Peptide epoxy ketones for proteasome inhibition

FIELD: medicine.

SUBSTANCE: invention refers to a compound having the structure of formula (I), or its pharmaceutically acceptable salt, wherein specified radicals are presented in the description, and also concerns a compound representing or its pharmaceutically acceptable salt. The present invention declares a pharmaceutical composition possessing inhibitory activity in the relation to 20S proteasome containing a pharmaceutically acceptable carrier or a diluent and a therapeutically effective amount of the compound, and also the invention refers to methods of treating the immune diseases, such as inflammatory intestinal disease, to treating cancer, to treating infection, to treating proliferative diseases, to treating neurodegenerative disease or asthma.

EFFECT: higher clinical effectiveness.

34 cl, 21 ex, 2 dwg

 

Prior art

In eukaryotes, protein degradation is mainly mediated through the metabolic pathway of ubiquitin, in which proteins are targeted for destruction, legirovanyh with 76 amino acid polypeptide of ubiquitin. Then, after targeting ubiquitinated proteins serve as substrates for the 26S proteasome, polimetallicheskoe protease that cleaves proteins into short peptides by the action of the three major proteolytic activities. Along with the existing main function in functional intracellular protein loop-mediated proteasome degradation also plays a key role in many processes, such as the presentation of major histocompatibility complex (MHC) class I, apoptosis and cell viability, the processing of antigen, activation of NF-kB and transduction of Pro-inflammatory signals.

20S Proteasome is politicalticker complex protease, which has a cylindrical shape, 700 kDa, including 28 subunits classified as α - and β-type, which is arranged in the form of 4 stacked (stacked in a pile) heptameric rings. In yeast and other eukaryotes, 7 different α subunits form the outer ring, and 7 different β subunits include an inner ring. Subunit α serve as binding sites for regulatory set xov 19S (RA) and 11S (RA), and also as a physical barrier for the inner proteolytic chamber formed by the rings of the two β subunits. So, I think that in vivo proteasome exists in the form of 26S particles ("26S proteasome"). Experiments in vivo have shown that inhibition of 20S forms of the proteasome can be easily correlated with the inhibition of the 26S proteasome.

Splitting aminobenzoic of proposedvalue β subunits during formation of the particles reveals aminobenzene threonine residues, which serve as the catalytic nucleophiles. Therefore, the subunit responsible for the catalytic activity of the proteasome, have aminobenzoic nucleophilic residue, and these subunits belong to the family of N-terminal nucleophilic (Ntn) hydrolases (where the nucleophilic N-terminal residue is, for example, Cys, Ser, Thr, and other nucleophilic fragments). This family includes, for example, penicillin G acylase (PGA), penicillin V acylase (PVA), glutamine PRPP amidotransferase (GAT) and bacterial glucosylceramidase. In addition to expressing the ubiquitin β subunits of higher vertebrates also have three interferon-γ-inducible β subunits (LMP7, LMP2 and MECL1), which replace their own replaceable parts, β5, β1 and β2, respectively. When all three IFN-γ-inducible subunit, proteasome on what to see “immunoproteasome”. Therefore, eukaryotic cells can have two forms of the proteasome in various ratios.

Using a variety of peptide substrates has three main proteolytic activity of eukaryotic 20S proteasomes: the chymotrypsin-like activity (CT-L), which splits the subsequent large hydrophobic residues; trypsin-like activity (T-L), which breaks down further remains of the main character, and peptidylglutamyl gidrolizutaya activity (PGPH), which splits the subsequent acid residues. Also described two additional less-characterized activity of the proteasome: the BrAAP activity, which breaks down further branched chain amino acids, and the activity of SNAAP, which splits the subsequent small neutral amino acids. Although both forms of the proteasome have all five enzymatic activities, on the basis of specific substrates described differences in the magnitude of activities between forms. Apparently, for both forms of the proteasome, the major proteolytic activity of the proteasome contribute through the different catalytic sites within the 20S core.

There are several examples of small molecules that are used for inhibiting the activity of the proteasome, however, such compounds are usually not sufficiently specific for transcipt is retireve between the two forms of the proteasome. It is therefore not possible to study and research the role of each specific form of the proteasome at the cellular and molecular level. Therefore, it is necessary to create inhibitor(s) of small molecule, which preferably inhibits one form of the proteasome, to make possible the study of the role of each form of the proteasome at the cellular and molecular level.

The invention

One aspect of the invention relates to inhibitors that preferentially inhibit the activity of immunoproteasome compared with the activity of the constitutive proteasome. In some embodiments implementing the invention relates to treating an immune disease, comprising introducing the compound of the invention. In some embodiments implementing the invention relates to the treatment of cancer, comprising introducing the compound of the invention.

One aspect of the invention relates to compounds having the structure of formula (I)or their pharmaceutically acceptable salt,

where each Ar independently represents an aromatic or heteroaromatic group, optionally substituted by 1-4 substituents;

each And independently selected from C=O, C=S and SO2preferably, C=O, or

And does not necessarily represent covalent bond when adjacent to on against the structure to present Z;

In absent or represents-N(R9R10preferably, missing;

L is absent or selected from C=O, C=S or SO2preferably, SO2or C=O;

M is absent or represents a C1-12alkyl, preferably With1-8alkyl;

Q is absent or selected from O, NH or N-C1-6of alkyl;

X is selected from O, S, NH and N1-6the alkyl, preferably O;

Y is absent or represents C=O, and SO2;

each Z is independently selected from O, S, NH and N1-6the alkyl, preferably O; or

Z is an optional covalent bond, when it is related to present And;

R1selected from H, -C1-6alkyl, C1-6hydroxyalkyl,1-6alkoxyalkyl, aryl and C1-6arylalkyl;

R2and R3each independently selected from aryl, C1-6arylalkyl, heteroaryl and C1-6heteroallyl;

R4represents N(R5)L-Q-R6;

R5selected from hydrogen, HE, WITH1-6arylalkyl and C1-6the alkyl, preferably, hydrogen;

R6selected from hydrogen, C1-6of alkyl, C2-6alkenyl,2-6the quinil, Ar-Y-, carbocycle, heterocyclyl, N-terminal protective group, aryl, C1-6arylalkyl, heteroaryl,1-6heteroallyl, R11ZZ-C1-8the alkyl-, R14Z-Csub> 1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8alkyl-ZAZ-C1-8the alkyl-, R11ZAZ-C1-8alkyl-ZAZ-C1-8the alkyl-, ZAZ-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8the alkyl-, (R13)2N-C1-12the alkyl-, (R13)3N+-C1-12the alkyl-, heterocyclyl, carbocyclic-, R14SO2C1-8the alkyl and R14SO2NH, preferably, N-capirola group, or

R5and R6together represent a1-6the alkyl-Y-C1-6alkyl, C1-6alkyl-ZAZ-C1-6alkyl, ZAZ-C1-6alkyl-ZAZ-C1-6alkyl, ZAZ-C1-6alkyl-ZAZ or1-6alkyl, thereby forming a ring;

R7and R8independently selected from hydrogen, C1-6the alkyl and C1-6arylalkyl, preferably, hydrogen;

R9selected from hydrogen, HE, and1-6the alkyl, preferably With1-6of alkyl, and

R10represents the N-terminal protective group;

R11and R12independently selected from hydrogen, metal cation, With1-6of alkyl, C2-6alkenyl,2-6the quinil, aryl, heteroaryl,1-6arylalkyl and C1-6heteroallyl, preferably from hydrogen, metal cation and C1-6the alkyl, or R11and R12together represent a1-6alkyl, thereby forming a ring;

each R13independently selected from bodoro the a and C 1-6the alkyl, preferably With1-6of alkyl, and

R14independently selected from hydrogen, C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle, heterocyclyl, aryl, heteroaryl,1-6arylalkyl and C1-6heteroallyl;

R15selected from hydrogen, C1-6of alkyl, C1-6hydroxyalkyl,1-6alkoxy,

-S(O)OS1-6of alkyl, -C(O)NHC1-6the alkyl and C1-6arylalkyl;

provided that in any case the presence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.

