding the number of carbons behind the group, eg alkynyl (C2-C6), alkynyl (C2-C8). Examples of alkynyl groups include ethynyl, propargyl, 3-methyl-1-pentinyl, 2-heptenyl.

"Cycloalkyl" means saturated mono- or bicyclic carbocyclic rings, each of which has 3 to 8 carbon atoms. The term also includes monocyclic rings fused to an aryl group in which the point of attachment is in the non-aromatic portion. The size of the cycloalkyl can be further specified by adding the number of carbons behind the group, eg cycloalkyl (C3-C7), cycloalkyl (C5-C10). Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl.

"Aryl" means mono- or bicyclic aromatic rings containing only carbon atoms. The term also includes an aryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is in the aromatic portion. The aryl size can be specified further by adding the number of carbons behind the group, eg aryl (C6-C12). Examples of aryl groups include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl.

"Heteroaryl" means a mono- or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, and each ring contains 5 to 6 atoms. The term also includes a heteroaryl group fused to a mono-cyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is in the aromatic portion. Examples of heteroaryl groups include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo (2,3b) pyridyl, quinolyl, indolyl, isoquinolyl.

"Heterocyclyl" means saturated mono- or bicyclic rings containing at least one heteroatom selected from N, O, S, and each of said rings has 5 to 8 atoms in which the point of attachment may be carbon or nitrogen. The term also includes a monocyclic heterocycle fused to an aryl group or to a heteroaryl group in which the point of attachment is in the non-aromatic portion. In addition, the term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- and 4-pyridones attached by means of nitrogen. Other examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, imidazolinyl, 2,3-dihydrofuro (2,3-b) pyridyl, benzoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindonyl.

The term "cycloalkyl-alkyl", as used herein, refers to a "cycloalkyl," as defined above, attached to the original molecular moiety through an alkyl group, as defined above. The size of the cycloalkyl and alkyl can be further specified by adding the number of carbons behind the group, eg cycloalkyl (C3-C7) alkyl (C1-C6), cycloalkyl (C3C5) alkyl (C1-C2). Representative examples of cycloalkyl-alkyl include, but are not limited to, cyclohexylmethyl, 1-cyclohexylethyl, 2-cyclopentylethyl.

The term "aryl-alkyl," as used herein, refers to "aryl," as defined above, attached to the original molecular moiety through a (C1-C6) alkyl group, as described. defined above. The size of the aryl or alkyl can be further specified by adding the number of carbons behind the group, eg aryl-(C1-C6) alkyl, aryl (C6-C12) -alkyl (C1-C3). Representative examples of aryl-alkyl include, but are not limited to, 2-naphthylmethyl, 1- (2-indanyl) ethyl, 2- tetrahydronaphthylethyl.

The term "heteroaryl-alkyl," as used herein, refers to a "heteroaryl," as defined above, attached to the originating molecular moiety through an alkyl group, as defined above. The size of the alkyl can be further specified by adding the number of carbons behind the group, eg heteroaryl (C1-C6) alkyl, heteroaryl (C1-C2) alkyl. Representative examples of heteroaryl-alkyl include, but are not limited to 2- (2-pyridyl) propyl, 2-benzothiophenylmethyl, 4- (2-quinolyl) butyl.

The term "Cy-alkyl", as used herein, refers to a "Cy", as defined above, attached to the original molecular moiety through an alkyl group, as defined above. The size of the alkyl can be further specified by adding the number of carbons behind the group, eg Cy-alkyl (C1-C6), Cy-alkyl (C1-C3). Representative examples of Cy-alkyl include, but are not limited to, benzyl, 1- (2-naphthyl) ethyl, 2-cyclohexylethyl.

The term "halogen", as used herein, refers to chlorine, bromine, fluorine or iodine.

The compounds of formula I, as well as the pharmaceutically acceptable salts and esters thereof, are referred to below as the compounds of the invention, unless otherwise indicated.

The invention includes within its scope all possible stereoisomers of the compounds, which include geometric isomers, eg Z and E isomers (cis and trans isomers), and optical isomers, eg diastereomers and enantiomers. In addition, the invention includes within its scope both individual isomers and mixtures thereof, eg racemic mixtures. The individual isomers can be obtained by using the corresponding isomeric forms of the starting material, or they can be separated after the preparation of the final compound according to conventional separation methods. For the separation of optical isomers, eg enantiomers, conventional resolution methods, eg fractional crystallization, can be used from mixing.

Some of the compounds of the invention may also exist in the form of tautomers, specifically having different binding points for hydrogen. For example, ketones may also exist in their enol form (keto-enol tautomerie). Individual tautomers, as well as mixtures thereof, are included in the compounds of the invention.

Pharmaceutically acceptable salts, eg acid addition salts with both organic and inorganic acids are well known in the field of pharmaceuticals. Non-limiting examples of these salts include chlorides, bromides, sulfates, nitrates, phosphates, sulphonates, formates, tartrates, maleates, citrates, benzoates, salicylates and ascorbates. Pharmaceutically acceptable esters, when applicable, can be prepared by known methods using pharmaceutically acceptable acids that are conventional in the field of pharmaceuticals and that retain the pharmacological properties of the free form. Non-limiting examples of these esters include esters of aliphatic or aromatic alcohols, eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl esters.

The pharmaceutical compositions of the compounds of the invention can be formulated in a conventional manner by the use of one or more pharmaceutically acceptable carriers or excipients. The formulations may allow, for example, oral, oral, topical, intranasal, parenteral (eg intravenous, intramuscular or subcutaneous) or rectal administration, or administration by inhalation or insufflation. The compounds of the invention can also be formulated for sustained administration.

For oral administration, suitable composition forms include, but are not limited to, tablets, chewable tablets and capsules. These can be prepared by conventional means with pharmaceutically acceptable excipients, such as binding agents (eg pregelatinized corn starch), disintegrants (eg potato starch), fillers (eg lactose) or lubricants (p .exe. magnesium stearate). The tablets may be coated by methods well known in the art. For oral administration, possible liquid preparations include, but are not limited to, solutions, syrups or suspensions, or they may exist in the form of a dry powder for reconstitution with water or other suitable vehicle before use. These liquid preparations can be prepared by conventional means with pharmaceutically acceptable agents, such as suspending agents, non-aqueous vehicles, preservatives and emulsifiers.

A possible dose of the active compounds of the invention for oral, parenteral, oral or topical dosing to a human adult is between 0.1 and 500 mg of the active compound per unit dose, which can be administered, for example, 1 to 4 go

Ces a day.

It is well known that those skilled in the art can determine the exact dose, the route of administration and the dosage range. It is also well known that these variables depend on multiple factors, which include, but are not limited to, the activity

The therapeutic compound, its formulation, the pharmacokinetic properties (such as absorption, distribution, metabolism and excretion) of the therapeutic compound, the nature and location of the selected target tissue or organ and the problems related to the state of a disease or disorder in a patient who needs treatment. In addition, when the compounds of

The invention is administered with additional pharmaceutically active ingredients, one or more pharmaceutical compositions can be used for the administration of all agents, which can be administered together, or at different times, as determined by those skilled in the art. The compounds of the present invention can be considered to consist of

20 three different motifs: an "aromatic part", a "carboxylic acid" and a part of "sulfonylamino". Thus, the compounds of the invention are named as amides in which the "carboxylic acid" forms the original structure that is amidated by the "aromatic part" and further substituted by the "sulfonylamino" and an additional basic function. The nomenclature is exemplified with the following structures:

image 1

N - ((S) -1-carbamoyl-2-phenylethyl) -5-guanidino- (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) pentanamide

image2

N-benzyl-4- (N'-isopropyl) amino- (S) -2- (N "- (4-methyl-1-naphthalenesulfonyl) -amino) butanamide.

A preferred embodiment of the compounds of formula I are those in which Q is

image 1

and R5 is -C (O) NH2. For this purpose, R4 is preferably Cy or Cy (C1-C3) alkyl in which Cy is optionally substituted with one to three substituents selected from Rd; even more preferably, Cy is phenyl. Preferred substituents are selected from halogen, (C1-C3) alkyl and -O-(C1-C3) alkyl.

Another preferred embodiment of the compounds of formula I are those in which Q is

image 1

and R5 is -C (O) NH2. For this embodiment, R4 is preferably benzyl, in which the benzyl carbon is substituted with an additional phenyl.

Another preferred embodiment of the compounds of formula I are those in which Q is

image 1

and R5 is hydrogen or (C1-C3) alkyl and R4 is phenyl or benzyl, optionally substituted at positions 2 or 3 with one to two substituents selected from Rd. The most preferred substituents are selected from halogen and (C1-C3) alkyl .

Another preferred embodiment of the compounds of formula I are those in which R1 is hydrogen or (C1-C3) alkyl, and more preferably hydrogen.

Still another preferred embodiment of the compounds of formula I are those in which R2 is hydrogen, (C1-C3) alkyl, cycloalkyl (C3-C5) or -C (= NH) NH2.

Still another preferred embodiment of the compounds of formula I are those in which R3 is hydrogen or (C1-C6) alkyl. Still another preferred embodiment of the compounds of formula I are those in which A is hydrogen. Yet another preferred embodiment of the compounds of formula I are those in which B is hydrogen.

Still another preferred embodiment of the compounds of formula I are those in which D is aryl, which is optionally substituted with one to three substituents selected from Rd. In a more preferred embodiment, D is naphthyl, which is optional

It is substituted with one to two groups selected from Rd, and the preferred substitutions are selected from halogen, (C1-C6) alkyl, -NRbRb and -ORb. Even more preferred substitutions are halogen and (C1-C3) alkyl.

Still another preferred embodiment of the compounds of formula I are those in which n is an integer 1 or 2. 15 Yet another preferred embodiment of the compounds of formula I are those in which k is 0.

Still another preferred embodiment of the compounds of formula I are those in which the absolute configuration of the carbon containing the substitution of group A is S.

In another aspect, the invention provides novel compounds of formula II,

image 1

and pharmaceutically acceptable salts and esters thereof, wherein R1, R3, A, B and Q are as defined above for formula I, and each R2 is independently selected from

1) H, 2) (C1-C6) alkyl, 3) (C2-C6) alkenyl, 4) (C2-C6) alkynyl,

5) cycloalkyl (C3-C7) or 6) cycloalkyl (C3-C7) alkyl (C1-C6);

or the symbols R2 together with the nitrogen to which they are attached form a saturated 5- to 7-membered ring containing 1 to 2 heteroatoms selected from N, O and S;

and when Q is a group of formula

image 1

then R4 is as defined above for formula I;

R5 is 1 HOUR, 2) (C1-C6) alkyl, 3) alkenyl (C2-C6), 4) (C2-C6) alkynyl, 5) aryl, 6) aryl (C1-C6) alkyl, 7) heteroaryl or 8) heteroaryl (C1-C6) alkyl;

wherein the aryl and heteroaryl are each optionally substituted with one to four substituents selected from Rd; or R4 and R5, together with the atom to which they are attached, form a 3- to 8-membered ring containing 0 to 2 heteroatoms selected from N, O and S, in which said ring may be substituted with one to three selected substituents of Rd; or said ring may be fused to the aryl or heteroaryl which may be substituted with one to three substituents selected from Rd; R6 is independently selected from

1 HOUR, 2) halogen, 3) -NO2, 4) -NRbRb, 5) -CN, 6) -ORb,

7) -SRb, 8) -C (O) Rb, 9) (C1-C6) alkyl, 10) alkenyl (C2-C6), 11) (C2-C6) alkynyl, 12) cycloalkyl (C3-C7) or 13) -CF3;

t is an integer from 0 to 3; n is an integer from 1 to 2; X is a bond or C (R6); L is C (R6), S or N; whereby the combination of L and X is chosen in such a way that the aromatic nature of the bicyclic ring system to which L and X belong is maintained; Y Rb and Rd are as defined above for formula I. In a more preferred embodiment of Formula II, Q is

image 1

R1 is H; R2 is independently H or (C1-C6) alkyl; R3 is H or (C1-C3) alkyl; R4 is phenyl or benzyl optionally substituted with a group selected from Ra as defined above for formula I; R6 is independently selected from H, halogen, (C1-C6) alkyl or -CF3; t is an integer from 0 to 1; A is H; B is H; L is C (R6), X is C (R6); and R5 and n are as defined above for formula II.

Still another preferred embodiment of the compounds of formula II are those in which the carbon containing group A has the absolute S configuration.

Experimental Part

List of abbreviations: The compounds of the invention can be prepared by using the following general synthesis schemes.

ACN

acetonitrile

Boc

tert-butyloxycarbonyl

BSA

bovine serum albumin

- 19

2-Cl-Z

2-chloro-benzyloxycarbonyl

DBU

1,8-diazabicyclo [5.4.0] undec-7-eno

DCM

dichloromethane

DEC

diisopropylcarbodiimide

DIPEA

N, N-diisopropylethylamine

DMF

N, N-dimethylformamide

EDTA

ethylenediamine tetraacetic acid

ESI

electrospray ionization

Fmoc

9-fluorenylmethoxycarbonyl

HEPES

N- (2-hydroxyethyl) piperazin-N'-2-ethanesulfonic acid

HOBt

1-hydroxybenzotriazole

HPLC

high performance liquid chromatography

LC

liquid chromatography

MS

mass spectrometry

Pbf

2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl

PG

protective group

Pmc

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

RP-HPLC

reverse phase high performance liquid chromatography

TORCH

triethylamine

TFA

trifluoroacetic acid

THF

tetrahydrofuran

FTA

Thin layer chromatography

TMOF

trimethyl orthoformate

TMS

tetramethylsilane

TRIS

tris (hydroxymethyl) aminomethane

Scheme 1. Dissolution phase synthesis scheme for the compounds of the invention Scheme 2. Solid phase synthesis scheme for the compounds of the invention

image3

image4

5

It is clear to one skilled in the art that these general schemes can be modified further, for example using different protecting groups (eg those described in TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 2nd ed. Wiley, 1991, New York, USA), or adding or removing stages

10 in the middle or after the steps described, which allows additional modifications of the synthesis.

Departure Materials

Rink resin was obtained from Advanced ChemTech, R.U. Amino acids were purchased from Advanced ChemTech, R.U. or Novabiochem, Switzerland, unless otherwise specified. DIC, HOBt, acetic anhydride and piperidine were products of Acros Organics, Belgium. DIPEA was from Fluka AG, Germany. All other reagents or solvents were purchased from Aldrich or Merck, Germany, if not otherwise specified. The reagents were used as such, and the solvents were purified and dried according to the methods described in W.L.F. Armareggo and D.D. Perrin, "Purification of Laboratory Chemicals", 4th ed. Butterworth-Heinemann, 1996, Bath, Great Britain.

Overview of MS analyzes

The molecular weight of the compound was determined with a Micromass Micro triple quadrupole mass spectrometer. The essential parameters of MS were: cone voltage 30 V, capillary voltage 3.5 kV, low mass resolution in MS1 15, high mass resolution in MS1 15, ion energy in MS1 1.0, source temperature 110 ° C, desolvation temperature 250 ° C and desolvation gas flow 700 l / h. Samples were introduced using a Waters Alliance HPLC 2695. The flow rate of 0.3 ml / min was formed by an eluent of 10% water and 90% MeOH (containing 0.01% HCOOH). A sample volume of 10 μl was injected by means of a 2.1 x 10 mm Waters Symmetry Shield C18 pre-column.