Another aspect of the invention relates to compounds having the structure of formula (II), or pharmaceutically acceptable salt

where each Ar independently represents an aromatic or heteroaromatic group, optionally substituted by 1-4 substituents;

each And independently selected from C=O, C=S and SO2preferably, C=O, or

And does not necessarily represent covalent bond when it is related to present Z;

In absent or represents-N(R9R10preferably, missing;

L is absent or selected from C=O, C=S and SO2preferably, SO2or C=O;

M is absent or represents a C1-12alkyl, suppose the equipment, With1-8alkyl;

Q is absent or selected from O, NH and N1-6of alkyl;

X is selected from O, S, NH and N1-6the alkyl, preferably O;

Y is absent or selected from C=O and SO2;

each Z is independently selected from O, S, NH and N1-6the alkyl, preferably O; or

Z is an optional covalent bond, when it is related to present And;

R2and R3each independently selected from aryl, C1-6arylalkyl, heteroaryl and C1-6heteroallyl;

R4represents N(R5)L-Q-R6;

R5selected from hydrogen, HE, WITH1-6arylalkyl and C1-6the alkyl, preferably, hydrogen;

R6selected from hydrogen, C1-6of alkyl, C2-6alkenyl,2-6the quinil, Ar-Y-, carbocycle, heterocyclyl, N-terminal protective group, aryl, C1-6arylalkyl, heteroaryl,1-6heteroallyl, R11ZAZ-C1-8the alkyl-, R14Z-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8alkyl-ZAZ-C1-8the alkyl-, R11ZAZ-C1-8alkyl-ZAZ-C1-8the alkyl-, ZAZ-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8the alkyl-, (R13)2N-C1-12the alkyl-, (R13)3N+-C1-12the alkyl-, heterocyclyl, carbocyclic-, R14SO2C1-8the alkyl and R14SO2NH, preferably, N-capiro the soup group or

R5and R6together represent a1-6the alkyl-Y-C1-6alkyl, C1-6alkyl-ZAZ-C1-6alkyl, ZAZ-C1-6alkyl-ZAZ-C1-6alkyl, ZAZ-C1-6alkyl-ZAZ or1-6alkyl, thereby forming a ring;

R8selected from hydrogen, C1-6the alkyl and C1-6arylalkyl, preferably, hydrogen;

R9selected from hydrogen, HE, and1-6the alkyl, preferably With1-6of alkyl, and

R10represents the N-terminal protective group;

R11and R12independently selected from hydrogen, metal cation, With1-6of alkyl, C2-6alkenyl,2-6the quinil, aryl, heteroaryl,1-6arylalkyl and C1-6heteroallyl, preferably from hydrogen, metal cation and C1-6the alkyl, or R11and R12together represent a1-6alkyl, thereby forming a ring;

each R13independently selected from hydrogen and C1-6the alkyl, preferably With1-6of alkyl; and

R14independently selected from hydrogen, C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle, heterocyclyl, aryl, heteroaryl,1-6arylalkyl and C1-6heteroallyl;

R15selected from hydrogen, C1-6of alkyl, C1-6hydroxyalkyl,1-6alkoxy, -S(O)OS1-6of alkyl, -C(O)NH1-6the alkyl and C1-6arylalkyl;

provided that in any case the presence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.

Another aspect of the invention relates to compounds having the structure of formula (III), or their pharmaceutically acceptable salt,

where is each And independently selected from C=O, C=S and SO2preferably, C=O, or

And does not necessarily represent covalent bond when it is related to present Z;

In absent or represents-N(R9R10preferably, missing;

L is absent or selected from C=O, C=S and SO2preferably, SO2or C=O;

M is absent or represents a C1-12alkyl, preferably With1-8alkyl;

W is selected from-Cho, and-IN(OR11)2;

Q is absent or selected from O, NH and N1-6of alkyl;

Y is absent or selected from C=O and SO2;

each Z is independently selected from O, S, NH and N1-6the alkyl, preferably O; or

Z is an optional covalent bond, when it is related to present And;

R1selected from H, -C1-6alkyl, C1-6hydroxyalkyl,1-6alkoxyalkyl, aryl and C1-6arylalkyl;

R2and R3each independently selected from aryl, sub> 1-6arylalkyl, heteroaryl and C1-6heteroallyl;

R4represents N(R5)L-Q-R6;

R5selected from hydrogen, HE, WITH1-6arylalkyl and C1-6the alkyl, preferably, hydrogen;

R6selected from hydrogen, C1-6of alkyl, C2-6alkenyl,2-6the quinil, Ar-Y-, carbocycle, heterocyclyl, N-terminal protective group, aryl, C1-6arylalkyl, heteroaryl,1-6heteroallyl, R11ZAZ-C1-8the alkyl-, R14Z-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8alkyl-ZAZ-C1-8the alkyl-, R11ZAZ-C1-8alkyl-ZAZ-C1-8the alkyl-, ZAZ-C1-8the alkyl-, (R11)(R12O)P(=O)O-C1-8of alkyl, R13)2N-C1-12the alkyl-, (R13)3N+-C1-12the alkyl-, heterocyclyl, carbocyclic-, R14SO2C1-8the alkyl and R14SO2NH, preferably, N-capirola group, or

R5and R6together represent a1-6the alkyl-Y-C1-6alkyl, C1-6alkyl-ZAZ-C1-6alkyl, ZAZ-C1-6alkyl-ZAZ-C1-6alkyl, ZAZ-C1-6alkyl-ZAZ or1-6alkyl, thereby forming a ring;

R7and R8independently selected from hydrogen, C1-6the alkyl and C1-6arylalkyl, preferably, hydrogen;

R9selected from hydrogen, HE, and1-6the alkyl, preferably With1-6is Lila, and

R10represents the N-terminal protective group;

R11and R12independently selected from hydrogen, metal cation, With1-6of alkyl, C2-6alkenyl,2-6the quinil, aryl, heteroaryl,1-6arylalkyl and C1-6heteroallyl, preferably from hydrogen, metal cation and C1-6the alkyl, or R11and R12together represent a1-6alkyl, thereby forming a ring;

each R13independently selected from hydrogen and C1-6the alkyl, preferably With1-6of alkyl, and

R14independently selected from hydrogen, C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle, heterocyclyl, aryl, heteroaryl,1-6arylalkyl and C1-6heteroallyl;

each R16independently selected from hydrogen and C1-6the alkyl, or two R11together can be a1-6alkyl, thereby forming a ring together with atoms of boron and oxygen to which they are attached;

provided that in any case the presence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.

Another aspect of the invention relates to compounds having the structure of formula (IV), or their pharmaceutically acceptable salt,

where ka is each And independently selected from C=O, C=S and SO2preferably, C=O, or

And does not necessarily represent covalent bond when it is related to present Z;

L is absent or selected from C=O, C=S and SO2preferably, SO2or C=O;

M is absent or represents a C1-12alkyl, preferably With1-8alkyl;

W is selected from SNO IN(OR11)2;

Q is absent or selected from O, NH and N1-6of alkyl;

Y is absent or selected from C=O and SO2;

each Z is independently selected from O, S, NH and N1-6the alkyl, preferably O; or

Z is an optional covalent bond, when it is related to present A;

R2and R3each independently selected from aryl, C1-6arylalkyl, heteroaryl and C1-6heteroallyl;

R4represents N(R5)L-Q-R6;

R5selected from hydrogen, HE, WITH1-6arylalkyl and C1-6the alkyl, preferably, hydrogen;

R6selected from hydrogen, C1-6of alkyl, C2-6alkenyl,2-6the quinil, Ar-Y-, carbocycle, heterocyclyl, N-terminal protective group, aryl, C1-6arylalkyl, heteroaryl,1-6heteroallyl, R11ZAZ-C1-8of alkyl, R14Z-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8alkyl-ZAZ-C1-8the alkyl-, R11ZAZ-C1-8and the Kil-ZAZ-C 1-8the alkyl-, ZAZ-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8the alkyl-, (R13)2N-C1-12the alkyl-, (R13)3N+-C1-12the alkyl-, heterocyclyl, carbocyclic-, R14SO2C1-8the alkyl and R14SO2NH, preferably, N-capirola group, or

R5and R6together represent a1-6the alkyl-Y-C1-6alkyl, C1-6alkyl-ZAZ-C1-6alkyl, ZAZ-C1-6alkyl-ZAZ-C1-6alkyl, ZAZ-C1-6alkyl-ZAZ or1-6alkyl, thereby forming a ring;

R8selected from hydrogen, C1-6the alkyl and C1-6arylalkyl, preferably, hydrogen;

R9selected from hydrogen, HE, and1-6the alkyl, preferably With1-6of alkyl, and

R10represents the N-terminal protective group;

R11and R12independently selected from hydrogen, metal cation, With1-6of alkyl, C2-6alkenyl,2-6the quinil, aryl, heteroaryl,1-6arylalkyl and C1-6heteroallyl, preferably from hydrogen, metal cation and C1-6the alkyl, or R11and R12together represent a1-6alkyl, thereby forming a ring;

each R13independently selected from hydrogen and C1-6the alkyl, preferably With1-6of alkyl; and

R14independently selected from hydrogen, C1-6of alkyl, C2-6alkenyl, With2-6the quinil, carbocycle, heterocyclyl, aryl, heteroaryl,1-6arylalkyl and C1-6heteroallyl;

each R16independently selected from hydrogen and C1-6the alkyl, or two R11together can be a1-6alkyl, thereby forming a ring together with atoms of boron and oxygen to which they are attached;

provided that in any case the presence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.

Brief description of drawings

Figure 1 shows the level of expression of immunoproteasome some cell lines and samples from the body of the patient, including multiple myeloma, leukemia, lymphoma and solid tumors.

Figure 2(A) shows the effect of compound14on the development of the disease in mouse models of rheumatoid arthritis (RA), where the dosage was started when the animals first showed symptoms of the disease (arrows), and demonstrate the data represent the average quantitative indicator diseases (±SEM; N=7/group) and are representative of three independent experiments.

Figure 2(B) shows the effect of compound14on the development of the disease in mouse models of RA, where RA was induced on day 0 in female DBA/1 mice by immunization cow is collagen type II in CFA, where dosing was started when the animals first showed symptoms of the disease (arrows), and demonstrate the data represent the average quantitative indicator diseases (±SEM; N=10/group).

Detailed description of the invention

The invention includes compounds which are useful as inhibitors of the enzyme. Such compounds are primarily useful for inhibition of enzymes having a nucleophilic group at the N-Terminus. For example, the activity of enzymes or subunits of enzymes with N-terminal amino acids with nucleophiles in side chains, such as threonine, serine, or cysteine, can be successfully inhibit described in this description of inhibitors of the enzyme. The activity of enzymes or subunits of enzymes having diaminotoluene nucleophilic group at the N-ends, such as, for example, protective groups or carbohydrates, it is also possible to successfully inhibit described in this description of inhibitors of the enzyme.

Not based on any particular theory of action, it is expected that such N-terminal nucleophiles Ntn form covalent adducts with epoxy, aziridine, aldehyde or borate functional group described inhibitors of the enzyme. For example, suppose that in the β5 subunit/Pre2 20S proteasome N-terminal threonine irreversibly forms of morpholino or piperazine derivatives adduct after interaction is the major with a peptide epoxide or aziridine, such as described below. Such formation of the adduct may include splitting with ring opening of the epoxide or aziridine.

In regard to stereochemistry, apply rules of Ken-Ingold-Prelog for determination of absolute stereochemistry. These rules are described, for example, in Organic Chemistry, Fox and Whitesell; Jones and Bartlett Publishers, Boston, MA (1994); Section 5-6, pp.177-178, which is thus included in the present description by reference. The peptides can have a repetitive structure of the main chain with side chains originating from the units of the main chain. Typically, each unit of the main chain has a related side chain, although in some cases the side chain represents a hydrogen atom. In other embodiments, the implementation is not each unit of the main chain is attached a side chain. The peptides used in the peptide or peptide epoxides aziridine have two or more units of the main chain. In some embodiments, the implementation used for the inhibition chymotrypsinogen (CT-L) activity of the proteasome, is from two to eight units of the main chain, and in some preferred embodiments, the implementation for the inhibition of CT-L is from two to six units of the main chain.

Side chains originating from the units of the main chain may include side chains of natural aliphatic or aromatic amino acid is t, such as hydrogen (glycine), methyl (alanine), isopropyl (valine), sec-butyl (isoleucine), isobutyl (leucine), phenylmethyl (phenylalanine), and a side chain comprising the amino acid Proline. Side chains can be also other aliphatic or aromatic groups, branched or unbranched structure, such as ethyl, n-propyl, n-butyl, tert-butyl, and aryl-substituted derivatives such as 1-phenylethyl, 2-phenylethyl, (1-naphthyl)methyl, (2-naphthyl)methyl, 1-(1-naphthyl)ethyl, 1-(2-naphthyl)ethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl and the like. Aryl groups can be optionally substituted C1-6alkyl groups are branched or non-branched structure, or a substituted alkyl group, acetyl and the like, or an additional aryl groups or substituted aryl groups such as benzoyl and the like. Heteroaryl groups can also be used as substituents of the side chains. Heteroaryl groups include nitrogen-, oxygen - and sulfur-containing aryl group, such as thienyl, benzothiazyl, naftotiekis, thianthrene, furyl, pyranyl, isobenzofuranyl, bromanil, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, indolyl, purinol, chinosol and the like.

In some embodiments, the implementation of polar or charged residues can be introduced into the peptide epoxides isopeptide aziridine. For example, can be introduced natural amino acids, such as hydroxycobalamine (Thr, Tyr, Ser) or sulfur-containing (Met, Cys), and amino acids, non-essential, such as taurine, carnitine, citrulline, cystine, ornithine, norleucine and others. Can also be included deputies of the side chains unnatural origin with charged or polar groups, such as, for example, With1-6alkyl chains or6-12aryl group with one or more hydroxy groups, having a short chain alkoxy, sulfide, thio, carboxyl, ester, phospho, amido or amino groups, or substituents, substituted by one or more halogen atoms. In some preferred embodiments, the implement has at least one aryl group present in the side chain of the peptide fragment.

In some embodiments, the implementation unit of the main chain are amide units [-NH-CHR-C(=O)-], where R represents a side chain. This designation does not preclude the natural amino acid Proline or other unnatural cyclic secondary amino acids, which will be obvious to specialists in this field.

In other embodiments, the implementation units of the basic circuit are N-alkylated amide units (for example, N-methyl and the like), OLE the new analogues in which one or more amide bonds substituted olefinic bonds), analogues of tetrazole (in which the ring tetrazole introduces a CIS-configuration in the main chain), or a combination of such links, the main chain. In other embodiments, the implementation of the α-carbon atom of the amino acid-modified α-alkyl substitution, for example aminoadamantane acid. In some of the following options exercise of the side chains are locally modified, for example, ΔΕ or ΔZ by dihydromorphinone, in which the double bond is present between α and β atoms of the side chain, or, for example, ΔΕ or ΔZ cyclopropane modification in which cyclopropyl group is present between the α and β atoms of the side chain. In the following implementation options using amino acid groups can apply D-amino acids. The following options for implementation may include the cyclization of the side chain to the main chain, the formation of a disulfide bond, the formation of lactam, asosiasi and other modifications discussed in “Peptides and Mimics, Design of Conformationally Constrained” Hruby and Boteju, “Molecular Biology and Biotechnology: A Comprehensive Desk Reference, ed. Robert A.Meyers, VCH Publishers (1995), pp.658-664, which are included in this description by reference.