Overview of the LC-MS analysis

For the LC-MS analysis, the gradient started from 100% water (containing 0.01% HCOOH) (A), which changed linearly in ten minutes to 100% ACN (containing 0.01% HCOOH) (B). In addition, a 2.1 x 50 mm C18 Waters Symmetry Shield column was purged with the corresponding pre-column for two minutes with B. The flow rate was 0.4 ml / min and 10 µl of sample was injected. Certain essential DM parameters were increased compared to the standard MS analysis: desolvation temperature at 350 ° C and desolvation gas flow rate at 900 l / h. The UV chromatogram was recorded with a Waters 996 diode network detector.

Overview of the NMR analysis

NMR spectra were recorded on a Bruker DMX 500 spectrometer that operated at 500.13 MHz for 1H. CD3OD was used as solvent and TMS as internal standard.

Overview of purification by flash chromatography

Purification by flash chromatography was carried out with an Argonaut FlashMaster II automated purification system (Argonaut Technologies, R.U.) using normal phase columns (Supelco DSC-Si 20 g). The flow rate was 7 ml / min, and the detection wavelength was 230 nm. The standard elution program was 25 minutes, with the following gradient: 100% DCM for 3 minutes, followed by a gradual increase up to 25% MeOH for 17 minutes and a gradual increase up to 100% MeOH during the last 5 minutes. After verification by MS, the fractions containing the product were combined and evaporated.

Overview of purification using RP-HPLC

Purifications were carried out by semi-preparative RP-HPLC with a Waters 616 pump, controlled by a Waters 600 control unit. The instrument was equipped with a Waters 2487 UV detector and a Waters fraction collector. A 10 X 150 mm Xterra Prep C18 RP column with a 7.8 X 20 mm pre-column was used for purifications. The flow rate was 6.6 ml / min, and the wavelength was 254 nm. The gradient started with water (containing 0.3% HCOOH) (A) that changed linearly to ACN (containing 0.3% HCOOH) (B) in ten minutes. In addition, the column was purged with B for two minutes. The fraction collector was programmed to collect fractions of 30 s. The fractions were analyzed by MS.

Overview of purity analysis using LC

The purity of the compounds was determined by HPLC with the use of a Waters 616 pump, controlled by a Waters 600 control unit. The instrument was also equipped with a Waters 2487 UV detector (detection wavelengths of 254 nm and 220 nm ). A 2.1 x 50 mm C18 Waters Symmetry Shield column with the corresponding pre-column and a flow rate of 0.4 ml / min was used. A linear gradient that started with water (containing 0.01% HCOOH) (A) to acetonitrile (containing 0.01% HCOOH) (B) was applied for 17 minutes and then 100% B during 1 minute.

Example 1 Synthesis of 5-amino-N- (3-chlorobenzyl) - (S) -2- (N '- (1-naphthalenesulfonyl) amino) pentanamide

Stage I

Fmoc-Om (Boc) -OH (70.0 mg, 454.52 g / mol, 0.15 mmol, 1 eq), DIC (24.1 μl, 126.20 g / mol, 0.806 g /) was dissolved cm3, 0.15 mmol, 1 eq) and HOBt (20.8 mg, 135.12 g / mol, 0.15 mmol, 1 eq) in dry DMF / DCM (1/1, 5 ml). After 5 minutes 3-chlorobenzylamine (18.8 μl, 141.60 g / mol, 1.159 g / cm 3, 0.15 mmol, 1 eq, Acros) was added to the reaction mixture. According to the TLC analysis, the reaction was completed after stirring overnight. The solvent was then evaporated and the yellow residue was purified by flash chromatography. 5- (N-Boc-amino) -N '- (3-chlorobenzyl) - (S) -2 (N "-Fmoc-amino) pentanamide was obtained in the form of a white foam with a quantitative yield.

Stage II

Fmoc protection was removed by dissolving 5- (N-Boc-amino) -N '- (3-chlorobenzyl) - (S) -2- (N "-Fmoc-amino) pentanamide in 5 ml of 20% vol piperidine vol in DMF After stirring for 30 minutes, the solvent and excess piperidine were evaporated.The product was used without purification for step III.

Stage III

(S) -2-amino-5- (N-Boc-amino) -N '- (3-chlorobenzyl) pentanamide (0.15 mmol) was dissolved in DMF (2.5 ml, dry), and chloride was added of 1-naphthalenesulfonyl (45.4 mg, 226.68 g / mol, 0.2 mmol, 1.3 eq, Acros) in THF (2.5 ml, dry). TEA (27.8 μl, 101.19 g / mol, 0.73 g / cm 3, 0.2 mmol, 1.3 eq, Baker) was added to the solution. After 15 minutes, a certain precipitate was observed. After stirring overnight, the solvent was evaporated and the residue was purified by flash chromatography to provide 5- (N-Boc-amino) -N '- (3-chlorobenzyl) - (S) -2- (N "- (1-Naphthalenesulfonyl) amino) pentanamide.

Stage IV

5- (N-Boc-amino) -N '- (3-chlorobenzyl) - (S) -2- (N "- (1-naphthalenesulfonyl) amino) pentanamide was dissolved in 25% TFA in DCM (2 ml) and the mixture was stirred for 30 minutes Evaporation of the solvent gave 75.8 mg of 5-amino-N- (3-chlorobenzyl) (S) -2- (N '- (1-naphthalenesulfonyl) amino) pentanamide as a Brown oil Part of the product was further purified by RP-HPLC to provide 11.5 mg of 5-amino-N- (3-chlorobenzyl) - (S) -2- (N '- (l-naphthalenesulfonyl) amino) - Pentanamide in the form of a white powder, total yield of 13% MS-ESI + (m / z): 446 1H NMR (500 MHz, CD3OD; �, ppm): 8.70 (m, 1H), 8.21 ( m, 1H), 8.13 (d, 1H), 8.01 (m, 1H), 7.66-7.60 (m, 2H), 7.53 (m, 1H), 7.24-7 , 17 (m, 2H), 7.02 (m, 1H), 6.84 (m, 1H), 3.87 (d, 2H), 3.80 (m, 1H), 2.82 (m, 2H), 1.76-1.57 (m, 4H).

Example 2 Synthesis of 5-amino- (S) -2- (N- (4-methyl-1-naphthalenesulfonyl) amino) -N '- (phenyl) pentanamide

Stage I

Fmoc-Orn (Boc) -OH (50.0 mg, 454.52 g / mol, 0.11 mmol, 1 eq), DIC (17.2 μl, 126.20 g / mol, 0.806 g /) was dissolved cm3, 0.11 mmol, 1 eq) and HOBt (15.0 mg, 135.12 g / mol, 0.12 mmol, 1 eq) in dry DMF / DCM (1/1, 4 ml). After 10 minutes, aniline (10.0 μl, 93.13 g / mol, 1.022 g / cm 3, 0.11 mmol, 1 eq, Acros) was added to the reaction mixture. After stirring overnight, the temperature rose to 40 ° C and remained there for 2 hours. The solvent was then evaporated and the residue was purified by flash chromatography. 5- (N-Boc-amino) - (S) -2- (N'-Fmocamino) -N "- (phenyl) pentanamide was obtained as a white powder with a quantitative yield.

Stage II

The Fmoc protection was removed by dissolving 5- (N-Boc-amino) - (S) -2- (N'-Fmocamino) -N "- (phenyl) pentanamide in 5 ml of 20% vol piperidine in DMF. Then After stirring for 45 minutes, the solvent and excess piperidine were evaporated.The product was used without purification for step III.

Stage III

(S) -2-amino-5- (N-Boc-amino) -N '- (phenyl) pentanamide (0.11 mmol) was dissolved in DMF (1 ml, dry), and 4-methyl chloride was added -1-naphthalenesulfonyl (26.5 mg, 240.71 g / mol, 0.11 mmol, 1 eq, Maybridge) in THF (1 ml, dry). Finally, TEA (15.3 μl, 101.19 g / mol, 0.73 g / cm 3, 0.11 mmol, 1 eq, Baker) was added to the solution. After 15 minutes, a certain amount of precipitate was observed. After stirring overnight, the solvent was evaporated and the residue was purified by flash chromatography to provide 5- (N-Boc-amino) - (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) -N "- (phenyl) pentanamide.

Stage IV

5- (N-Boc-amino) - (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) -N "(phenyl) pentanamide was dissolved in 30% TFA in DCM (3 ml) ) and the mixture was stirred for 45 minutes After evaporation of the solvent and flash chromatography, 21.8 mg of 5-amino- (S) -2- (N- (4-methyl-1-naphthalenesulfonyl) amino were obtained ) -N '- (phenyl) pentanamide; 48% yield. MS-ESI + (m / z): 412 1H NMR (500 MHz, CD3OD; �, ppm): 8.73 (m, 1H), 8.15 (d, 1H), 7.99 (m, 1H), 7.757.60 (m, 2H), 7.32 (m, 1H), 7.15-7.09 (m, 2H), 7.00 ( m, 1H), 6.80 (m, 2H), 3.79 (m, 1H), 2.92 (m, 2H), 2.50 (d, 3H), 1.90-1.60 (m , 4H).

Example 3 Synthesis of 5-amino- (S) -2- (N- (4-methyl-1-naphthalenesulfonyl) amino) -N '- ((R) -1- (2-naphthyl) ethyl) pentanamide

Stage I

Fmoc-Om (Boc) -OH (100.2 mg, 454.52 g / mol, 0.22 mmol, 1 eq), DIC (34.4 μl, 126.20 g / mol, 0.806 g /) was dissolved cm3, 0.22 mmol, 1 eq) and HOBt (29.7 mg, 135.12 g / mol, 0.22 mmol, 1 eq) in dry DMF / DCM (1/1, 4 ml). After 10 minutes (R) -1- (2-naphthyl) ethylamine (37.7 mg, 171.24 g / mol, 0.22 mmol, 1 eq, Acros) was added to the reaction mixture. After stirring overnight, the temperature rose to 40 ° C and remained there for 2 hours. The solvent was then evaporated and the residue was purified by flash chromatography. 5- (N-Boc-amino) - (S) -2- (N'-Fmocamino) -N "- ((R) -1- (2-naphthyl) ethyl) pentanamide was obtained in quantitative yield.

Stage II

Fmoc protection was removed by dissolving 5- (N-Boc-amino) - (S) -2- (N'-Fmocamino) -N "- ((R) -1- (2-naphthyl) ethyl) pentanamide in 5 ml of 20% vol piperidine in DMF After stirring for 45 minutes, the solvent and excess piperidine were evaporated The product was used without purification for step III.

Stage III

(S) -2-amino-5- (N-Boc-amino) -N '- ((R) -1- (2-naphthyl) ethyl) pentanamide (0.22 mmol) was dissolved in DMF (1 ml, dry), and 4-methyl-1-naphthalenesulfonyl chloride (53.1 mg, 240.71 g / mol, 0.22 mmol, 1 eq, Maybridge) in THF (1 ml, dry) was added. Finally, TEA (30.5 μl, 101.19 g / mol, 0.73 g / cm 3, 0.22 mmol, 1 eq, Baker) was added to the solution. After 15 minutes, a certain amount of precipitate was observed. After stirring overnight, the solvent was evaporated and the residue was purified by flash chromatography to provide 5- (N-Boc-amino) - (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) -N "- ((R) -1- (2- naphthyl) ethyl) pentanamide.

Stage IV

5- (N-Boc-amino) - (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) -N "((R) -1- (2-naphthyl) ethyl) was dissolved) pentanamide in 30% TFA in DCM (3 ml), and the mixture was stirred for 45 minutes After evaporation of the solvent and flash chromatography, 11.4 mg of 5-amino- (S) -2- ( N- (4-methyl-1-naphthalenesulfonyl) amino) -N '- ((R) 1- (2-naphthyl) ethyl) pentanamide; 11% total yield. MS-ESI + (m / z): 490 1 H NMR (500 MHz, CD3OD; �, ppm): 8.68 (m, 1H), 8.05-7.94 (m, 2H), 7.84 (m, 1H), 7.77-7.68 ( m, 2H), 7.61 (m, 2H), 7.48 (m, 3H), 7.04 (m, 2H), 4.75 (m, 1H), 3.90 (m, 1H), 2.97-2.83 (m, 2H), 2.47 (s, 3H), 1.85-1.62 (m, 4H), 1.15 (d, 3H).

Example 4 Synthesis of 5-amino-N- (2- (3-chlorophenyl) ethyl) - (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) pentanamide

The compound was synthesized according to the procedure described in example 3, but (R) -1- (2-naphthyl) ethylamine was substituted by 2- (3-chlorophenyl) ethylamine (30.6 µl, 155.63 g / mol , 1,119 g / cm3, 0.22 mmol, 1 eq). Final deprotection of Boc and subsequent flash chromatography provided 73.3 mg of 5-amino-N- (2- (3-chlorophenyl) ethyl) - (S) -2- (N '- (4methyl-1-naphthalenesulfonyl) -amino) pentanamide; 68% yield

MS-ESI + (m / z): 474 1H NMR (500 MHz, CD3OD; �, ppm): 8.72 (m, 1H), 8.17 (m, 1H), 8.13 (d, 1H), 7.70 (m, 2H), 7.45 (m, 1H), 7.23-7.15 (m, 2H), 7.03 (m, 1H), 6.92 (m, 1H), 3.68 (m, 1H ), 2,932.75 (m, 4H), 2.74 (d, 3H), 2.28-2.15 (m, 2H), 1.75-1.52 (m, 4H).

Example 5 Synthesis of 5-amino-N- (1,2-diphenylethyl) - (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) pentanamide

The compound was synthesized according to the procedure described in example 3, but (R) -1- (2-naphthyl) ethylamine was substituted by 1,2-diphenylethylamine (42.6 µl, 197.28 g / mol, 1.020 g / cm3, 0.22 mmol, 1 eq). Stage I provided 118.1 mg of 5- (N-Boc-amino) N '- (1,2-diphenylethyl) - (S) 2- (N "-Fmoc-amino) pentanamide; 85% yield. the final deprotection of Boc and subsequent flash chromatography, 27.1 mg of 5-amino-N- (1,2-diphenylethyl) - (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) were obtained ) amino) pentanamide; 28% yield. MS-ESI + (m / z): 516 1H NMR (500 MHz, CD3OD; �, ppm): 8.75 (m, 1H), 8.67 (m, 1H) , 8.21-8.08 (m, 3H), 7.97 (d, 1H), 7.77-7.61 (m, 4H), 7.47 (m, 2H), 7.25-7 , 05 (m, 12H), 7.00-6.76 (m, 8H), 4.54 (m, 2H), 3.81 (m, 2H), 2.87-2.69 (m, 8H ), 2.64 (d, 3H), 2.58 (m, 1H), 2.44 (m, 1H), 2.31 (m, 1H), 1.75-1.31 (m, 8H) .