One aspect of the invention relates to compounds having the structure of formula (I)or their pharmaceutically acceptable salt,

where each Ar independently represents particularly the aromatic or heteroaromatic group, optionally substituted by 1-4 substituents;

each And independently selected from C=O, C=S and SO2preferably, C=O, or

And does not necessarily represent covalent bond when it is related to present Z;

In absent or represents-N(R9R10preferably, missing;

L is absent or selected from C=O, C=S or SO2preferably, SO2or C=O;

M is absent or represents a C1-12alkyl, preferably With1-8alkyl;

Q is absent or selected from O, NH or N-C1-6of alkyl;

X is selected from O, S, NH and N1-6the alkyl, preferably O;

Y is absent or represents C=O, and SO2;

each Z is independently selected from O, S, NH and N1-6the alkyl, preferably O; or

Z is an optional covalent bond, when it is related to present And;

R1selected from H, -C1-6alkyl, C1-6hydroxyalkyl,1-6alkoxyalkyl, aryl and C1-6arylalkyl;

R2and R3each independently selected from aryl, C1-6arylalkyl, heteroaryl and C1-6heteroallyl;

R4represents N(R5)L-Q-R6;

R5selected from hydrogen, HE, WITH1-6arylalkyl and C1-6the alkyl, preferably, hydrogen;

R6selected from odorata, With1-6of alkyl, C2-6alkenyl,2-6the quinil, Ar-Y-, carbocycle, heterocyclyl, N-terminal protective group, aryl, C1-6arylalkyl, heteroaryl,1-6heteroallyl, R11ZZ-C1-8the alkyl-, R14Z-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8alkyl-ZAZ-C1-8the alkyl-, R11ZAZ-C1-8alkyl-ZAZ-C1-8the alkyl-, ZAZ-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8the alkyl-, (R13)2N-C1-12the alkyl-, (R13)3N+-C1-12the alkyl-, heterocyclyl, carbocyclic-, R14SO2C1-8the alkyl and R14SO2NH, preferably, N-capirola group, more preferably tert-butoxycarbonyl or benzyloxycarbonyl, or

R5and R6together represent a1-6the alkyl-Y-C1-6alkyl, C1-6alkyl-ZAZ-C1-6alkyl, ZAZ-C1-8alkyl-ZAZ-C1-6alkyl, ZAZ-C1-6alkyl-ZAZ or1-6alkyl, thereby forming a ring;

R7and R8independently selected from hydrogen, C1-6the alkyl and C1-6arylalkyl, preferably, hydrogen;

R9selected from hydrogen, HE, and1-6the alkyl, preferably With1-6of alkyl, and

R10represents the N-terminal protective group;

R11and R12independently selected from hydrogen, metal cation, With1-6of alkyl, C2-6alkene is La, With2-6the quinil, aryl, heteroaryl,1-6arylalkyl and C1-6heteroallyl, preferably from hydrogen, metal cation and C1-6the alkyl, or R11and R12together represent a1-6alkyl, thereby forming a ring;

each R13independently selected from hydrogen and C1-6the alkyl, preferably With1-6of alkyl, and

R14independently selected from hydrogen, C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle, heterocyclyl, aryl, heteroaryl,1-6arylalkyl and C1-6heteroallyl;

R15selected from hydrogen, C1-6of alkyl, C1-6hydroxyalkyl,1-6alkoxy,

-S(O)OS1-6of alkyl, -C(O)NHC1-6the alkyl and C1-6arylalkyl, preferably, With1-6the alkyl and C1-6hydroxyalkyl, more preferably, methyl, ethyl, hydroxymethyl and 2-hydroxyethyl;

provided that in any case the presence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.

In some embodiments, the implementation of R1selected from-C1-6alkyl-b and C1-6arylalkyl. In some such embodiments, the implementation of R1substituted by one or more substituents selected from hydroxy, halogen, amide, amine, carboxylic acid (or salt thereof), ester is (including complex 1-6alkilany ester, complex With1-5alkilany ether and complex arrowy ester), thiol, or simple tiefer. In some preferred embodiments, the implementation of R1substituted by one or more substituents selected from a carboxylic acid and a complex ester. In some embodiments, the implementation of R1selected from methyl, ethyl, isopropyl, carboxymethyl and benzyl. In some embodiments, the implementation of R1represents-C1-6alkyl-b and C1-6arylalkyl. In certain preferred such embodiments, the implementation is missing.

In some embodiments, the implementation of R2selected from C1-6arylalkyl and C1-6heteroallyl. In some such embodiments, the implementation of R2selected from C1-6alkylphenyl,1-6alcyonaria,1-6alkylthiol,1-6alkylaryl and C1-6alkalization, where the alkyl part may contain six, five, four, three, two or one carbon atom, preferably one or two. In some such embodiments, the implementation of R2substituted by one or more substituents selected from hydroxy, halogen, amide, amine, carboxylic acid (or its salts), complex ether (including complex1-6alkilany ester, complex With1-5alkilany ether and complex arrowy ester), thiol, or simple tiefer. is some such embodiments, the implementation of R 2replaced by Deputy selected from alkyl, trihalomethyl, alkoxy, hydroxy or cyano. In some such embodiments, the implementation of R2selected from C1-6alkylphenyl and C1-6alcyonaria. In some such preferred embodiments, the implementation of R2chosen from:

where D is selected from H, OMe, O-tert-Bu, OH, CN, CF3and CH3. In some embodiments, the implementation of D is selected from H, OMe, OH, CN, CF3and CH3.

In certain preferred such embodiments, the implementation, where D is attached to the six-membered ring D is attached in position 4 relative to the point of attachment, preferably, excluding cases of implementation, where the position 4 of the ring are occupied by the nitrogen of the pyridine ring.

In some embodiments, the implementation of R3selected from C1-6arylalkyl and C1-6heteroallyl, where the alkyl part may contain six, five, four, three, two or one carbon atom, preferably one or two. In some such embodiments, the implementation of R3substituted by one or more substituents selected from hydroxy, halogen, amide, amine, carboxylic acid (or its salts), complex ether (including complex1-6alkilany ester, complex With1-5alkilany ether and complex arrowy ester), thiol, or simple tiefer. In some that the variants of implementation of R 3replaced by Deputy selected from alkyl, trihalomethyl, alkoxy, hydroxy or cyano. In some such embodiments, the implementation of R3selected from C1-6alkylphenyl and C1-6alcyonaria. In certain preferred such embodiments, the implementation of R3chosen from:

where D is selected from H, OMe, O-tert-Bu, OH, CN, CF3or CH3. In some embodiments, the implementation of D is selected from H, OMe, HE, CN, CF3or CH3.

In some embodiments, the implementation of R5represents hydrogen, L represents C=O or SO2, R6is an Ar-Y-, and each Ar is independently selected from phenyl, indolyl, benzofuranyl, naphthyl, chinoline, chinolone, teinila, pyridyl, pirila and the like. In some such embodiments, the implementation of the Ar may be substituted Ar-E-, where E is selected from a direct link, -O - and1-6the alkyl. In some other embodiments, the implementation, where Q represents C1-6alkyl, Q may be substituted, preferably, Ar, such as phenyl.

In some embodiments, the implementation of R5represents hydrogen, Q is absent, L is a C=O or SO2and R6selected from Ar-Y and heterocyclyl. In certain preferred such embodiments, the implementation heterocyclyl selected from chromonica, Romania, morpholino and PI is eridania. In some other preferred such embodiments, the implementation of Ar is selected from phenyl, indolyl, benzofuranyl, naphthyl, chinoline, chinolone, teinila, pyridyl, pirila and the like.

In some embodiments, the implementation of R5represents hydrogen, L represents C=O or SO2Q is absent, and R6represents a C1-6alkenyl, where C1-6alkenyl represents a substituted vinyl group, where Deputy preferably represents aryl or heteroaryl group, more preferably phenyl group, optionally substituted by one to four substituents.

In some embodiments, the implementation of L and Q are absent, and R6selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil,1-6arylalkyl and C1-6heteroallyl. In some such embodiments, the implementation of R5represents a C1-6alkyl, and R6selected from butyl, allyl, propargyl, phenylmethyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.