Example 6 Synthesis of 5-amino-N-2-ethoxybenzyl- (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) pentanamide

The compound was synthesized according to the procedure described in Example 3, but (R) -1- (2-naphthyl) ethylamine was replaced by 2-ethoxy-benzylamine (34.1 μl, 151.21 g / mol, 1.015 g / cm3, 0.23 mmol, 1 eq). Stage I provided 5- (N-Boc-amino) -N'-2-ethoxybenzyl- (S) -2- (N "-Fmoc-amino) pentanamide with quantitative yield. After the final de-protection of Boc and Purification by subsequent preparative TLC, 24 mg of 5-amino-N-2-ethoxybenzyl- (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) pentanamide were obtained; yield 23%. MS-ESI + (m / z): 470 1H NMR (500 MHz, CD3OD; �, ppm): 8.71 (m, 1H), 8.17 (m, 1H), 8.11 (d, 1H), 7.67 (m, 2H), 7.40 (m, 1H), 7.17 (m, 1H), 6.84 (d, 1H), 6.80-6.73 (m, 2H), 3 , 98 (m, 2H), 3.89 (m, 2H), 3.80 (m, 1H), 2.85-2.72 (m, 5H), 1.70 (m, 2H), 1, 60 (m, 2H), 1.35 (t, 3H).

Example 7 Synthesis of 4-amino-N-cyclohexyl- (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) butanamide (Compound 1)

The compound was synthesized according to the procedure described in Example 3, but in step I (R) -1- (2-naphthyl) ethylamine was replaced by cyclohexylamine (26 µl, 99.18 g / mol, 0.867 g / cm3 , 0.23 mmol, 1 eq) and Fmoc-Orn (Boc) -OH by Fmoc-Dbu (Boc) -OH (100.6 mg, 440.5 g / mol, 0.23 mmol, 1 eq). Stage I provided 4- (N-Boc-amino) -N'cyclohexyl- (S) -2- (N "-Fmoc-amino) butanamide in quantitative yield. After final deprotection of Boc and purification by preparative TLC Subsequently, 34 mg of 4-amino-N-cyclohexyl- (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) butanamide were obtained; 37% total yield. MS-ESI + (m / z): 404 1H NMR (500 MHz, CD3OD; �, ppm): 8.71 (m, 1H), 8.20 (m, 1H), 8.14 (d, 1H), 7.72 (m, 2H), 7.46 (m, 1H), 3.81 (m, 1H), 3.04 (m, 2H), 2.94 (m, 1H), 2.77 (d, 3H), 1, 99 (m, 1H), 1.86 (m, 1H), 1.49 (m, 3H), 1.37 (m, 1H), 1.17-0.94 (m, 4H), 0.58 (m, 1H), 0.45 (m, 1H).

Example 8 Synthesis of 4-amino- (S) -2-N- (4-methyl-1-naphthalenesulfonyl) amino-N '- (1-naphthylmethyl) butanamide

Stage I

Fmoc-Dbu (Boc) -OH (100 mg, 440.5 g / mol, 0.23 mmol, 1 eq), DIC (36 μl, 126.20 g / mol, 0.806 g / cm 3, 0, was dissolved. 23 mmol, 1 eq) and HOBt (31 mg, 135.12 g / mol, 0.23 mmol, 1 eq) in dry DMF / DCM (1/1, 3 ml). After 5 minutes 1-naphthylmethylamine (33 μl, 157.22 g / mol, 1.092 g / cm 3, 0.23 mmol, 1 eq, Fluka) was added to the reaction mixture. After stirring overnight at 50 ° C, the solvent was evaporated and the residue was dissolved in 30 ml of ethyl acetate and washed three times with 20 ml of water. The organic phase was dried with Na2SO4 and evaporated. The residue was purified by flash chromatography. 78.5 mg of 4-N-Boc-amino- (S) -2-N'-Fmocamino-N "-1-naphthylmethylbutanamide were obtained, yield 60%.

Stage II

4-N-Boc-amino- (S) -2-N'-Fmoc-amino-N "-1-naphthylmethylbutanamide was dissolved in 8 ml of 20% vol piperidine in DMF. After stirring for 45 minutes, it was evaporated the solvent and the excess of piperidine The residue was used without purification for stage III.

Stage III

(S) -2-amino-4-N-Boc-amino-N '- (1-naphthylmethyl) butanamide (50.0 mg, 357.46 g / mol, 0.14 mmol, 1 eq) was dissolved in THF (4 ml, dry), and 4-methyl-1-naphthalenesulfonyl chloride (49 mg, 240.71 g / mol, 0.20 mmol, 1.5 eq, Maybridge) in THF (4 ml, dry) was added. TEA (28 μl, 101.19 g / mol, 0.73 g / cm 3, 1.5 eq, Baker) was then added to the solution. After 15 minutes, a certain amount of precipitate was observed. After stirring overnight, the solvent was evaporated and the residue was purified by flash chromatography.

Stage IV

4-N-Boc-amino- (S) -2-N '- (4-methyl-1-naphthalenesulfonyl) amino-N "- (1naphthylmethyl) butanamide was dissolved in 25% TFA in DCM (5 ml) and the The mixture was stirred for 30 minutes. Evaporation of the solvent and subsequent purification by RP-HPLC provided 26 mg of 4-amino- (S) -2-N- (4-methyl-1-naphthalenesulfonyl) amino-N "- ( 1-Naphthylmethyl) butanamide in the form of a white solid, yield 42%. MS-ESI + (m / z): 462 1H NMR (500 MHz, CD3OD; �, ppm): 8.67 (m, 1H), 8.13 (m, 1H), 8.08 (d, 1H), 7.86 (d, 1H), 7.78 (d, 1H), 7.72 (d, 1H), 7.63 (m, 2H), 7.48 (m, 1H), 7.42 (m , 1H), 7.32 (m, 2H), 7.06 (d, 1H), 4.44 (d, 1H), 4.27 (d, 1H), 3.90 (m, 1H), 2 , 97 (m, 1H), 2.87 (m, 1H), 2.73 (s, 3H), 2.01 (m, 1H), 1.89 (m, 1H).

Example 9 Synthesis of 4-amino-N-2- (3-chlorophenyl) ethyl- (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) butanamide

Stage I

Fmoc-Dbu (Boc) -OH (250.8 mg, 440.5 g / mol, 0.57 mmol, 1 eq), DIC (89 μl, 126.20 g / mol, 0.806 g / cm 3, was dissolved, 0.57 mmol, 1 eq) and HOBt (77.6 mg, 135.12 g / mol, 0.57 mmol, 1 eq) in dry DMF / DCM (1/1, 6 ml). After 5 minutes, 2 (3-chlorophenyl) ethylamine (79 μl, 155.63 g / mol, 1,119 g / cm 3, 0.57 mmol, 1 eq) was added to the reaction mixture. The temperature was raised to 35 ° C and the mixture was stirred overnight. The solvent was then evaporated and the residue was dissolved in DCM, which was washed twice with water and once with brine. The organic phase was subsequently dried with Na2SO4 and evaporated. The residue was purified by silica column chromatography (mobile phase starting from DCM to 5% MeOH in DCM). 4 (N-Boc-amino) -N'-2- (3-chlorophenyl) ethyl- (S) 2- (N "-Fmoc-amino) butanamide was obtained in quantitative yield.

Stage II

Fmoc protection was removed by dissolving 4- (N-Boc-amino) -N'-2- (3-chlorophenyl) ethyl- (S) -2- (N "-Fmoc-amino) butanamide in 5 ml of piperidine at 20% vol in DMF After stirring for 30 minutes, the solvent and excess piperidine were evaporated.The product was used without purification for step III.

Stage III

(S) -2-amino-4- (N-Boc-amino) -N '- (2- (3-chlorophenyl) ethyl) butanamide (0.57 mmol) was dissolved in DMF (3 ml, dry), and 4-methyl-1-naphthalenesulfonyl chloride (206 mg, 240.71 g / mol, 0.86 mmol, 1.5 eq, Maybridge) in THF (3 mL, dry) was added. Finally, TEA (119 μl, 101.19 g / mol, 0.73 g / cm 3, 0.86 mmol, 1.5 eq, Baker) was added to the solution. After 15 minutes, a certain amount of precipitate was observed. After stirring overnight, the solvent was evaporated and the residue was purified by silica column chromatography (5% MeOH mobile phase in DCM) to provide 220 mg of 4- (N-Boc-amino) -N ' - (2- (3-chlorophenyl) ethyl) - (S) -2- (N "- (4-methyl-1-naphthalenesulfonyl) amino) butanamide, yield 67%.

Stage IV

4- (N-Boc-amino) -N '- (2- (3-chlorophenyl) ethyl) - (S) -2- (N "- (4-methyl-1-naphthalenesulfonyl) amino) butanamide (220 mg, 560.11 g / mol, 0.39 mmol) in 25% TFA in DCM (10 ml) and the mixture was stirred for 45 minutes, after evaporation of the solvent and silica column chromatography (mobile phase from DCM to 10% MeOH in DCM) 163 mg of 4-amino-N-2- (3-chlorophenyl) ethyl- (S) -2 (N '- (4-methyl-1-naphthalenesulfonyl) amino) butanamide were obtained ; 91% yield. MS-ESI + (m / z): 460 1H NMR (500 MHz, CD3OD; �, ppm): 8.72 (m, 1H), 8.18 (m, 1H), 8.14 (d, 1H), 7,767.67 (m, 2H), 7.46 (m, 1H), 7.22-7.15 (m, 2H), 7.03 (t, 1H), 6.91 ( m, 1H), 3.76 (m, 1H), 2.99-2.84 (m, 3H), 2.83-2.73 (m, 4H), 2.22 (m, 2H), 1 , 89 (m, 1H), 1.79 (m, 1H).

Example 10 Synthesis of 5-amino-N-benzyl- (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) pentanamide

Stage I

Fmoc-Om (Boc) -OH (250.9 mg, 454.5 g / mol, 0.55 mmol, 1 eq), DIC (86 μl, 126.20 g / mol, 0.806 g / cm 3, was dissolved, 0.55 mmol, 1 eq) and HOBt (74.2 mg, 135.12 g / mol, 0.55 mmol, 1 eq) in dry DMF / DCM (1/1, 6 ml). After 5 minutes, benzylamine (60 μl, 107.16 g / mol, 0.981 g / cm 3, 0.55 mmol, 1 eq) was added to the reaction mixture. The temperature was raised to 35 ° C and the mixture was stirred overnight. The solvent was then evaporated and the residue was dissolved in DCM, which was washed twice with water and once with brine. The organic phase was subsequently dried (Na2SO4) and evaporated. The residue was purified by silica column chromatography (mobile phase from DCM to 10% MeOH in DCM). N-benzyl-5-N'-Boc-amino (S) 2- (N "-Fmoc-amino) pentanamide was obtained in quantitative yield.

Stage II

Fmoc protection was removed by dissolving the N-benzyl-5-N'-Boc-amino- (S) -2 (N "-Fmoc-amino) pentanamide in 5 ml of 20% vol piperidine in DMF. After stirring for 1.5 hours, the solvent and excess piperidine were evaporated.The product was used without purification for stage III.

Stage III

(S) -2-amino-N-benzyl-5- (N'-Boc-amino) pentanamide (0.55 mmol) was dissolved in DMF (2.5 ml, dry), and 4-methyl chloride was added -1-naphthalenesulfonyl (200 mg, 240.71 g / mol, 0.83 mmol, 1.5 eq, Maybridge) in THF (2.5 ml, dry). Finally, TEA (115 μl, 101.19 g / mol, 0.73 g / cm 3, 0.83 mmol, 1.5 eq, Baker) was added to the solution. After 15 minutes, a certain amount of precipitate was observed. After stirring overnight, the solvent was evaporated and the residue was purified by silica column chromatography (10% MeOH mobile phase in DCM) to provide N-benzyl-5- (N'-Boc-amino) - (S) -2- (N "- (4-methyl-1-naphthalenesulfonyl) amino) pentanamide in quantitative yield.

Stage IV

N-benzyl-5- (N'-Boc-amino) - (S) -2- (N "- (4-methyl-1-naphthalenesulfonyl) amino) pentanamide (289 mg, 525.67 g / mol, 0.55 mmol) in 25% TFA in DCM (10 ml) and the mixture was stirred for 1 hour After evaporation of the solvent and purification by RP-HPLC, 96.6 mg of 5-amino-N was obtained. -benzyl- (S) -2- (N '(4-methyl-1-naphthalenesulfonyl) amino) pentanamide; 41% yield. MS-ESI + (m / z): 426 1 H NMR (500 MHz, CD3OD; �, ppm): 8.81 (m, 1H), 8.27 (m, 1H), 8.19 (d, 1H), 7.77 (m, 2H), 7.49 (d, 1H), 7, 28 (m, 3H), 6.99 (m, 2H), 3.94 (d, 2H), 3.87 (m, 1H), 2.91 (m, 2H), 2.85 (s, 3H ), 1.80 (m, 2H), 1.71 (m, 2H).

Example 11 Synthesis of 4-amino-N- (S) -1-carbamoyl-2-phenylethyl- (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) butanamide (Compound 2)

Stage I

H-Phe-NH2 hydrochloride (114.2 mg, 200.7 g / mol, 0.57 mmol, 1 eq, Advanced ChemTech) was dissolved in 2 ml of dry DMF / DCM (1/1), and added TEA (95 μl, 101.19 g / mol, 0.73 g / cm 3, 0.68 mmol, 1.2 eq). After 30 minutes, a DMF / DCM solution (1/1, 4 ml) containing Fmoc-Dbu (Boc) -OH (250.2 mg, 440.5 g / mol, 0.57 mmol, 1 was added eq), DIC (89 μl, 126.20 g / mol, 0.805 g / cm3, 0.57 mmol, 1 eq) and HOBt (77.6 mg, 135.12 g / mol, 0.57 mmol, 1eq ). After stirring overnight, the solvent was evaporated and DCM (30 ml) was added. The organic phase was washed three times with water (10 ml) and once with brine (10 ml). Part of the product precipitated from the aqueous phase and after filtration it was combined with the evaporated organic phase. 333 mg of 4- (N-Boc-amino) -N '- ((S) -1-carbamoyl-2-phenylethyl) - (S) -2- (N "-Fmocamino) butanamide were obtained as a powder. white with quantitative performance.

Stage II

Fmoc protection was removed by treating 4- (N-Boc-amino) -N '- ((S) -1-carbamoyl2-phenylethyl) - (S) -2- (N "-Fmoc-amino) butanamide with 4, 5 ml of 20% vol piperidine in DMF for 45 minutes The solvent was then evaporated to provide (S) -2-amino-4- (N-Boc-amino) -N '- ((S) -1-carbamoyl-2 -phenylethyl) butanamide in the form of a white solid.

Stage III

The residue from step II was dissolved in 9 ml of a dry THF / DMF solution (1/1), and 4-methyl-1-naphthalenesulfonyl chloride (205.3 mg, 240.71 g / mol, was added, 0.85 mmol, 1.5 eq, Maybridge) and finally ASD (120 μl, 101.19 g / mol, 0.73 g / cm 3, 0.85 mmol, 1.5 eq, Baker). After the reaction overnight, the solvent was evaporated and the residue was purified by silica column chromatography (mobile phase from 5% MeOH in DCM to 20% MeOH in DCM). 238 mg of 4- (N-Boc-amino) -N '- ((S) -1-carbamoyl-2-phenylethyl) - (S) -2- (N "- (4-methyl-1-naphthalenesulfonyl) were obtained ) amino) butanamide in the form of a white powder; 75% yield.

Stage IV

Boc protection was removed by dissolving the product of step III in 2.5 ml of 25% vol TFA in DCM and stirring for 1 h. The solvent was then evaporated and the residue was purified by RP-HPLC to provide 52.5 mg of 4-amino-N- (S) -1carbamoyl-2-phenylethyl- (S) -2- (N '- (4- methyl-1-naphthalenesulfonyl) amino) -butanamide; 26.8% yield. MS-ESI + (m / z): 469 1H NMR (500 MHz, CD3OD; �, ppm): 8.69 (m, 1H), 8.16 (m, 1H), 8.07 (m, 1H), 7.69 (m, 2H), 7.39 (d, 1H), 7.25-7.16 (m, 3H), 7.06 (m, 2H), 4.21 (t, 1H), 3 , 84 (m, 1H), 2,842.69 (m, 6H), 2.49 (m, 1H), 1.94-1.74 (m, 2H).

Example 12 Synthesis of 4-amino-N-benzyl- (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) butanamide

Stage I

Fmoc-Dbu (Boc) -OH (1.00 g, 440.5 g / mol, 2.27 mmol, 1 eq), DIC (355 μl, 126.20 g / mol, 0.806 g / cm 3, was dissolved, 2.27 mmol, 1 eq) and HOBt (308.2 mg, 135.12 g / mol, 2.27 mmol, 1 eq) in dry DMF / DCM (1/1, 10 ml). After 5 minutes, benzylamine (248 μl, 107.16 g / mol, 2.27 mmol, 1 eq, Acros) was added to the reaction mixture and the temperature was raised to 35 ° C. After stirring overnight, the solvent was evaporated and the residue was dissolved in DCM and washed twice with water and once with brine. The organic phase was dried with Na2SO4 and the solvent was evaporated. The residue was purified by silica column chromatography (mobile phase from DCM to 10% MeOH in DCM). N-benzyl-4- (N'-Boc-amino) - (S) -2- (N "-Fmocamino) butanamide was obtained in quantitative yield.

Stage II

The Fmoc protection was removed by dissolving the N-benzyl-4- (N'-Boc-amino) - (S) -2 (N "-Fmoc-amino) butanamide (1.12 g, 529.64 g / mol, 2 , 1 mmol, 1 eq) in 10 ml of 20% vol piperidine in DMF After stirring for 1.5 hours, the solvent and excess piperidine were evaporated.The product was used without purification for step III.

Stage III

(S) -2-Amino-N-benzyl-4- (N'-Boc-amino) butanamide (2.1 mmol) was dissolved in THF (7 mL, dry), and 4-methyl-1- chloride was added naphthalenesulfonyl (761 mg, 240.71 g / mol, 3.15 mmol, 1.5 eq, Maybridge). Finally, TEA (440 μl, 101.19 g / mol, 0.73 g / cm 3, 3.15 mmol, 1.5 eq, Baker) was added to the solution. After 15 minutes, a certain amount of precipitate was observed. After stirring overnight, the solvent was evaporated and the residue was purified by silica column chromatography (5% MeOH mobile phase in DCM) to provide 860 mg of N-benzyl-4 (N'-Boc-amino ) - (S) -2 - ((4-methyl-1-naphthalen) amino) butanamide; 80% yield.

Stage IV

N-benzyl-4- (N'-Boc-amino) - (S) -2 - ((4-methyl-1-naphthalen) amino) -butanamide (850 mg, 511.64 g / mol, 1, 66 mmol) in 25% TFA in DCM (10 ml) and the mixture was stirred for 1 hour. After evaporation of the solvent and silica column chromatography, 4-amino-N-benzyl- (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) butanamide was obtained in quantitative yield . MS-ESI + (m / z): 412 1H NMR (500 MHz, CD3OD; �, ppm): 8.69 (m, 1H), 8.16 (m, 1H), 8.10 (d, 1H), 7.66 (m, 2H), 7.39 (d, 1H), 7.17 (m, 3H), 6.88 (m, 2H), 3.88 (d, 2H), 3.84 (m , 1H), 2.91 (m, 1H), 2.82 (m, 1H), 2.74 (s, 3H), 1.96 (m, 1H), 1.83 (m, 1H).

Example 13 Synthesis of N-benzyl-4- (N ', N'-dicyclopropyl) amino- (S) -2- (N "- (4-methyl-1-naphthalenesulfonyl) amino) butanamide

Stage I

4-Amino-N-benzyl- (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) butanamide (45.9 mg, 411.52 g / mol, 0.11 mmol) was dissolved ) prepared in Example 12 in dry MeOH and acetic acid (32 μl, 60.05 g / mol, 1.05 g / cm 3, 0.55 mmol, 5 eq, Acros), and molecular sieves (3 Å) were added ). Finally, (1-ethoxycyclopropoxy) trimethylsilane (66 l, 173.42 g / mol, 0.867 g / cm3, 0.33 mmol, 3 eq, Acros) and sodium cyanoborohydride (18 mg, 62.84 g / mol, 0 , 28 mmol, 2.5 eq, Acros). The mixture was refluxed overnight, the molecular sieves were filtered and the filtrate was evaporated. The residue was dissolved in ethyl acetate and washed with saturated NaHCO3 and water. The organic phase was then dried with Na2SO4 and evaporated. The residue was purified by preparative TLC (10% MeOH in DCM as mobile phase) and 7 mg of N-benzyl-4- (N ', N'-dicyclopropyl) amino- (S) -2- (N " - (4-methyl-1-naphthalenesulfonyl) amino) butanamide; 13% yield. MS-ESI + (m / z): 492 1 H NMR (500 MHz, CD3OD; �, ppm): 8.75 (m, 1H) , 8.18 (m, 1H), 8.13 (d, 1H), 7.69 (m, 2H), 7.43 (m, 1H), 7.28-7.18 (m, 3H), 7.10 (m, 2H), 4.07 (d, 2H), 3.70 (m, 1H), 2.76 (d, 3H), 2.40 (m, 1H), 2.30 (m , 1H), 1.90 (m, 1H), 1.73 (m, 1H), 1.55 (m, 2H), 0.30-0.13 (m, 8H).

Example 14 Synthesis of N-benzyl-4- (N'-isopropyl) amino- (S) -2- (N "- (4-methyl-1-naphthalenesulfonyl) amino) butanamide (Compound 3)

4-amino-N-benzyl- (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) -butanamide (50.0 mg, 411.52 g / mol, 0.12 mmol) prepared in example 12 was dissolved in TMOF and acetone (8.8 µl, 58.08 g / mol, 0.79 g / cm3, 0.12 mmol, 1 eq, Prolabo), acetic acid (10, 3 l, 60.05 g / mol, 1.05 g / cm3, 0.18 mmol, 1.5 eq, Acros) and finally sodium triacetoxyborohydride (39 mg, 211.94 g / mol, 0.18 mmol, 1.5 eq, Acros). The mixture was stirred for 2 hours and another 0.5 eq of acetone was added. After stirring overnight, the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with water. After drying with Na2SO4, the organic phase was evaporated. The product was purified by preparative TLC (10% MeOH in DCM as mobile phase) and 18 mg of N-benzyl-4- (N'-isopropyl) amino- (S) -2- (N "- (4) -methyl-1-naphthalenesulfonyl) amino) butanamide, 33% yield MS-ESI + (m / z): 454 1H NMR (500 MHz, CD3OD; �, ppm): 8.72 (m, 1H), 8, 20 (m, 1H), 8.14 (d, 1H), 7.70 (m, 2H), 7.44 (m, 1H), 7.24-7.19 (m, 3H), 6.97 (m, 2H), 4.00 (m, 2H), 3.87 (m, 1H), 3.11 (m, 1H), 2.83 (m, 1H), 2.77 (s, 3H) , 2.73 (m, 1H), 1.98 (m, 1H), 1.85 (m, 1H), 1.16 (m, 6H).

Example 15 Synthesis of N-benzyl-4-guanidino- (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) butanamide (Compound 4)

Stage I

4-amino-N-benzyl- (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) -butanamide (123 mg, 451.59 g / mol, 0.27 mmol, 1 eq ) prepared in Example 12 was dissolved in 4 ml of dry DCM under argon, and TEA (190 μl, 101.19 g / mol, 0.73 g / cm 3, 0.82 mmol, 3 eq, Baker) was added to dissolution. N, N'-Bis (tert-butoxycarbonyl) -N "-triflylguanidine (273 mg, 391.4 g / mol, 0.41 mmol, 1.5 eq) was dissolved in DCM (1 ml) and added dropwise to drop to the reaction mixture After stirring for 18 h, the solvent was evaporated and purified by silica column chromatography (mobile phase from DCM to 2.5% MeOH in DCM) to provide 250 mg of N-benzyl -4- (N ', N "-diBocguanidino) - (S) -2- (N"' - (4-methyl-1-naphthalenesulfonyl) amino) butanamide, 83% yield.

Stage II

Boc protections were removed by dissolving the product after step I in 25% vol TFA in DCM (10 ml) and the mixture was stirred for 1 hour. Subsequent evaporation of the solvent and purification by flash chromatography provided 172 mg of N-benzyl-4-guanidino- (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) butanamide in quantitative yield. MS-ESI + (m / z): 454 1H NMR (500 MHz, CD3OD; �, ppm): 8.73-8.71 (m, 1H), 8.20-8.18 (m, 1H), 8 , 13-8.11 (m, 1H), 7.76-7.71 (m, 2H), 7.41-7.39 (m, 1H), 7.22-7.20 (m, 3H) , 6.93-6.70 (m, 2H), 4.00-3.95 (m, 2H), 3.85-3.82 (m, 1H), 3.19-3.07 (m, 2H), 2.76 (s, 3H), 1.93-1.87 (m, 1H) 1.77-1.70 (m, 1H).

Example 16 Synthesis of 5-N-methylamino- (S) -2- (N '- (1-naphthalenesulfonyl) amino) -N "-phenylpentanamide

Stage I

Boc-Orn (2-Cl-Z) -OH (1.0 g, 400.86 g / mol, 2.5 mmol, 1 eq), DIC (390

He, 126.20 g / mol, 0.806 g / cm3, 2.5 mmol, 1 eq) and HOBt (339.7 mg, 135.12 g / mol, 2.5 mmol, 1 eq) in dry DMF ( 5 ml) After 5 minutes, aniline (228 μl, 93.13 g / mol, 1.022 g / cm 3, 2.5 mmol, 1 eq) in dry DCM (5 ml) was added. The temperature was raised to 35 ° C and the solution was stirred overnight. After solution was evaporated, DCM was added and the solution was washed twice with water and once with brine. The organic phase was dried with Na2SO4 and evaporated. Subsequent silica column chromatography (2% MeOH in DCM as mobile phase) provided 1.12 g of 5-N (2-Cl-Z) amino- (S) -2- (N'-Boc-amino) -N "-phenyl-pentanamide, 94% yield.

Stage II

The 2-Cl-Z protection was removed by dissolving the product of step I in MeOH (60 ml) and 10% Pd / C (200 mg) was added. The reaction vessel was purged three times with argon before the introduction of hydrogen (atmospheric pressure). The mixture was stirred for 4 h, the catalyst was filtered and finally the filtrate was evaporated. 5-amino- (S) -2- (N-Boc-amino) -N'-phenylpentanamide was used without purification for the step

III.

Stage III

5-Amino- (S) -2- (N-Boc-amino) -N'-phenylpentanamide (720 mg, 307.39 g / mol, 2.34 mmol, 1 eq) was dissolved in dry DMF (5 ml) TEA (324 µl, 101.19 g / mol, 0.73 g / cm3, 2.34 mmol, 1 eq, Baker) was added and the mixture was cooled in an ice bath. 2-Nitrobenzenesulfonyl chloride (520.7 mg, 221.62 g / mol, 2.34 mmol, 1 eq) in dry DCM (1 ml) was added, the ice bath was removed and the solution was stirred overnight . After the solvent was evaporated, DCM was added and the solution was washed twice with saturated NaHCO3 and once with water. The organic phase was dried (Na2SO4), evaporated and finally the residue was purified by silica column chromatography (2.5% MeOH mobile phase in DCM). 440 mg of (S) -2- (N-Bocamino) -5-N '- (2-nitrobenzenesulfonyl) amino) -N "-phenylpentanamide were obtained, yield 38%.

Stage IV

(S) -2- (N-Boc-amino) -5-N '- (2-nitrobenzenesulfonyl) amino) -N "-phenylpentanamide (200.8 mg, 492.55 g / mol, 0.41 mmol) , 1 eq) in dry DMF (0.5 ml), and DBU (61 l, 152.24 g / mol, 1.018 g / cm 3, 0.41 mmol, 1 eq, Acros) was added. The solution was cooled then in an ice bath and methyl iodide (25 μl, 141.94 g / mol, 2.28 g / cm 3, 0.41 mmol, 1 eq) was added dropwise, cooling and mixing were removed. stirred overnight, another 0.5 eq of methyl iodide and DBU were added, and after 2 hours another 0.5 eq of methyl iodide and DBU After 2 hours, the solvent was evaporated, DCM was added and the solution was washed twice with saturated NaHCO3 and once with water.The organic phase was dried (Na2SO4) and evaporated.After purification by preparative TLC, 135 mg of (S) -2- (N-Boc) was obtained. -amino) 5- (N'-2-nitrobenzenesulfonyl-N'-methylamino) -N "-phenylpentanamide, 65% yield.

Stage V

The Boc protection was removed by dissolving the product after step IV in 3 ml of 25% vol TFA in DCM and stirring the solution for 45 minutes. The solvent was then evaporated and the product was used without purification for step VI.

Stage VI

(S) -2-Amino-5- (N-2-nitrobenzenesulfonyl-N-methylamino) -N'phenylpentanamide (100 mg, 406.46 g / mol, 0.25 mmol, 1 eq) was dissolved in dry THF ( 3 ml), and 1-naphthalenesulfonyl chloride (67.4 mg, 226.68 g / mol, 0.30 ml, 1.2 eq) was added and finally TEA (87 μl, 101.19 g / mol, 0.73 g / cm3, 0.63 mmol, 2.5 eq, Baker). After stirring overnight, 0.2 eq of 1-naphthalenesulfonyl chloride and 1 eq of TEA were added, and the reaction temperature rose to 50 ° C. After another 1.5 hours, the solvent was evaporated and the residue was purified by silica column chromatography (2% MeOH mobile phase in DCM). 138 mg of (S) -2- (N-1-naphthalenesulfonylamino) -5- (N'-2-nitrobenzenesulfonyl-N'-methylamino) -N "-phenylpentanamide, yield 93%, were obtained.