In other embodiments, the implementation of L represents the SO2Q is absent, and R6selected from C1-6of alkyl and aryl. In some such embodiments, the implementation of R6selected from methyl and phenyl.

In some embodiments, the implementation of L represents C=O, and R6selected from C1-6of alkyl, 2-6alkenyl,2-6the quinil, aryl,

With1-6arylalkyl, heteroaryl,1-6heteroallyl,

R11ZA-C1-8the alkyl-, R14Z-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8of alkyl,

(R11O)(R12O)P(=O)O-C1-8alkyl-ZAZ-C1-8the alkyl-,

(R11O)(R12O)P(=O)O-C1-8alkyl-Z-C1-8the alkyl-,

R11ZA-C1-8alkyl-ZAZ-C1-8the alkyl-, ZAZ-C1-8of alkyl,

(R13)2N-C1-8the alkyl-, (R13)3N+-C1-8the alkyl-, heterocyclyl-,

carbocyclic-, R14SO2C1-8the alkyl and R14SO2NH-, where everyone present Z and a is independently other than a covalent bond. In some embodiments, the implementation of L represents C=O, Q is absent, and R6represents N.

In some embodiments, the implementation of R5represents a C1-6alkyl, R6represents a C1-6alkyl, Q is absent and L is a C=O. In some such embodiments, the implementation of R6represents ethyl, isopropyl, 2,2,2-triptorelin or 2-(methylsulphonyl)ethyl.

In other embodiments, the implementation of L represents C=O, Q is absent, and R6represents a C1-6arylalkyl. In some such embodiments, the implementation of R6selected from 2-phenylethyl, phenylmethyl, (4-way shall Setenil)methyl, (4-chlorophenyl)methyl and (4-forfinal)bromide.

In other embodiments, the implementation of L represents C=O, Q is absent, R5represents a C1-6alkyl, and R6represents aryl. In some such embodiments, the implementation of R6represents a substituted or unsubstituted phenyl.

In some embodiments, the implementation of L represents C=O, Q is absent, and R6selected from heteroaryl and C1-6heteroallyl. In some such embodiments, R6is heteroaryl selected from pyrrole, furan, thiophene, imidazole, isoxazol, oxazole, oxadiazole, thiazole, thiadiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine. In some such alternative embodiments, the implementation of R6represents a C1-6heteroaromatic selected from pyrrolidinyl, furylmethyl, thienylmethyl, imidazolidinyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolylmethyl, thiadiazolyl, triazolylmethyl, parasaissetia, pyridylmethyl, personalitie, pyridinylmethyl and pyrimidinylidene.

In some embodiments, the implementation of L represents C=O, Q is absent or represents O, and R6represents carbocyclic-, where M represents a C0-1alkyl. In some such embodiments, assests is of R 6is cyclopropyl or cyclohexyl.

In some embodiments, the implementation of L and a are C=O, Q is absent, Z represents O, M represents a C1-8alkyl, preferably methylene, and R6selected from R11ZA-C1-8the alkyl-, R14Z-C1-8the alkyl-, R11ZA-C1-8alkyl-ZAZ-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8alkyl-ZAZ-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8alkyl-Z-C1-8the alkyl - and ZAZ-C1-8the alkyl-, where everyone present And a is independently other than a covalent bond. In some such embodiments, the implementation of R6represents ZAZ-C1-8alkyl-, where heterocyclyl represents a substituted or unsubstituted oxadiazolyl or N(R16)(R17), where R16and R17together represent a1-6the alkyl-Y-C1-6alkyl, preferably1-3the alkyl-Y-C1-3alkyl, thereby forming a ring.

In some preferred embodiments, the implementation of L represents C=O, Q is absent, M is a C1-8alkyl, and R6selected from (R11O)(R12O)P(=O)O-C1-8of alkyl, R13)2NC1-8of alkyl, R13)3N+C1-8the alkyl - and heterocyclyl-M-. In some such embodiments, the implementation of R6is with the combat (R 13)2NC1-8alkyl or (R13)3N+C1-8alkyl-, where R13represents a C1-6alkyl. In some other such embodiments, the implementation of R6represents heterocyclyl-where heterocyclyl selected from morpholino, piperidino, piperazine derivatives and pyrrolidino.

In some embodiments, the implementation of L represents C=O, R5represents a C1-6alkyl, Q is selected from O and NH, and R6selected from C1-6of alkyl, cycloalkyl-M1-6arylalkyl and C1-6heteroallyl. In other embodiments, the implementation of L represents C=O, R5represents a C1-6alkyl, Q is selected from O and NH, and R6represents a C1-6alkyl, where C1-6alkyl selected from methyl, ethyl and isopropyl. In the following embodiments, the implementation of L represents C=O, R5represents a C1-6alkyl, Q is selected from O and NH, and R6represents a C1-6arylalkyl where arylalkyl represents phenylmethyl. In other embodiments, the implementation of L represents C=O, R5represents a C1-6alkyl, Q is selected from O and NH, and R6represents a C1-6heteroaromatic where heteroaromatic represents (4-pyridyl)methyl.

In some embodiments, the implementation of L is absent or represents C=O, and R5and R6postpredstva a 1-6the alkyl-Y-C1-6alkyl, C1-6alkyl-ZA-C1-6alkyl or C1-6alkyl-And where each participant Z and a is independently other than a covalent bond, thereby forming a ring. In some preferred embodiments, the implementation of L represents C=O, Q and Y are absent, and R5and R6together represent a1-3the alkyl-Y-C1-3alkyl. In another preferred embodiment, L and Q are absent, and R5and R6together represent a1-3the alkyl-Y-C1-3alkyl. In another preferred embodiment, L represents C=O, Q is absent, Y is selected from NH and N1-6of alkyl, and R5and R6together represent a1-3the alkyl-Y-C1-3alkyl. In another preferred embodiment, L represents C=O, Y is absent, and R5and R6together represent a1-3the alkyl-Y-C1-3alkyl. In another preferred embodiment, L and a are C=O, and R5and R6together represent a1-2alkyl-ZA-C1-2alkyl. In another preferred embodiment, L and a are C=O, and R5and R6together represent a2-3alkyl-A.

In some embodiments, the implementation of R7and R8independently selected from hydrogen and C1-6the alkyl. In some of the which preferred embodiments of implementation of R 7and R8independently selected from hydrogen and methyl. In preferred such embodiments, the implementation of R7and R8both represent hydrogen.

In some embodiments, implementation of the X represents Oh, R2and R3each independently represents a C1-6arylalkyl, and R1selected from C1-6of alkyl, C1-6hydroxyalkyl,1-6alkoxyalkyl, aryl and C1-6arylalkyl, any of which is optionally substituted by one or more of amide, amine, carboxylic acid (or its salt), esters (including complex1-6alkilany ester, complex With1-5alkilany ether and complex arrowy ester), thiol, or simple thioester deputies.

Suitable N-terminal protective group known in the field of peptide synthesis include tert-butoxycarbonyl (BOC), benzoyl (Bz), fluoren-9-ylmethoxycarbonyl (Fmoc), triphenylmethyl (trityl), trichlorocyanuric (Troc) and the like. The use of various N-protecting groups, for example benzyloxycarbonyl group or tert-butyloxycarbonyl group (BOC), various reagent combinations, such as dicyclohexylcarbodiimide (DCC), 1,3-diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), N-hydroxyisobutyrate (HATU), carbonyldiimidazole or monohydrate 1-hydroxy is benzotriazole (NOVT), and various conditions of cleavage, for example triperoxonane acid (TFUC, TFA), HCl in dioxane, hydrogenation on Pd-C in organic solvents (such as methanol or ethyl acetate), Tris(triptorelin)boron and cyanogenmod, and interaction in solution, with the isolation and purification of intermediate products, well-known in the field of peptide synthesis and applies equally to obtain the presented compounds. Suitable for protecting the N-terminal protective group can also be found, for example, Greene, T.W.; Wuts, P.G.M. “Protective Groups in Organic Synthesis”, 3rded.; Willey: New York, 1999, or Kocienski, P.J., “Protecting Groups”, Georg Thieme Verlag, 1994.

In some embodiments, the implementation of the stereochemical configuration of the carbon atoms with substituents R1, R2or R3independently represents D or L. In some preferred embodiments, the implementation of the stereochemical configuration at least one of the carbon atoms with substituents R1, R2and R3thus represents a D. In some such preferred embodiments, the implementation of the stereochemical configuration of the carbon atom having the substituents R1is a D. In some such embodiments, the implementation of the stereochemical configuration of the carbon atom having the substituents R2that is when the fight D. In some such embodiments, the implementation of the stereochemical configuration of the carbon atom having the substituents R3is a D. In some embodiments, the implementation of the stereochemical configuration at least two carbon atoms having substituents R1, R2and R3accordingly, represents a D. in another preferred embodiment, the stereochemical configuration of all three of the carbon atoms with substituents R1, R2and R3accordingly, represents a D.

Another aspect of the invention relates to compounds having the structure of formula (II), or pharmaceutically acceptable salt

each Ar independently represents an aromatic or heteroaromatic group, optionally substituted by 1-4 substituents;

each And independently selected from C=O, C=S and SO2preferably, C=O, or

And does not necessarily represent covalent bond when it is related to present Z;

In absent or represents-N(R9R10preferably, missing;

L is absent or selected from C=O, C=S and SO2preferably, SO2or C=O;

M is absent or represents a C1-12alkyl, preferably With1-8alkyl;

Q no is no, or selected from Oh, NH and N1-6of alkyl;

X is selected from O, S, NH and N1-6the alkyl, preferably O;

Y is absent or selected from C=O and SO2;

each Z is independently selected from O, S, NH and N1-6the alkyl, preferably O; or

Z is an optional covalent bond, when it is related to present And;

R2and R3each independently selected from aryl, C1-6arylalkyl, heteroaryl and C1-6heteroallyl;

R4represents N(R5)L-Q-R6;

R5selected from hydrogen, HE, WITH1-6arylalkyl and C1-6the alkyl, preferably, hydrogen;

R6selected from hydrogen, C1-6of alkyl, C2-6alkenyl,2-6the quinil, Ar-Y-, carbocycle, heterocyclyl, N-terminal protective group, aryl, C1-6arylalkyl, heteroaryl,1-6heteroallyl, R11ZAZ-C1-8the alkyl-, R14Z-C1-8the alkyl-, (R14O)(R12O)P(=O)O-C1-8alkyl-ZAZ-C1-8the alkyl-, R11ZAZ-C1-8alkyl-ZAZ-C1-8the alkyl-, ZAZ-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8the alkyl-, (R13)2N-C1-12the alkyl-, (R13)3N+-C1-12the alkyl-, heterocyclyl, carbocyclic-, R14SO2C1-8the alkyl and R14SO2NH, preferably, N-capirola group, more preferably tert-butoxy is bonila or benzyloxycarbonyl, or

R5and R6together represent a1-6the alkyl-Y-C1-6alkyl, C1-6alkyl-ZAZ-C1-6alkyl, ZAZ-C1-6alkyl-ZAZ-C1-6alkyl, ZAZ-C1-6alkyl-ZAZ or1-6alkyl, thereby forming a ring;

R8selected from hydrogen, C1-6the alkyl and C1-6arylalkyl, preferably, hydrogen;

R9selected from hydrogen, HE, and1-6the alkyl, preferably With1-6of alkyl, and

R10represents the N-terminal protective group;

R11and R12independently selected from hydrogen, metal cation, With1-6of alkyl, C2-6alkenyl,2-6the quinil, aryl, heteroaryl,1-6arylalkyl and C1-6heteroallyl, preferably from hydrogen, metal cation and C1-6the alkyl, or R11and R12together represent a1-6alkyl, thereby forming a ring;

each R13independently selected from hydrogen and C1-6the alkyl, preferably With1-6of alkyl; and

R14independently selected from hydrogen, C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle, heterocyclyl, aryl, heteroaryl,1-6arylalkyl and C1-6heteroallyl;

R15selected from hydrogen, C1-6of alkyl, C1-6hydroxyalkyl,1-6alkoxy, -S(O)OS1-6of alkyl, -C(O)NH1-6the alkyl and C1-6arylalkyl, p is edocfile, With1-6the alkyl and C1-6hydroxyalkyl, more preferably, methyl, ethyl, hydroxymethyl and 2-hydroxyethyl;

provided that in any case the presence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.

In some embodiments, the implementation of R2selected from C1-6arylalkyl and C1-6heteroallyl. In some such embodiments, the implementation of R2selected from C1-6alkylphenyl,1-6alcyonaria,1-6alkylthiol,1-6alkylaryl and C1-6alkalization, where the alkyl part may contain six, five, four, three, two or one carbon atom, preferably one or two. In some such embodiments, the implementation of R2substituted by one or more substituents selected from hydroxy, halogen, amide, amine, carboxylic acid (or its salts), complex ether (including complex1-6alkilany ester, complex With1-5alkilany ether and complex arrowy ester), thiol, or simple tiefer. In some such embodiments, the implementation of R2replaced by Deputy selected from alkyl, trihalomethyl, alkoxy, hydroxy or cyano. In some such embodiments, the implementation of R2selected from C1-6alkylphenyl and C1-6alcyonaria. In some preferred the exercise of such options R 2chosen from:

where D is selected from H, OMe, O-tert-Bu, HE, CN, CF3and CH3. In some embodiments, the implementation of D is selected from H, OMe, HE, CN, CF3and CH3.

In certain preferred such embodiments, the implementation, where D is attached to the six-membered ring D is attached in position 4 with respect to the place of connection, preferably, excluding cases of implementation, where the position 4 of the ring are occupied by the nitrogen atom of the pyridine ring.

In some embodiments, the implementation of R3selected from C1-6arylalkyl and C1-6heteroallyl. In some cases, the alkyl part may contain six, five, four, three, two or one carbon atom, preferably one or two. In some such embodiments, the implementation of R3substituted by one or more substituents selected from hydroxy, halogen, amide, amine, carboxylic acid (or its salts), complex ether (including complex1-6alkilany ester, complex With1-5alkilany ether or complex arrowy ester), thiol, or simple tiefer. In some such embodiments, the implementation of R3replaced by Deputy selected from alkyl, trihalomethyl, alkoxy, hydroxy or cyano. In some such embodiments, the implementation of R3selected from C1-6alkylphenyl and C1-6alcyonaria. In kotoryj preferred such embodiments, the implementation of R 3chosen from:

where D is selected from H, OMe, O-tert-Bu, OH, CN, CF3or CH3. In some embodiments, the implementation of D is selected from H, OMe, HE, CN, CF3or CH3.

In some embodiments, the implementation of R5represents hydrogen, L represents C=O or SO2, R6is an Ar-Y-, and each Ar is independently selected from phenyl, indolyl, benzofuranyl, naphthyl, chinoline, chinolone, teinila, pyridyl, pirila and the like. In some such embodiments, the implementation of the Ar may be substituted Ar-E-, where E is selected from a direct link, -O - and1-6the alkyl. In some other such embodiments, the implementation, where Q represents C1-6alkyl, Q may be substituted, preferably, Ar, such as phenyl.

In some embodiments, the implementation of R5represents hydrogen, Q is absent, L is a C=O or SO2and R6selected from Ar-Y and heterocyclyl. In certain preferred such embodiments, the implementation heterocyclyl selected from Romania, Romania, morpholino and piperidinyl. In some other preferred such embodiments, the implementation of Ar is selected from phenyl, indolyl, benzofuranyl, naphthyl, chinoline, chinolone, teinila, pyridyl, pirila and the like.