Stage VII

(S) -2- (N-1-Naphthalenesulfonylamino) -5- (N'-2-nitrobenzenesulfonyl-N'methylamino) -N "-phenylpentanamide (67 mg, 596.69 g / mol, 0.11 mmol) , 1 eq) in dry DMF (0.5 ml) and a solution containing thiophenol (115 μl, 110.18 g / mol, 1.078 g / cm3, 1.1 mmol, 10 eq), K2CO3 (40) was added , 4 mg, 138.21 g / mol, 0.28 mmol, 2.5 eq, Baker) and water (200 μl) Finally, ASD (155 μl, 101.19 g / mol, 0, 73 g / cm3, 1.1 mmol, 10 eq, Baker) and the temperature rose to 50 ° C. After 1.5 hours, the solvent was evaporated, DCM was added and the solution was washed twice with water and once with brine. The organic phase was dried (Na2SO4) and evaporated. Flash chromatography gave 18.4 mg of 5-N-methylamino- (S) -2-N '- (1-naphthalenesulfonyl) amino-N " phenylpentanamide; 41% yield. MS-ESI + (m / z): 412 1H NMR (500 MHz, CD3OD; �, ppm): 8.78 (m, 1H), 8.22 (m, 1H), 7.98 (d, 1H), 7.90 (d, 1H), 7.68 (m, 1H), 7.57 (m, 1H), 7.46 (m, 1H), 7.13 (m, 2H), 7.03-6 , 96 (m, 3H), 3.82 (m, 1H), 2.42 (m, 2H), 2.28 (s, 3H), 1.64 (m, 2H), 1.52 (m, 1H), 1.40 (m, 1H).

Example 17 Synthesis of N - ((S) -1-carbamoyl-2-phenylethyl) -5-guanidino- (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) pentanamide (Compound 5)

Stage I

The Rink amide resin (1 g, 0.7 mmol / g, 0.7 mmol) was washed twice with DMF before use. The washed resin was dissolved in 12.5 ml of 20% vol piperidine in DMF and the mixture was stirred for 35 minutes. The resin was then washed three times with DMF, three times with MeOH, twice with DCM and finally twice with THF. The resin was used immediately for stage II.

Stage II

Fmoc-Phe-OH (813.6 mg, 387.44 g / mol, 2.1 mmol, 3 eq) and DIC (328.8 μl, 126.20 g / mol, 0.806 g / cm3, 2 were dissolved , 1 mmol, 3 eq) in dry DMF (12.5 ml), and after 10 minutes they were mixed with the resin. After stirring for 18 hours, the solvent was removed by filtration and fresh solution was introduced with half of the original amounts of Fmoc-Phe-OH and DIC in dry DMF. After another 5.5 hours, the solvent was removed again by filtration and the resin was washed three times with DMF, three times with MeOH, three times with DCM and three times with THF.

Stage III

The amino groups of the resin that possibly had not reacted were acetylated with a solution consisting of acetic anhydride (1 ml, 102.09 g / mol, 1.087 g / cm3, 10.6 mmol) and DIPEA (250 μl, 129 , 25 g / mol, 0.755 g / cm3, 1.46 mmol) in dry DMF (12 ml) for 45 minutes. The resin was then filtered and washed three times with DMF, three times with MeOH, twice with DCM and twice with THF.

Stage IV

Fmoc protection of bound phenylalanine was removed according to the procedure described in step I, but without any washing before treatment with piperidine / DMF.

Stage V

Fmoc-Arg (Pmc) -OH (928.0 mg, 662.8 g / mol, 1.4 mmol, 2 eq) was coupled to the resin-bound compound by using the same coupling agent and procedure described in the stage II

Stage VI

The phenylalanine amino groups that had not reacted by using the procedure described in step III were acetylated.

Stage VII

Fmoc protection of the arginine bound in stage V was removed according to the procedure described in stage I, but again without any washing before treatment with piperidine / DMF.

Stage VIII

4-Methyl-1-naphthalenesulfonyl chloride (337.0 mg, 240.71 g / mol, 1.4 mmol, 2 eq, Maybridge) was dissolved in dry THF (12.5 ml) and mixed with the resin. TEA (194.1 μl, 101.19 g / mol, 0.73 g / cm 3, 1.4 mmol, 2 eq, Baker) was added to the mixture. After stirring overnight, the solvent was filtered and the resin was washed three times with THF, three times with MeOH, three times with DMF, once with MeOH and finally three times with DCM.

Stage IX

The resin bound product was cleaved and the Pmc protection was removed by treating the resin with 50% vol TFA in DCM (12.5 ml) for 1 hour. The resulting red solution was collected and evaporated. 116.5 mg of N - ((S) -1-carbamoyl-2-phenylethyl) -5-guanidino- (S) -2- (N '- (4-methylnaphthalen-1-sulfonyl) amino) -pentanamide were obtained as of a dark oil. The product was purified by the use of flash chromatography to provide 50.8 mg of N - ((S) -1-carbamoyl-2-phenylethyl) -5-guanidino- (S) -2- (N '(4-methyl -1-naphthalenesulfonyl) amino) pentanamide in the form of a white solid, total yield of 14%. MS-ESI + (m / z): 525 1H NMR (500 MHz, CD3OD; �, ppm): 8.79 (m, 1H), 8.23 (m, 1H), 8.14 (d, 1H), 7.76 (m, 2H), 7.47 (m, 1H), 7.33-7.18 (m, 5H), 4.39 (m, 1H), 3.62 (m, 1H), 3 , 03 (m, 1H), 2,942.78 (m, 5H), 2.68 (m, 1H), 1.50 (m, 2H), 1.35 (m, 1H), 1.21 (m, 1 HOUR).

Example 18 Synthesis of 5-amino-N - ((S) -1-carbamoylmethyl-2- (1-naphthyl) ethyl) - (S) -2- (N '- (4-methyl-1benzenesulfonyl) amino) pentanamide

Stage I

The Rink amide resin (200.2 mg, 0.7 mmol / g, 0.14 mmol) was washed twice with DMF before use. The washed resin was dissolved in 2.5 ml of 20% vol piperidine in DMF and the mixture was stirred for 30 minutes. The resin was then washed three times with DMF, twice with MeOH, twice with DCM and finally twice with THF. The resin was used immediately for stage II.

Stage II

Fmoc- (S) -3-amino-4- (naphthyl) butyric acid (124 mg, 451.52 g / mol, 0.28 mmol, 2 eq, PepTech) and DIC (44 l, 126.20) were dissolved g / mol, 0.806 g / cm3, 0.28 mmol, 2 eq) in dry DMF, and after 5 minutes they were mixed with the resin. After 6 hours, the solvent was removed by filtration and fresh solution was introduced with the same amounts of Fmoc- (S) -3-amino-4- (naphthyl) butyric acid and DIC in dry DMF. After another 6 hours, the solvent was removed again by filtration and the resin was washed twice with DMF, twice with MeOH, once with DCM and once with THF.

Stage III

The amino groups that possibly had not reacted were acetylated by treating the resin with a solution consisting of acetic anhydride (100 μl, 102.09 g / mol, 1.087 g / cm 3, 1.06 mmol) and DIPEA (17 μl, 129.25 g / mol, 0.755 g / cm3, 0.1 mmol) in dry DMF (2.1 ml) for 30 minutes. The resin was then filtered and washed twice with DMF, twice with MeOH, once with DCM and once with THF.

Stage IV

Fmoc protection of the bound Fmoc- (S) -3-amino-4- (naphthyl) -butyric acid was removed according to the procedure described in step I but without any washing before treatment with piperidine / DMF.

Stage V

Fmoc-Om (Boc) -OH (197.5 mg, 454.5 g / mol, 0.44 mmol, 3 eq) was coupled to the resin-bound compound by using the same coupling agent and procedure described in the stage II

Stage VI

The amino groups that possibly had not reacted were acetylated by using the procedure described in step III.

Stage VII

The Fmoc protection of the ornithine bound in stage V was removed according to the procedure described in stage I, but without any washing before treatment with piperidine / DMF.

Stage VIII

4-Toluenesulfonyl chloride (80 mg, 190.65 g / mol, 0.42 mmol, 3 eq) was dissolved in dry THF (2.5 ml), mixed with the resin and TEA (58 μl, 101.19 g / mol, 0.73 g / cm3, 0.42 mmol, 3 eq, Baker) to the mixture. After stirring overnight, the solvent was filtered and the resin was washed three times with THF, twice with MeOH, twice with DMF, once with MeOH and finally three times with DCM.

Stage IX

The resin bound product was cleaved and the Boc protection was removed by treating the resin with 25% vol TFA in DCM (2.5 ml) for 45 minutes. The resulting red solution was collected and evaporated. The residue was purified by RP-HPLC to provide 12 mg of 5-amino-N - ((S) -1-carbamoylmethyl-2- (1-naphthyl) ethyl) - (S) -2- (N '- (4methyl) -1-benzenesulfonyl) amino) pentanamide in the form of a white solid, total yield of 17%. MS-ESI + (m / z): 497 1H NMR (500 MHz, CD3OD; �, ppm): 8.15-8.07 (m, 1H), 7.90-7.86 (m, 1H), 7 , 77-7.76 (m, 1H), 7.71-7.69 (m, 1H), 7.55-7.48 (m, 2H), 7.40-7.37 (m, 1H) , 7.29-7.21 (m, 3H), 4.37-4.31 (m, 1H), 3.79-3.77 (m, 1H), 3.35-3.34 (m, 2H), 2.97-2.80 (m, 4H), 2.28-2.19 (m, 1H), 2.15 (m, 3H), 1.69-1.54 (m, 3H) .

Example 19 Synthesis of N - ((S) -1-carbamoyl-2-phenylethyl) -6-guanidino- (S) -3- (N '- (1-naphthalenesulfonyl) amino) hexanamide

Stage I

The Rink amide resin (208.6 mg, 0.7 mmol / g, 0.15 mmol) was washed twice with DMF before use. The washed resin was dissolved in 2.5 ml of 20% vol piperidine in DMF and the mixture was stirred for 30 minutes. The resin was then washed three times with DMF, twice with MeOH, twice with DCM and finally twice with THF. The resin was used immediately for stage II.

Stage II

Fmoc-Phe-OH (114.9 mg, 387.44 g / mol, 0.30 mmol, 2 eq) was coupled to the resin using the same procedure and coupling agent described in step II of Example 18.

Stage III

The amino groups that possibly had not reacted were acetylated by using the procedure described in step III of example 18.

Stage IV

Fmoc protection of bound phenylalanine was removed according to the procedure described in step I, but without any washing before treatment with piperidine / DMF.

Stage V

N-Fmoc-L-beta-homo-arginine (Pbf) -OH (281.0 mg, 662.8 g / mol, 0.42 mmol, 3 eq) was coupled to the resin-bound compound by use thereof coupling agent and process described in step II of example 18.

Stage VI

The amino groups that possibly had not reacted were acetylated by using the procedure described in step III of example 18.

Stage VII

Fmoc protection of bound beta-homo-arginine was removed according to the procedure described in step I, but without any washing before treatment with piperidine / DMF.

Stage VIII

1-Naphthalenesulfonyl chloride (78.5 mg, 226.7 g / mol, 0.34 mmol, 2.5 eq, Acros) was introduced according to the procedure described in step VIII of Example 18.

Stage IX

The resin-bound product was cleaved and the Pbf protection was removed by treating the resin with 40% vol TFA in DCM (2.5 ml) for 45 minutes. The resulting red solution was collected and evaporated. The residue was purified by RP-HPLC to provide 14.9 mg of N - ((S) -1-carbamoyl-2-phenylethyl) -6-guanidino- (S) -3- (N '- (1-naphthalenesulfonyl) amino) hexanamide in the form of a white solid, total yield of 19%. MS-ESI + (m / z): 525 1H NMR (500 MHz, CD3OD; �, ppm): 8.65-8.63 (m, 1H), 8.25-8.23 (m, 1H), 8 , 15-8.13 (m, 1H), 7.93-7.92 (m, 1H), 7.69-7.56 (m, 3H), 7.24-7.14 (m, 5H) , 4.53-4.48 (m, 1H), 3.45-3.41 (m, 1H), 3.12-3.08 (m, 1H), 2.78-2.67 (m, 3H), 2.19-2.15 (m, 1H), 2.03-1.98 (m, 1H), 1.26-0.95 (m, 4H).

Example 20 Synthesis of 6-amino- (S) -2- (N-benzenesulfonylamino) -N - ((S) -1-carbamoyl-2- (1 Hindol-3-yl) ethyl) hexanamide

Stage I

The Rink amide resin (205.8 mg, 0.7 mmol / g, 0.14 mmol) was washed twice with DMF before use. The washed resin was dissolved in 2.5 ml of 20% vol piperidine in DMF and the mixture was stirred for 30 minutes. The resin was then washed three times with DMF, twice with MeOH, twice with DCM and finally twice with THF. The resin was used immediately for stage II.

Stage II

Fmoc-Trp (Boc) -OH (161.4 mg, 526.6 g / mol, 0.31 mmol, 2 eq) was coupled to the resin using the same procedure and coupling agent described in step II of the example 18.

Stage III

The amino groups that possibly had not reacted were acetylated by using the procedure described in step III of example 18.

Stage IV

Fmoc protection of bound tryptophan was removed according to the procedure described in step I, but without any washing before treatment with piperidine / DMF.

Stage V

Fmoc-Lys (Boc) -OH (205.8 mg, 468.54 g / mol, 0.44 mmol, 3 eq) was coupled to the resin-bound compound by using the same coupling agent and procedure described in the stage II of example 18.

Stage VI

The amino groups that possibly had not reacted were acetylated by using the procedure described in step III.

Stage VII

Fmoc protection of bound lysine was removed according to the procedure described in step I, but without any washing before treatment with piperidine / DMF.

Stage VIII

Benzenesulfonyl chloride (76.3 mg, 176.6 g / mol, 0.43 mmol, 3 eq) was introduced according to the procedure described in step VIII of example 18.

Stage IX

The resin-bound product was cleaved and the Boc protection was removed by treating the resin with 20% vol TFA in DCM (2.5 ml) for 45 minutes. The resulting red solution was collected and evaporated. The residue was purified by RP-HPLC to provide 17.2 mg of 6-amino- (S) -2- (N-benzenesulfonylamino) -N - ((S) -1-carbamoyl2- (1H-indole-3-yl ) ethyl) hexanamide in the form of a white solid; 25% total yield. MS-ESI + (m / z): 472 1H NMR (500 MHz, CD3OD; �, ppm): 7.74-7.72 (m, 2H), 7.61-7.59 (m, 1H), 7 , 49-7.46 (m, 1H), 7.37-7.34 (m, 3H), 7.14-7.10 (m, 2H), 7.06-7.03 (m, 1H) , 4.45-4.43 (m, 1H), 3.67-3.64 (m, 1H), 3.35 (s, 2H), 3.24-3.20 (m, 1H), 3 , 02-2.97 (m, 1H), 2.74-2.70 (m, 2H), 1.54-1.42 (m, 4H), 1.21-1.09 (m, 2H) .

Example 21 Synthesis of 5-amino- (S) -2- (N-benzenesulfonylamino) -N '- ((S) -1-carbamoyl-2-phenylethyl) pentanamide

Stage I

The Rink amide resin (219.3 mg, 0.7 mmol / g, 0.15 mmol) was washed twice with DMF before use. The washed resin was dissolved in 2.5 ml of 20% vol piperidine in DMF and the mixture was stirred for 30 minutes. The resin was then washed three times with DMF, twice with MeOH, twice with DCM and finally twice with THF. The resin was used immediately for stage II.

Stage II

Fmoc-Phe-OH (119.3 mg, 387.44 g / mol, 0.30 mmol, 2 eq) was coupled to the resin using the same procedure and coupling agent described in step II of Example 18.

Stage III

The amino groups that possibly had not reacted were acetylated by using the procedure described in step III of example 18.

Stage IV

Fmoc protection of bound phenylalanine was removed according to the procedure described in step I, but without any washing before treatment with piperidine / DMF.

Stage V

Fmoc-Orn (Boc) -OH (140.2 mg, 454.5 g / mol, 0.31 mmol, 2 eq) was coupled to the resin-bound compound by using the same coupling agent and procedure described in the stage II of example 18.

Stage VI

The amino groups that possibly had not reacted were acetylated by using the procedure described in step III.

Stage VII

Fmoc protection of bound ornithine was removed according to the procedure described in step I, but without any washing before treatment with piperidine / DMF.

Stage VIII

Benzenesulfonyl chloride (81.3 mg, 176.62 g / mol, 0.46 mmol, 3 eq) was introduced according to the procedure described in step VIII of example 18.

Stage IX

The resin-bound product was cleaved and the Boc protection was removed by treating the resin with 20% vol TFA in DCM (2.5 ml) for 45 minutes. The resulting red solution was collected and evaporated. The residue was purified by RP-HPLC to provide 16.1 mg of 5-amino- (S) -2- (N-benzenesulfonylamino) -N '- ((S) -1-carbamoyl2-phenylethyl) pentanamide as a White solid, total yield of 25%. MS-ESI + (m / z): 419 1H NMR (500 MHz, CD3OD; �, ppm): 7.77 (m, 2H), 7.58 (m, 1H), 7.47-7.44 (m , 2H), 7.30-7.18 (m, 5H), 4.31 (m, 1H), 3.76 (m, 1H), 2.98 (m, 1H), 2.81-2, 48 (m, 2H), 2.75 (m, 1H), 1.66-1.51 (m, 4H).

Example 22 Synthesis of 6-amino-N - ((S) -1-carbamoyl-2- (1-naphthyl) ethyl) - (S) -2- (N '- (1-naphthalenesulfonyl) amino) hexanamide

Stage I

The Rink amide resin (218.3 mg, 0.7 mmol / g, 0.15 mmol) was washed twice with DMF before use. The washed resin was dissolved in 2.5 ml of 20% vol piperidine in DMF and the mixture was stirred for 30 minutes. The resin was then washed three times with DMF, twice with MeOH, twice with DCM and finally twice with THF. The resin was used immediately for stage II.

Stage II

Fmoc-1-naphthylalanine (134.4 mg, 437.49 g / mol, 0.31 mmol, 2 eq, PepTech) was coupled to the resin by using the same procedure and coupling agent described in step II of the example 18.

Stage III

The amino groups that possibly had not reacted were acetylated by using the procedure described in step III of example 18.

Stage IV

Fmoc protection of bound naphthylalanine was removed according to the procedure described in step I, but without any washing before treatment with piperidine / DMF.

Stage V

Fmoc-Lys (Boc) -OH (218.0 mg, 468.54 g / mol, 0.46 mmol, 3 eq) was coupled to the resin-bound compound by using the same coupling agent and procedure described in the stage II of example 18.

Stage VI

The amino groups that possibly had not reacted were acetylated by using the procedure described in step III.

Stage VII

Fmoc protection of bound lysine was removed according to the procedure described in step I, but without any washing before treatment with piperidine / DMF.

Stage VIII

1-Naphthalenesulfonyl chloride (107.9 mg, 226.68 g / mol, 0.48 mmol, 3 eq) was introduced according to the procedure described in step VIII of Example 18.

Stage IX

The resin-bound product was cleaved and the Boc protection was removed by treating the resin with 20% vol TFA in DCM (2.5 ml) for 45 minutes. The resulting red solution was collected and evaporated. The product was purified by RP-HPLC to provide 10.5 mg of 6-amino-N - ((S) -1-carbamoyl-2- (1-naphthyl) ethyl) - (S) -2- (N'- (1-Naphthalenesulfonyl) amino) hexanamide in the form of a white solid; 25% total yield. MS-ESI + (m / z): 533 1H NMR (500 MHz, CD3OD; �, ppm): 8.71 (d, 1H), 8.17 (m, 1H), 8.09 (d, 1H), 8,007.95 (m, 2H), 7.85 (m 1H), 7.75-7.69 (m, 2H), 7.62-7.59 (m, 1H), 7.55-7.47 (m, 3H), 7.36-7.33 (m, 1H), 7.30-7.28 (m, 1H), 4.49 (m, 1H), 3.56 (m, 1H), 3.41 (m, 1H), 3.01 (m, 1H), 2.56-2.52 (m, 2H), 1.39-1.21 (m, 4H), 1.04 (m, 1H), 0.87 (m, 1H).

Example 23 Synthesis of 6-amino-N - ((S) -1-carbamoyl-2- (1 H -indol-3-yl) ethyl) - (S) -2- (N '- (1-naphthalenesulfonyl) amino) hexanamide

Stage I

The Rink amide resin (201.0 mg, 0.7 mmol / g, 0.14 mmol) was washed twice with DMF before use. The washed resin was dissolved in 2.5 ml of 20% vol piperidine in DMF and the mixture was stirred for 30 minutes. The resin was then washed three times with DMF, twice with MeOH, twice with DCM and finally twice with THF. The resin was used immediately for stage II.

Stage II

Fmoc-Trp (Boc) -OH (147.2 mg, 526.6 g / mol, 0.28 mmol, 2 eq) was coupled to the resin using the same procedure and coupling agent described in step II of the example 18.

Stage III

The amino groups that possibly had not reacted were acetylated by using the procedure described in step III of example 18.

Stage IV

Fmoc protection of bound tryptophan was removed according to the procedure described in step I, but without any washing before treatment with piperidine / DMF.

Stage V

Fmoc-Lys (Boc) -OH (199.7 mg, 468.54 g / mol, 0.43 mmol, 3 eq) was coupled to the resin-bound compound by using the same coupling agent and procedure described in the stage II of example 18.

Stage VI

The amino groups that possibly had not reacted were acetylated by using the procedure described in step III.

Stage VII

Fmoc protection of bound lysine was removed according to the procedure described in step I, but without any washing before treatment with piperidine / DMF.

Stage VIII

1-Naphthalenesulfonyl chloride (97.9 mg, 226.68 g / mol, 0.43 mmol, 3 eq, Acros) was introduced according to the procedure described in step VIII of example 18.

Stage IX

The resin-bound product was cleaved and the Boc protection was removed by treating the resin with 20% vol TFA in DCM (2.5 ml) for 45 minutes. The resulting red solution was collected and evaporated. The product was purified by RP-HPLC to provide 7.3 mg of 6-amino-N - ((S) -1-carbamoyl-2- (1H-indole-3-yl) ethyl) - (S) -2- (N '- (1

naphthalenesulfonyl) amino) hexanamide in the form of a white solid; total yield of 10%. MS-ESI + (m / z): 522 1H NMR (500 MHz, CD3OD; �, ppm): 8.68 (d, 1H), 8.14 (m, 1H), 8.06 (m, 1H), 7.96 (m, 1H), 7.69-7.59 (m, 2H), 7.52-7.34 (m, 3H), 7.12-7.00 (m, 3H), 4.36 (m, 1H) , 3.60 (m, 1H), 3.12 (m, 1H), 2.86 (m, 1H), 2.55-2.51 (m, 2H), 1.49-1.23 (m, 4H), 1.11 -0.90 (m, 2H).

Example 24 Synthesis of 6-amino- (S) -2- (N- (4-butoxy-1-benzenesulfonyl) amino) -N '- ((S) -1-carbamoyl-2-phenylethyl) hexanamide

Stage I

The Rink amide resin (195.3 mg, 0.7 mmol / g, 0.14 mmol) was washed twice with DMF before use. The washed resin was dissolved in 2.5 ml of 20% vol piperidine in DMF and the mixture was stirred for 30 minutes. The resin was then washed three times with DMF, twice with MeOH, twice with DCM and finally twice with THF. The resin was used immediately for stage II.

Stage II

Fmoc-Phe-OH (105.3 mg, 387.4 g / mol, 0.27 mmol, 2 eq) was coupled to the resin using the same procedure and coupling agent described in step II of Example 18.

Stage III

The amino groups that possibly had not reacted were acetylated by using the procedure described in step III of example 18.

Stage IV

Fmoc protection of bound phenylalanine was removed according to the procedure described in step I, but without any washing before treatment with piperidine / DMF.

Stage V

Fmoc-Lys (Boc) -OH (196.1 mg, 468.54 g / mol, 0.42 mmol, 3 eq) was coupled to the resin-bound compound using the same coupling agent and procedure described in the stage II of example 18.

Stage VI

The amino groups that possibly had not reacted were acetylated by using the procedure described in step III.

Stage VII

Fmoc protection of bound lysine was removed according to the procedure described in step I, but without any washing before treatment with piperidine / DMF.

Stage VIII

4- (n-Butoxy) benzenesulfonyl chloride (106.6 mg, 248.73 g / mol, 0.43 mmol, 3 eq) was introduced according to the procedure described in step VIII of example 18.

Stage IX

The resin-bound product was cleaved and the Boc protection was removed by treating the resin with 20% vol TFA in DCM (2.5 ml) for 45 minutes. The resulting red solution was collected and evaporated. The product was purified by RP-HPLC to provide 18.3 mg of 6-amino- (S) -2- (N- (4-butoxy-1-benzenesulfonyl) -amino) -N '- ((S) 1- carbamoyl-2-phenylethyl) hexanamide in the form of a white solid, total yield of 35%. MS-ESI + (m / z): 505 1H NMR (500 MHz, CD3OD; �, ppm): 7.71 (m, 2H), 7.29-7.19 (m, 5H), 6.98 (m , 2H), 4.41 (m, 1H), 4.00 (m, 2H), 3.62 (m, 1H), 3.05 (m, 1H), 2.82-2.73 (m, 3H), 1.77-1.71 (m, 2H), 1.57-1.43 (m, 6H), 1.31-1.09 (m, 2H), 0.98-0.95 ( m 3H).

Example 25 Synthesis of N - ((S) -1-carbamoyl-2,2-diphenylethyl) -5-guanidino- (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) pentanamide (Compound 6)

Stage I

The Rink amide resin (1.5 g, 0.7 mmol / g, 1.02 mmol) was washed twice with DMF before use. The washed resin was dissolved in 21 ml of 20% vol piperidine in DMF and the mixture was stirred for 50 minutes. The resin was then washed three times with DMF, three times with MeOH, twice with DCM and finally twice with THF. The resin was used immediately for stage II.

Stage II

Fmoc-L-3,3-diphenylalanine (1.41 g, 463.53 g / mol, 3.05 mmol, 3 eq, PepTech) and DIC (477.3 μl, 126.20 g / mol, were dissolved, 0.806 g / cm3, 3.05 mmol, 3 eq) in dry DMF (21 ml) and after 10 minutes it was mixed with the resin. After stirring for 22 hours, the solvent was removed by filtration and a recent solution with similar amounts of Fmoc-L-3,3-diphenylalanine and DIC in dry DMF was introduced. After another 5 hours, the solvent was removed again by filtration and the resin was washed three times with DMF, three times with MeOH, three times with DCM and three times with THF.

Stage III

The amino groups of the resin that possibly had not reacted were acetylated with a solution consisting of acetic anhydride (700 μl, 102.09 g / mol, 1.087 g / cm 3, 7.5 mmol) and DIPEA (119 μl, 129.25 g / mol, 0.755 g / cm3, 0.7 mmol) in dry DMF (16.1 ml) for 45 minutes. The resin was then filtered and washed three times with DMF, three times with MeOH, twice with DCM and twice with THF.

Stage IV

Fmoc protection of bound 3,3-diphenylalanine was removed according to the procedure described in step I, but without any washing before treatment with piperidine / DMF.

Stage V

Fmoc-Arg (Pmc) -OH (1.34 g, 662.8 g / mol, 2.03 mmol, 2 eq) was coupled to the resin-bound compound by using the same coupling agent and procedure described in the stage II

Stage VI

The amino groups of 3,3-diphenylalanine that possibly had not reacted were acetylated by using the procedure described in step III.

Stage VII

Fmoc protection of the arginine bound in stage V was removed according to the procedure described in stage I, but again without any washing before treatment with piperidine / DMF.

Stage VIII

4-Methyl-1-naphthalenesulfonyl chloride (733.7 mg, 240.71 g / mol, 3.0 mmol, 3 eq, Maybridge) was dissolved in dry THF (21 ml) and mixed with the resin. TEA (422.5 µl, 101.19 g / mol, 0.73 g / cm3, 3.0 mmol, 3 eq, Baker) was added to the mixture. After stirring overnight, the solvent was filtered and the resin was washed three times with THF, three times with MeOH, three times with DMF, once with MeOH and finally three times with DCM.

Stage IX

The resin bound product was cleaved and the Pmc protection was removed by treating the resin with 50% vol TFA in DCM (21 ml) for 1 hour. The resulting red solution was collected and evaporated. The product was purified by RP-HPLC to provide 108.4 mg of N - ((S) -1-carbamoyl-2,2-diphenylethyl) -5-guanidino- (S) -2- (N '- (4methyl- 1-Naphthalenesulfonyl) amino) pentanamide in the form of a white solid, total yield of 16.4%. MS-ESI + (m / z): 601 1H NMR (500 MHz, CD3OD; �, ppm): 8.71 (m, 1H), 8.17 (m, 1H), 7.94 (m, 1H), 7.697.65 (m, 2H), 7.35 (m, 1H), 7.27-7.19 (m, 9H), 7.17-7.13 (m, 2H), 5.11 (m, 1H), 4.38 (d, 1H), 3.46 (m, 1H), 2.77 (s, 3H), 2.76-2.65 (m, 2H), 1.44-1.02 (m, 4H).

Example 26 Synthesis of 4-amino-N - ((S) -1-carbamoyl-2-phenylethyl) - (S) -2- (N'-methyl-N '- (4-methyl-1-naphthalenesulfonyl) amino) butanamide Stage I

The Rink amide resin (223.6 mg, 0.7 mmol / g, 0.16 mmol) was washed twice with DMF before use. The washed resin was dissolved in 2.5 ml of 20% vol piperidine in DMF and the mixture was stirred for 30 minutes. The resin was then washed three times with DMF, twice with MeOH, twice with DCM and finally twice with THF. The resin was used immediately for stage II.