In some embodiments, the implementation of R5the submitted is a hydrogen, L represents C=O or SO2Q is absent, and R6represents a C2-6alkenyl, where C2-6alkenyl represents a substituted vinyl group, where Deputy preferably represents an aryl or heteroaryl group, more preferably phenyl group, optionally substituted by one to four substituents.

In some embodiments, the implementation of L and Q are absent, and R6selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil,1-6arylalkyl and C1-6heteroallyl. In some such embodiments, the implementation of R5represents a C1-6alkyl, and R6selected from butyl, allyl, propargyl, phenylmethyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.

In other embodiments, the implementation of L represents the SO2Q is absent, and R6selected from C1-6of alkyl and aryl. In some such embodiments, the implementation of R6selected from methyl and phenyl.

In some embodiments, the implementation of L represents C=O, and R6selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil, aryl,

With1-6arylalkyl, heteroaryl,1-6heteroallyl,

R11ZA-C1-8the alkyl-, R14Z-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8the alkyl-,

(R11O)(R12O)P(=O)O-C1-8alkyl-ZAZ-C1-8and the Qila-,

(R11O)(R12O)P(=O)O-C1-8alkyl-Z-C1-8the alkyl-,

R11ZA-C1-8alkyl-ZAZ-C1-8the alkyl-, ZAZ-C1-8the alkyl-,

(R13)2N-C1-8the alkyl-, (R13)3N+-C1-8the alkyl-, heterocyclyl-,

carbocyclic-, R14SO2C1-8the alkyl and R14SO2NH-, where everyone present Z and a is independently other than a covalent bond. In some embodiments, the implementation of L represents C=O, Q is absent, and R6represents hydrogen.

In some embodiments, the implementation of R5represents a C1-6alkyl, R6represents a C1-6alkyl, Q is absent and L is a C=O. In some such embodiments, the implementation of R6represents ethyl, isopropyl, 2,2,2-triptorelin or 2-(methylsulphonyl)ethyl.

In other embodiments, the implementation of L represents C=O, Q is absent, and R6represents a C1-6arylalkyl. In some such embodiments, the implementation of R6selected from 2-phenylethyl, phenylmethyl, (4-methoxyphenyl)methyl, (4-chlorophenyl)methyl and (4-forfinal)bromide.

In other embodiments, the implementation of L represents C=O, Q is absent, R5represents a C1-6alkyl, and R6represents aryl. In some such embodiments, the implementation of R6PR is dstanley a substituted or unsubstituted phenyl.

In some embodiments, the implementation of L represents C=O, Q is absent, and R6selected from heteroaryl and C1-6heteroallyl.In some such embodiments, the implementation of R6is heteroaryl selected from pyrrole, furan, thiophene, imidazole, isoxazol, oxazole, oxadiazole, thiazole, thiadiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine. In some such alternative embodiments, the implementation of R6represents a C1-6heteroaromatic selected from pyrrolidinyl, furylmethyl, thienylmethyl, imidazolidinyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolylmethyl, thiadiazolyl, triazolylmethyl, parasaissetia, pyridylmethyl, personalitie, pyridinylmethyl and pyrimidinylidene.

In some embodiments, the implementation of L represents C=O, Q is absent or represents O, and R6represents carbocyclic-, where M represents a C0-1alkyl. In some such embodiments, the implementation of R6is cyclopropyl or cyclohexyl.

In some embodiments, the implementation of L and a are C=O, Q is absent, Z represents O, M represents a C1-8alkyl, preferably methylene, and R6selected from R11FOR-C1-8the alkyl-, R4 Z-C1-8the alkyl-, R11ZA-C1-8alkyl-ZAZ-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8alkyl-ZAZ-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8alkyl-Z-C1-8the alkyl - and ZAZ-C1-8the alkyl-, where everyone present And a is independently other than a covalent bond. In some such embodiments, the implementation of R6represents ZAZ-C1-8alkyl-, where heterocyclyl represents a substituted or unsubstituted oxadiazolyl or N(R16)(R17), where R16and R17together represent a1-6the alkyl-Y-C1-6alkyl, preferably With1-3the alkyl-Y-C1-3alkyl, thereby forming a ring.

In some preferred embodiments, the implementation of L represents C=O, Q is absent, M is a C1-8alkyl, and R6selected from (R11O)(R12O)P(=O)O-C1-8the alkyl-, (R13)2NC1-8the alkyl-, (R13)3N+With1-8the alkyl - and heterocyclyl-M-. In some such embodiments, the implementation of R6represents (R13)2NC1-8alkyl or (R13)3N+C1-8alkyl-, where R13represents a C1-6alkyl. In some other such embodiments, the implementation of R6represents heterocyclyl-where heterocyclyl selected from morpholino, piperidino, is piperazino and pyrrolidino.

In some embodiments, the implementation of L represents C=O, R5represents a C1-6alkyl, Q is selected from O and NH, and R6selected from C1-6of alkyl, cycloalkyl-M1-6arylalkyl and C1-6heteroallyl. In other embodiments, the implementation of L represents C=O, R5represents a C1-6alkyl, Q is selected from O and NH, and R6represents a C1-6alkyl, where C1-6alkyl selected from methyl, ethyl and isopropyl. In the following embodiments, the implementation of L represents C=O, R5represents a C1-6alkyl, Q is selected from O and NH, and R6represents a C1-6arylalkyl where arylalkyl represents phenylmethyl. In other embodiments, the implementation of L represents C=O, R5represents a C1-6alkyl, Q is selected from O and NH, and R6represents a C1-6heteroaromatic where heteroaromatic represents (4-pyridyl)methyl.

In some embodiments, the implementation of L is absent or represents C=O, R5and R6together represent a1-6the alkyl-Y-C1-6alkyl, C1-6alkyl-ZA-C1-6alkyl or C1-6alkyl-And where each participant Z and a is independently other than a covalent bond, thereby forming a ring. In some preferred embodiments, the implementation of L represents C=O, Q Yiwu no, and R5and R6together represent a1-3the alkyl-Y-C1-3alkyl. In another preferred embodiment, L and Q are absent, and R5and R6together represent a1-3the alkyl-Y-C1-3alkyl. In another preferred embodiment, L represents C=O, Q is absent, Y is selected from NH and N1-6of alkyl, and R5and R6together represent a1-3the alkyl-Y-C1-3alkyl. In another preferred embodiment, L represents C=O, Y is absent, and R5and R6together represent a1-3the alkyl-Y-C1-3alkyl. In another preferred embodiment, L and a are C=O, and R5and R6together represent a1-2the alkyl-Y-C1-2alkyl. In another preferred embodiment, L and a are C=O, and R5and R6together represent a2-3alkyl-A.

In some embodiments, the implementation of R8selected from hydrogen and C1-6the alkyl. In certain preferred such embodiments, the implementation of R8selected from hydrogen and methyl. In preferred such embodiments, R8represents hydrogen.

In some embodiments, implementation of the X represents Oh, R2and R3each independently represents a C1-6Ariel the sludge, and R1selected from C1-6of alkyl, C1-6hydroxyalkyl,1-6alkoxyalkyl, aryl and C1-6arylalkyl, any of which is optionally substituted by one or more substituents selected from amide, amine, carboxylic acid (or its salts), complex ether (including complex1-6alkilany ester, complex With1-5alkilany ether and complex arrowy ester), thiol, or simple tiefer.

In some embodiments, the implementation of the stereochemical configuration of the carbon atoms with substituents R2or R3represents independently D or L. In some preferred embodiments, the implementation of the stereochemical configuration at least one of the carbon atoms with substituents R2and R3accordingly, represents a D. In some such embodiments, the implementation of the stereochemical configuration of the carbon atom having the substituents R2is a D. In such scenarios, the implementation of the stereochemical configuration of the carbon atom having the substituents R3is a D. In some embodiments, the implementation of the stereochemical configuration of both of the carbon atoms with substituents R2and R3accordingly, represents a D.