Stage II

Fmoc-Phe-OH (184 mg, 387.44 g / mol, 0.47 mmol, 3 eq) and DIC (74

He, 126.20 g / mol, 0.806 g / cm3, 0.47 mmol, 3 eq) in dry DMF and after 5 minutes they were mixed with the resin. After stirring for 6 hours, the solvent was removed by filtration and a recent solution with the same amounts of Fmoc-Phe-OH and DIC in dry DMF was introduced. After another 6 hours, the solvent was removed again by filtration and the resin was washed twice with DMF, twice with MeOH, once with DCM and once with THF.

Stage III

The amino groups that possibly had not reacted were acetylated by treating the resin with acetic anhydride (100 μl, 102.09 g / mol, 1.087 g / cm 3, 1.06 mmol), DIPEA (17 μl, 129.25 g / mol, 0.755 g / cm3, 0.1 mmol) and dry DMF (2.1 ml) for 30 minutes. The resin was then filtered and washed twice with DMF, twice with MeOH, once with DCM and once with THF.

Stage IV

Fmoc protection of phenylalanine was removed according to the procedure described in step I, but without any washing before treatment with piperidine / DMF.

Stage V

Fmoc-Dbu (Boc) -OH (211.3 mg, 440.5 g / mol, 0.47 mmol, 3 eq) was coupled to the resin-bound compound by using the same coupling and process agents described in stage II

Stage VI

The amino groups that possibly had not reacted were acetylated by using the procedure described in step III.

Stage VII

The Fmoc protection of the amino acid bound in stage V was removed according to the procedure described in stage I, but without any washing before treatment with piperidine / DMF.

Stage VIII

4-Methyl-1-naphthalenesulfonyl chloride (115 mg, 240.71 g / mol, 0.47 mmol, 3 eq, Maybridge) was dissolved in dry THF (2.5 ml), mixed with the resin and added TEA (65 μl, 101.19 g / mol, 0.73 g / cm 3, 0.47 mmol, 3 eq, Baker) to the mixture. After stirring overnight, the solvent was filtered and the resin was washed three times with THF, twice with MeOH, twice with DMF, once with MeOH and finally three times with DCM.

Stage IX

The resin (0.16 mmol) was expanded with dry DMF (2.5 ml), and DBU (240 μl, 152.24 g / mol, 1.018 g / cm 3, 1.6 mmol, 10 eq, Acros was added ) To the mix. Then methyl iodide (1.6 mmol, 141.94 g / mol, 2.28 g / cm3, 1.6 mmol, 10 eq, Acros) was added dropwise to the mixture. After stirring overnight, the solvent was filtered and the resin was washed twice with DMF, twice with MeOH, twice with DCM and twice with THF.

Stage X

The resin bound product was cleaved and the Boc protection was removed by treating the resin with 25% vol TFA in DCM (2.5 ml) for 45 minutes. The resulting red solution was collected and evaporated. The residue was purified by RP-HPLC to provide 10.2 mg of 4-amino-N - ((S) -1-carbamoyl-2-phenylethyl) - (S) -2- (N'-methyl-N'- (4methyl-1-naphthalenesulfonyl) amino) butanamide in the form of a white solid, total yield of 13%. MS-ESI + (m / z): 483 1H NMR (500 MHz, CD3OD; �, ppm): 8.64 (m, 1H), 8.28 (m, 1H), 8.16 (d, 1H), 7.75 (m, 2H), 7.52 (d, 1H), 7.05 (m, 1H), 6.98 (t, 2H), 6.69 (d, 2H), 4.78 (m , 1H, shielded), 4.42 (m, 1H), 3.00 (m, 1H), 2.82 (s, 3H), 2.79 (t, 2H), 2.34 (m, 1H) , 2.23 (s, 3H), 2.12 (m, 1H), 1.75 (m, 1H).

Example 27 Synthesis of 4-amino-N - ((S) -1-hydroxymethyl-2-phenylethyl) - (S) -2- (N'-4-methyl-1-naphthalenesulfonylamino) butanamide

Stage I

The trityl resin (129.0 mg, 1.5 mmol / g, 0.19 mmol) was washed twice with dry DMF before use. Fmoc-phenylalaninol (220.8 mg, 373.45 g / mol, 0.58 mmol, 3 eq, Advanced ChemTech) and DIPEA (106 he, 129.25 g / mol, 0.755 g / cm3, 0, 58 mmol, 3 eq) in dry DMF and after 5 minutes they were mixed with the resin. After stirring for 4 hours, the solvent was removed by filtration and a recent solution with the same amounts of Fmoc-phenylalaninol and DIPEA in dry DMF was introduced. After stirring overnight, the solvent was removed again by filtration and the resin was washed twice with DMF, twice with MeOH, once with DCM and once with THF.

Stage II

The chlorine groups that possibly had not reacted were protected by treating the resin with methanol (300 μl, 32.04 g / mol, 0.79 g / cm 3, 7.4 mmol) and DIPEA (100

He, 129.25 g / mol, 0.755 g / cm3, 0.1 mmol) in dry DCM (1.7 ml) for 30 minutes. The resin was then filtered and washed twice with DCM, twice with MeOH, once with DMF and once with THF.

Stage III

Dissolving the resin in 2.5 ml of 20% vol piperidine in DMF and stirring the mixture for 30 minutes removed the Fmoc protection. The resin was then washed three times with DMF, twice with MeOH, twice with DCM and finally twice with THF. The resin was used immediately for stage IV.

Stage IV

Fmoc-Dbu (Boc) -OH (254.7 mg, 440.48 g / mol, 0.57 mmol, 3 eq) was coupled to the resin-bound compound by using the same coupling agent and procedure described in the step II of example 26.

Stage V

The amino groups that possibly had not reacted were acetylated by treating the resin with acetic anhydride (100 μl, 102.09 g / mol, 1.087 g / cm 3, 1.06 mmol) and DIPEA (17 μl, 129.25 g / mol, 0.755 g / cm3, 0.1 mmol) in dry DMF (2.1 ml) for 30 minutes. The resin was then filtered and washed twice with DMF, twice with MeOH, once with DCM and once with THF.

Stage VI

The Fmoc protection of the amino acid bound in stage IV was removed according to the procedure described in stage III.

Stage VII

4-Methyl-1-naphthalenesulfonyl chloride (115.4 mg, 240.71 g / mol, 0.47 mmol, 3 eq, Maybridge) was dissolved in dry THF (2.5 ml), mixed with the resin and TEA (65 μl, 101.19 g / mol, 0.73 g / cm 3, 0.47 mmol, 3 eq, Baker) was added to the mixture. After stirring overnight, the solvent was filtered and the resin was washed three times with THF, twice with MeOH, twice with DMF, once with MeOH and finally three times with DCM.

Stage VIII

The resin-bound product was cleaved and the Boc protection was removed by treating the resin with 5% vol TFA in DCM (2.5 ml) for 45 minutes. The resulting red solution was collected and evaporated. 14 mg of 4-amino-N - ((S) -1-hydroxymethyl-2-phenylethyl) - (S) -2- (N'-4-methyl-1-naphthalenesulfonylamino) -butanamide were obtained as an oil yellow. The product was further purified with RP-HPLC to provide 2.3 mg of 4-amino-N - ((S) -1-hydroxymethyl-2-phenylethyl) - (S) -2- (N'-4-methyl- 1-Naphthalenesulfonylamino) butanamide in the form of a white solid, total yield of 3%. MS-ESI + (m / z): 456 1H NMR (500 MHz, CD3OD; �, ppm): 8.70 (d, 1H), 8.13 (d, 1H), 8.11 (d, 1H), 7.73-7.63 (m, 2H), 7.42 (d, 1H), 7.20-7.10 (m, 3H), 6.95 (d, 2H), 3.83 (m, 1H), 3.63 (m, 1H), 3.16 (m, 1H), 3.05 (m, 1H), 2.94-2.81 (m, 2H), 2.70 (s, 3H ), 2.29 (m, 1H), 2.00-1.89 (m, 2H), 1.81 (m, 1H).

Example 28

Additional compounds were prepared according to the methods described in Examples 1-27, but by using the corresponding starting materials.

Name MS-ESI + (m / z) Example

5-amino-N - ((S) -1-carbamoyl-2-phenylethyl) - (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) pentanamide (Compound 7) 4-amino-N- ((S) -1-carbamoyl-2-phenylethyl) - (S) -2- (N '- (4-ethyl-1- naphthalenesulfonyl) amino) butanamide (Compound 8) 4-amino-N - ((S) -1-carbamoyl-2,2-diphenylethyl) - (S) -2- (N '- (4methyl-1-naphthalenesulfonyl) amino) butanamide (Compound 9) 4-amino-N - ((S) -1-carbamoyl -2-phenylethyl) - (S) -2- (N '- (1naphthalenesulfonyl) amino) butanamide (Compound 10) N-benzyl-4-N'-cyclohexylamino- (S) -2- (N "- (4- methyl-1-naphthalenesulfonyl) amino) butanamide (Compound 11) (S) -2-N- (4-butoxybenzenesulfonyl) amino-N '- ((S) -1-carbamoyl-2-phenylethyl) -5-guanidinopentanamide (Compound 12) 4-amino-N - ((S) -1-carbamoyl-2-methylpropyl) - (S) -2- (N '- (4-methyl1-naphthalenesulfonyl) amino) butanamide (Compound 13) 4-amino- (S ) -2-N- (4-bromo-2-ethylbenzenesulfonyl) -amino-N '((S) -1-carbamoyl-2-phenylethyl) butanamide (Compound 14) N-1-carbamoyl-2-phenylethyl- (S ) -2-N '- (4-Chloro-3-nitrobenzenesulfonyl) amino-5-guanidinopentanamide N- (1-carbamoyl-2-phenylethyl) -5-guanidi no- (S) -2- (N '- (2,4,6-triisopropylbenzenesulfonyl) amino) pentanamide N - ((S) -1-carbamoyl-2-phenylethyl) -5-guanidino- (S) -2- (N '- (2naphthalenesulfonyl) amino) pentanamide (Compound 15) N - ((S) -1-carbamoyl-2-phenylethyl) -5-guanidino- (S) -2- (N' - (3-phenylbenzenesulfonyl) amino) pentanamide (Compound 16) 5-N-isopropylamino- (S) -2-N '- (4-methyl-1-naphthalen-sulfonyl) amino-N "- (1,2,3,4-tetrahydro-1-naphthyl) -pentanamide (Compound 17) N - ((S) -1-carbamoyl-2-phenylethyl) -6-guanidino- (S) -3- (N '- (4methyl-1-naphthalenesulfonyl) amino) hexanamide

483 18 483 18 545 18 455 18 494 1, 14 533 17 421 18

511, 513 18 540 17 587 17 511 17 537 17

508 1, 14

539 17

Name MS-ESI + (m / z) Example

4-amino- (S) -2-N- (4-methyl-1-naphthalenesulfonyl) -amino-N '(1,2,3,4-tetrahydro-1-naphthyl) butanamide (Compound 18) N - (( S) -1-carbamoyl-2-phenylethyl) -5-guanidino- (S) -2- (N '- (4-phenylbenzenesulfonyl) amino) pentanamide 5-amino-N- (2- (2-carbamoyl) indanyl) - ( S) -2- (N '- (4-methyl-1naphthalenesulfonyl) amino) pentanamide (Compound 19) 5-amino-N- (2- (1H-indole-3-yl) ethyl) - (S) 2- ( N '- (4-methyl-1naphthalenesulfonyl) amino) pentanamide (Compound 20) 5-amino-N - ((S) -1-carbamoyl-2-phenylethyl) - (S) -2- (N' - (2-phenylbenzenesulfonyl) amino) pentanamide 5-amino-N - ((S) -1-carbamoyl-2- (3-chlorophenyl) ethyl) - (S) -2- (N '- (4methyl-1-naphthalenesulfonyl) amino) -pentanamide ( Compound 21) 5-amino-N- (2- (2-carbamoyl) -1,2,3,4-tetrahydronaphthyl) - (S) -2 (N '- (4-methyl-1-naphthalenesulfonyl) amino) - Pentanamide (Compound 22) N- (2- (3-chlorophenyl) ethyl) -4-N'-methylamino- (S) -2- (N "- (4-methyl-1naphthalenesulfonyl) amino) -butanamide (Compound 23) N - ((S) -1-carbamoyl-2-phenylethyl) -5-guanidino- (S) -2- (N '- (8quinolinasulfonyl) amino) pentanamide (S) -2-N- (4-acetylbenzenesulfonyl) amino -N '- ((S ) -1-carbamoyl2-phenylethyl) -5-guanidinopentanamide N-benzyl-5-N ', N'-dimethylamino- (S) -2- (N "- (4-methyl-1naphthalenesulfonyl) amino) pentanamide 5-amino- N - ((S) -1-carbamoyl-2-phenylethyl) - (S) -2- (N '- (3thiophenesulfonyl) amino) pentanamide 5-amino- (S) -2-N- (3-benzo [b ] thiophenesulfonyl) amino-N '- ((S) -1carbamoyl-2-phenylethyl) pentanamide 5-amino-N - ((S) -1-carbamoyl-2-phenylethyl) - (S) -2- (N'- (5- (1,3oxazol-5-yl) -2-thiophenonosulfonyl) amino) -pentanamide 5-amino-N - ((S) -1-carbamoyl-2-phenylethyl- (S) -2- (N'- (5-Chloro-1naphthalenesulfonyl) amino) pentanamide N - ((S) -1-carbamoyl-2- (4-biphenyl) ethyl) -5-guanidino- (S) -2- (N '- (1- naphthalenesulfonyl) amino) pentanamide

452 1 537 17 495 18 479 1 495 18

517 18

509 18

474 1, 14 512 17 503 17 454 1, 14 425 18 475 18 492 18 503 18 587 17

Name MS-ESI + (m / z) Example

5-amino-N - ((S) -1-carbamoyl-2- (3-pyridinyl) ethyl) - (S) -2- (N '- (4484 18

methyl-1-naphthalenesulfonyl) amino) pentanamide

5-amino-N - ((S) -1-carbamoyl-2-phenylethyl) -N-methyl- (S) -2- (N '- (4497 18

methyl-1-naphthalenesulfonyl) amino) -pentanamide

5-amino-N- (2-benzyloxy- (S) -1-carbamoylethyl) - (S) -2- (N '- (4513 18

methyl-1-naphthalenesulfonyl) amino) pentamide

4-amino- (S) 2-N- (4-methyl-1-naphthalenesulfonyl) -amino-N'-1448 1

naphthylbutanamide

4-amino-N-cyclohexyl- (S) -2- (N '- (4-methyl-1-naphthalen404 1

sulfonyl) amino) butanamide

4-amino- (S) -2- (N- (4-methyl-1-naphthalenesulfonyl) 322 18

amino) butanamide

5-amino- (S) -2-N- (4-methyl-1-naphthalenesulfonyl) -amino-N'466 1

(1,2,3,4-tetrahydro-1-naphthyl) pentanamide

5-N-Methylamino- (S) -2-N '- (4-methyl-1-naphthalen-sulfonyl) amino480 1,14 N "- (1,2,3,4-tetrahydro-1-naphthyl) -pentanamide

Example 29

Binding affinity in human somatostatin receptor subtypes

The affinity of the compounds of the invention for the five was determined

5 subtypes of human somatostatin receptors (SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5) in competitive binding assays with (125I-Tyr) - [Leu8, DTrp22] -somatostatin-28 (125I-LTT-sst-28). The biological material for these experiments consisted of Chinese hamster ovary (CHO) membranes stably transfected with one of the five subtypes of human somatostatin receptors. The were incubated

10 membranes (3-20 �g of total protein per sample) and a minimum amount of 125I-LTTsst-28 in 10 mM Hepes, 1 mM EDTA, 5 mM MgCl2, 5 mg / ml BSA and 30 �g / ml of bacitracin, pH 7.6 with six concentrations of the compounds. Each concentration was analyzed in duplicate. Nonspecific binding was defined by somatostatin-14 (sst-14) 1M, and corresponded to 5-25% of total binding. After 60 min to tem

At room temperature, the incubations were terminated by rapid vacuum filtration through GF / B glass fiber filters (previously soaked at 4 ° C in 200 ml of 10 mM Hepes, 1 mM EDTA, 5 mM MgCl 2, pH 7 , 6) and three 5 ml washes with ice wash buffer (20 mM TRIS, 1 mM EDTA, 5 mM MgCl2, pH 7.4). After

the filters were dried, impregnated with scintillation liquid and their radioactivity was measured

Give by a scintillation count. The analysis of the experiments was carried out

by adjusting nonlinear curves by least squares. Cons were calculated

affinity ratios (Ki) from the IC50 values according to the Cheng- equation

Prusoff (Cheng and Prusoff, 1973). The experiments were repeated a minimum of three

times.

Through the use of the aforementioned protocol, the

following test results.

Compound Ki (SSTR1) Ki (SSTR2) Ki (SSTR3) Ki (SSTR4) Ki (SSTR5) / nM / nM / nM / nM / nM

Compound 17 1.0 ± 0.4> 10000> 2000 84 ± 23> 10000 Compound 2 500 ± 150> 5000 1400 ± 100 1.2 ± 0.4 540 ± 80

In addition to these, a large group of compounds had a Ki of less than 300 nM for SSTR1. In this group were, for example: Compound 3 Compound 5 15 Compound 6 Compound 7 Compound 11 Compound 12 Compound 15 20 Compound 18 Compound 21 Compound 22 Compound 23

In addition, another subgroup of the compounds of the invention had a Ki of less than 300 nM for SSTR4. In this group were, for example:

Compound 1

Compound 3 30 Compound 4

Compound 5 Compound 6 Compound 7 Compound 8 Compound 9 Compound 10 Compound 13 Compound 14 Compound 16 Compound 19 Compound 20

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Claims (19)

1. The use of a compound of Formula I, image 1 5 in which What is it 1 HOUR, 2) aryl, 3) heteroaryl or 10 4) a group of formula image 1 in which the aryl and heteroaryl are unsubstituted or substituted with 1 to 4 substitutes selected entities of Ra; A is 15 1) H, 2) (C1-C6) alkyl or 3) cycloalkyl (C3-C5); B is independently selected from 20 1) H, 2) halogen or 3) (C1-C6) alkyl; or the symbols B together can form a double or triple bond between the atoms to which they are attached; D is aryl or heteroaryl, which may be unsubstituted or substituted with one to four groups selected from Rd; R1 is 1 HOUR, 2) (C1-C6) alkyl or 3) cycloalkyl (C3-C7); each R2 is independently selected from 1) H, 2) (C1-C6) alkyl, 3) (C2-C6) alkenyl, 4) (C2-C6) alkynyl, 5) cycloalkyl (C3-C7), 6) cycloalkyl ( C3-C7) (C1-C6) alkyl, 7) -NH2 or 8) -C (= NRb) NRbRb; in which the symbols Rb together with the atoms to which they are attached can also form an unsaturated or saturated ring of 5 to 6 members; or R2 and R2, together with the nitrogen to which they are attached, can form a 5- to 7-membered ring containing 1 to 3 heteroatoms selected from N, O and S, in which the formed ring may be saturated or unsaturated; R3 is 1 HOUR, 2) (C1-C6) alkyl, 3) alkenyl (C2-C6), 4) (C2-C6) alkynyl or 5) cycloalkyl (C3-C7); R4 is 1) H, 2) (C1-C6) alkyl, 3) (C2-C6) alkenyl, 4) (C2-C6) alkynyl, 5) Cy, 6) Cy-C1-C6 alkyl, 7) Cy-alkenyl (C2-C6) or 8) Cy-alkynyl (C2-C6); wherein the alkyl, alkenyl, alkynyl and Cy are each optionally substituted with one to two substituents selected from Rd; R5 is 1 HOUR, 2) (C1-C6) alkyl, 3) alkenyl (C2-C6), 4) (C2-C6) alkynyl, 5) aryl, 6) aryl (C1-C6) alkyl, 7) heteroaryl, 8) heteroaryl (C1-C6) alkyl or 9) - (CH2) kC (O) NHRb; wherein the aryl and heteroaryl are each optionally substituted with one to two substituents selected from Rd; or R4 and R5, together with the atom to which they are attached, form a 3 to 7 member ring containing 0 to 2 heteroatoms selected from N, O and S, in which said ring may be substituted with one to three selected substituents of Rd; or said ring may be fused to the aryl or heteroaryl which may be substituted with one to three substituents selected from Rd; Ra is independently 1 HOUR, 2) halogen, 3) -ORb, 4) (C1-C6) alkyl or 5) -CF3; Rb is independently 1) hydrogen, 2) (C1-C6) alkyl, 3) (C2-C6) alkenyl, 4) (C2-C6) alkynyl, 5) Cy o 6) Cy-C1-C4 alkyl; Rd is independently 1) a group selected from Rc, 2) (C1-C6) alkyl, 3) (C2-C6) alkenyl, 4) (C2-C6) alkynyl, 5) aryl, 6) aryl-C1-alkyl C6), 7) heteroaryl (C1-C6) alkyl, 8) (C3-C7) cycloalkyl or 9) heterocyclyl; wherein the alkyl, alkenyl, alkynyl, aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from Rc; Rc is independently 1) a selected group of Ra, 2) -NO2, 3) -SRb, 4) -NRbRb, 5) -CN or 6) -NRbC (O) Rb; k is an integer 0 or 1; n is an integer from 0 to 3; Y Cy is cycloalkyl, heterocyclyl, aryl or heteroaryl; or a pharmaceutically acceptable salt or ester thereof, for the preparation of a medicament for the treatment of a disease or condition in mammals in which interaction with the subtypes of somatostatin 1 and / or 4 receptors is indicated. 2. The use according to claim 1, wherein the compound of Formula I is a compound of Formula IA image 1 or a pharmaceutically acceptable salt or ester thereof, Wherein R2, R3, B and D are as defined in claim 1; R4 is benzyl which may be optionally substituted with one to two substituents selected from Ra as defined in claim 1; and n is an integer 1 or 2. The use according to claim 1, wherein the compound of Formula I is a compound of Formula IB image 1 or a pharmaceutically acceptable salt or ester thereof, wherein R2, R3, B and D are as defined in claim 1; R4 is phenyl or benzyl, which is unsubstituted or substituted with 1 to 2 substituents selected from Ra as defined in claim 1; R5 is hydrogen or (C1-C6) alkyl; and n is an integer 1 or 2. The use according to claim 1, wherein the compound of Formula I is a compound of Formula IC or a pharmaceutically acceptable salt or ester thereof, wherein R3, Q and D are as defined in claim 1 ; each R2 is independently selected from image2 5 1) H, 2) (C1-C3) alkyl, 3) cycloalkyl (C1-C3) or 4) -C (= NH) NH2; Y 10 n is an integer 1 or 2. 5. The use according to claim 1, wherein the compound of Formula I is a compound of Formula ID image 1 15 or a pharmaceutically acceptable salt or ester thereof, wherein R2, R3, B and Q are as defined in claim 1; Y R6 is independently 1) H, 2) Halogen, 3) -NO2, 4) -NRbRb, 5) -CN, 6) -ORb, 7) -SRb, 8) -C (O) Rb, 9) (C1-C6) alkyl, 10) alkenyl (C2-C6), 11) (C2-C6) alkynyl, 12) cycloalkyl (C3-C7) or 13) -CF3; Rb is as defined in claim 1; L is C (R6), S or N; n is an integer 1 or 2; t is an integer from 0 to 3; Y X is a bond or C (R6), so the combination of L and X is chosen in such a way that the aromatic nature of the bicyclic ring system to which L and X belong.

6.

The use according to any of claims 1, 2, 3, 4 or 5, wherein R3 is H or methyl.

7.

The use according to any one of claims 1, 2, 3, 4 or 5, wherein D is naphthyl, 4-alkyl-1-naphthyl, benzothiophenyl or indolyl.

8.

The use according to any of claims 1-7, wherein the compound is 4-amino- (S) -2-N- (4-methyl-1-naphthalenesulfonyl) amino-N '- (1,2,3, 4-tetra-hydro-1naphthyl) butanamide, 5-amino- (S) -2-N- (4-methyl-1-naphthalenesulfonyl) -amino-N '- (1,2,3,4-tetrahydro-1- naphthyl) pentanamide, N-benzyl-4-guanidino- (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) butanamide, 4-amino-N-2- (3-chlorophenyl) ethyl- (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) butanamide, 5-N-methylamino- (S) -2-N' - (4-methyl-1-naphthalenesulfonyl) amino-N "(1,2,3,4-tetrahydro-1-naphthyl) pentanamide or N-benzyl-4- (N'-isopropyl) amino- (S) -2- (N" - (4methyl-1-naphthalenesulfonyl) amino ) butanamide.

9.

The use according to claim 1 wherein the disease or condition is depression, anxiety, bipolar disorders, THDA, angiogenesis, restenosis, for

new blood vessel outbreaks, atherosclerosis, diabetic angiopathy, diabetic retinopathy, cancerous tumors and tumor metastases, elevated intraocular pressure or age-related macular degeneration. 10. A compound of Formula II image 1 or a pharmaceutically acceptable salt or ester thereof, wherein R1, R3, A, B and Q are as defined in claim 1; Y 10 each R2 is independently selected from 1) H, 2) (C1-C6) alkyl, 3) (C2-C6) alkenyl, 4) (C2-C6) alkynyl, 5) cycloalkyl (C3-C7) or 6) cycloalkyl (C3-C7) alkyl (C1-C6); or the symbols R2 together with the nitrogen to which they are attached form a saturated 5- to 7-membered ring containing 1 to 2 heteroatoms selected from N, O and 20 S; and when Q is a group of formula image 1 then R4 is as defined in claim 1; R5 is 25 1) H, 2) (C1-C6) alkyl, 3) alkenyl (C2-C6), 4) (C2-C6) alkynyl, 5) aryl, 6) aryl (C1-C6) alkyl, 7) heteroaryl or 8) heteroaryl (C1-C6) alkyl; wherein the aryl and heteroaryl are each optionally substituted with one to four substituents selected from Rd as defined in claim 1; or R4 and R5, together with the atom to which they are attached, form a 3- to 8-membered ring containing 0 to 2 heteroatoms selected from N, O and S, in which said ring may be substituted with one to three selected substituents of Rd; or said ring may be fused to the aryl or heteroaryl which may be substituted with one to three substituents selected from Rd; R6 is independently 1 HOUR, 2) halogen, 3) -NO2, 4) -NRbRb, 5) -CN, 6) -ORb, 7) -SRb, 8) -C (O) Rb, 9) (C1-C6) alkyl, 10) alkenyl (C2-C6), 11) (C2-C6) alkynyl, 12) cycloalkyl (C3-C7) or 13) -CF3; t is an integer from 0 to 3; n is an integer 1 or 2; X is a bond or C (R6); L is C (R6), S or N, whereby the combination of L and X is chosen such that the aromatic nature of the bicyclic ring system to which L and X belong belong is maintained. 11. A compound according to claim 10, which is a compound of Formula IIA, image 1 wherein R2, R3, B, L, X, n and t are as defined in claim 10; R4 is phenyl or benzyl; 10 which is unsubstituted or substituted with 1 to 2 substituents selected from Ra as defined in claim 1; R5 is H or (C1-C6) alkyl; and R6 is independently selected from H, halogen or (C1-C6) alkyl. 12. A compound according to claim 10, which is a compound of Formula IIB, image 1 wherein R3, L, X, R6, Q, n and t are as defined in claim 10; and R2 is independently selected from H, methyl, ethyl, isopropyl, cyclopropyl or cyclohexyl. 13. A compound according to any of claims 10 to 12, wherein R3 is H or methyl. 14. A compound according to any of claims 10 to 12, wherein L is C (R6), X is a bond or C (R6) and R6 is H. 15. A compound according to any of claims 10 to 13, wherein L and X is C (R6) and R6 is independently selected from H, (C1-C6) alkyl or halogen. 10 16. A compound according to any of claims 10 to 12, wherein L is N or S and X is a bond. 17. A compound of Formula II according to any of the claims 10 to 13 and 15, wherein the compound is 4-amino- (S) -2-N- (4-methyl-1-naphthalenesulfonyl) amino-N '- (1,2,3,4-tetrahydro- 1-naphthyl) butanamide, 5-amino- (S) -2-N- (4-methyl-1-naphthalenesulfonyl) amino-N '- (1,2,3,4-tetrahydro-1-naphthyl) pentanamide, 4 -amino-N-2- (3-chlorophenyl) ethyl- (S) -2- (N '- (4-methyl-1-naphthalenesulfonyl) amino) butanamide, 5-N-methylamino- (S) -2N'- (4-methyl-1-naphthalenesulfonyl) amino-N "- (1,2,3,4-tetrahydro-1-naphthyl) -pentanamide or N Benzyl-4- (N'-isopropyl) amino- (S) -2- (N "- (4-methyl-1-naphthalenesulfonyl) amino) butanamide. 18. A process for the preparation of a compound according to any of claims 10 to 17, which comprises reacting an amino acid amino acid of Formula III, image 1 wherein R1, A, B, Q and n are as defined in any of claims 10 to 17; R2 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or a protecting group; R3 is H, alkyl, cycloalkyl or a protecting group, with a sulfonyl acid derivative of Formula IV, image 1 wherein R6, L, X, n and t are as defined in any of claims 10 to 17; W is OH or a halogen, especially CI or Br, and in which the compounds of Formula III and IV are optionally protected. 19. A pharmaceutical composition comprising a compound of Fór Mule II according to claim 10 as an active ingredient together with a pharmaceutically acceptable diluent, carrier and / or excipient. 20. A compound of Formula II according to claim 10 for use in imaging healthy and diseased tissues and / or organs, such as brain, blood vessels or tumors, which possess SSTR1 and / or SSTR4 receptors. fifteen 21. The use of a compound of Formula II according to claim 10 for the preparation of a medicament for the treatment of a disease or condition in mammals in which interaction with the subtypes of somatostatin 1 and / or receptor subtypes is indicated. Four. twenty 22. The use according to claim 21, wherein the disease or condition is depression, anxiety, bipolar disorders, ADHD, angiogenesis, restenosis, formation of new blood vessel outbreaks, atherosclerosis, diabetic angiopathy, diabetic retinopathy, cancerous tumors and tumor metastasis, intraocular pressure 25 or macular degeneration associated with age.