Another aspect of the invention relates to compounds having a structure of the form is s (III), or their pharmaceutically acceptable salt,

where is each And independently selected from C=O, C=S and SO2preferably, C=O, or

And does not necessarily represent covalent bond when it is related to present Z;

In absent or represents-N(R9R10preferably, missing;

L is absent or selected from C=O, C=S and SO2preferably, SO2or C=O;

M is absent or represents a C1-12alkyl, preferably With1-8alkyl;

W is selected from-Cho, and-IN(OR11)2;

Q is absent or selected from O, NH and N1-6of alkyl;

Y is absent or selected from C=O and SO2;

each Z is independently selected from O, S, NH and N1-6the alkyl, preferably O; or

Z is an optional covalent bond, when it is related to present And;

R1selected from H, -C1-6alkyl, C1-6hydroxyalkyl,1-6alkoxyalkyl, aryl and C1-6arylalkyl;

R2and R3each independently selected from aryl, C1-6arylalkyl, heteroaryl and C1-6heteroallyl;

R4represents N(R5)L-Q-R6;

R5selected from hydrogen, HE, WITH1-6arylalkyl, preferably, hydrogen;

R6selected from hydrogen, C1-6 of alkyl, C2-6alkenyl,2-6the quinil, Ar-Y-, carbocycle, heterocyclyl, N-terminal protective group, aryl, C1-6arylalkyl, heteroaryl,1-6heteroallyl, R11ZAZ-C1-8the alkyl-, R14Z-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8alkyl-ZAZ-C1-8the alkyl-, R11ZAZ-C1-8alkyl-ZAZ-C1-8the alkyl-, ZAZ-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8of alkyl, R13)2N-C1-12the alkyl-, (R13)3N+-C1-12the alkyl-, heterocyclyl, carbocyclic-, R14SO2C1-8the alkyl and R14SO2NH, preferably, N-capirola group, more preferably tert-butoxycarbonyl or benzyloxycarbonyl; or

R5and R6together represent a1-6the alkyl-Y-C1-6alkyl, C1-6alkyl-ZAZ-C1-6alkyl, ZAZ-C1-6alkyl-ZAZ-C1-6alkyl, ZAZ-C1-6alkyl-ZAZ or1-6alkyl, thereby forming a ring;

R7and R8independently selected from hydrogen, C1-6the alkyl and C1-6arylalkyl, preferably, hydrogen;

R9selected from hydrogen, HE, and1-6the alkyl, preferably With1-6of alkyl, and

R10represents the N-terminal protective group;

R11and R12independently selected from hydrogen, metal cation, With1-6of alkyl, C2-6alkenyl,2-6 the quinil, aryl, heteroaryl,1-6arylalkyl and C1-6heteroallyl, preferably from hydrogen, metal cation and C1-6the alkyl, or R11and R12together represent a1-6alkyl, thereby forming a ring;

each R13independently selected from hydrogen and C1-6the alkyl, preferably With1-6of alkyl, and

R14independently selected from hydrogen, C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle, heterocyclyl, aryl, heteroaryl,1-6arylalkyl and C1-6heteroallyl;

each R16independently selected from hydrogen and C1-6the alkyl, or two R11together can be a1-6alkyl, thereby forming a ring together with atoms of boron and oxygen to which they are attached;

provided that in any case the presence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.

In some embodiments, the implementation of R1selected from-C1-6alkyl-b and C1-6arylalkyl. In some such embodiments, the implementation of R1substituted by one or more substituents selected from hydroxy, halogen, amide, amine, carboxylic acid (or its salts), complex ether (including complex1-6alkilany ether complex 1-5alkilany ether and arrowy ester), thiol and simple tiefer. In certain preferred such embodiments, the implementation of R1substituted by one or more substituents selected from a carboxylic acid and a complex ester. In some embodiments, the implementation of R1selected from methyl, ethyl, isopropyl, carboxymethyl and benzyl. In some embodiments, the implementation of R1represents-C1-6alkyl-b and C1-6arylalkyl. In certain preferred such embodiments, the implementation is missing.

In some embodiments, the implementation of R2selected from C1-6arylalkyl and C1-6heteroallyl. In some embodiments, the implementation of R2selected from C1-6alkylphenyl,1-6alcyonaria,1-6alkylthiol,1-6alkylaryl and C1-6alkalization, where the alkyl part may contain six, five, four, three, two or one carbon atom, preferably one or two. In some such embodiments, the implementation of R2substituted by one or more substituents selected from hydroxy, halogen, amide, amine, carboxylic acid (or its salts), complex ether (including complex1-6alkilany ester, complex With1-5alkilany ether and complex arrowy ester), thiol, or simple tiefer. In some such embodiments, the implementation of R 2replaced by Deputy selected from alkyl, trihalomethyl, alkoxy, hydroxy or cyano. In some such embodiments, the implementation of R2selected from C1-6alkylphenyl and C1-6alcyonaria. In certain preferred such embodiments, the implementation of R2chosen from:

where D is selected from H, OMe, O-tert-Bu, OH, CN, CF3and CH3. In some embodiments, the implementation of D is selected from H, OMe, HE, CN, CF3and CH3.

In certain preferred such embodiments, the implementation, where D is attached to the six-membered ring D is attached in position 4 with respect to the place of connection, preferably, excluding cases of implementation, where the position 4 of the ring are occupied by the nitrogen atom of the pyridine ring.

In some embodiments, the implementation of R3selected from C1-6arylalkyl and C1-6heteroallyl. In some cases, the alkyl part may contain six, five, four, three, two or one carbon atom, preferably one or two. In some such embodiments, the implementation of R3substituted by one or more substituents selected from hydroxy, halogen, amide, amine, carboxylic acid (or its salts), complex ether (including complex1-6alkilany ester, complex With1-5alkilany ether and complex arrowy ester), thiol, or proseguire. In some such embodiments, the implementation of R3replaced by Deputy selected from alkyl, trihalomethyl, alkoxy, hydroxy or cyano. In some such embodiments, the implementation of R3selected from C1-6alkylphenyl and C1-6alcyonaria. In certain preferred such embodiments, the implementation of R3chosen from:

where D is selected from H, OMe, O-tert-Bu, OH, CN, CF3and CH3. In some embodiments, the implementation of D is selected from H, OMe, HE, CN, CF3and CH3.

In some embodiments, the implementation of R5represents hydrogen, L represents C=O or SO2, R6is an Ar-Y-, and each Ar is independently selected from phenyl, indolyl, benzofuranyl, naphthyl, chinoline, chinolone, teinila, pyridyl, pirila and the like. In some embodiments, the implementation of the Ar may be substituted Ar-E-, where E is selected from a direct link, -O - and1-6the alkyl. In some other such embodiments, the implementation, where Q represents C1-6alkyl, Q may be substituted, preferably, Ar, such as phenyl.

In some embodiments, the implementation of R5represents hydrogen, Q is absent, L is a C=O or SO2, R6selected from Ar-Y -, and heterocyclyl. In certain preferred such embodiments, the implementation heterocyclyl selected the C chromonica, Romania, morpholino and piperidinyl. In some other preferred such embodiments, the implementation of Ar is selected from phenyl, indolyl, benzofuranyl, naphthyl, chinoline, chinolone, teinila, pyridyl, pirila and the like.

In some embodiments, the implementation of R5represents hydrogen, L represents C=O or SO2Q is absent, R6represents a C2-6alkenyl, where C2-6alkenyl represents a substituted vinyl group, where the Deputy is, preferably, aryl or heteroaryl group, more preferably phenyl group, optionally substituted by one to four substituents.

In some embodiments, the implementation of L and Q are absent, and R6selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil,1-6arylalkyl and C1-6heteroallyl. In some such embodiments, the implementation of R5represents a C1-6alkyl, and R6selected from butyl, allyl, propargyl, phenylmethyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.

In other embodiments, the implementation of L represents the SO2Q is absent, and R6selected from C1-6of alkyl and aryl. In some such embodiments, the implementation of R6selected from methyl and phenyl.

In some embodiments, the implementation of L represents C=O, and R selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil, aryl,

With1-6arylalkyl, heteroaryl,1-6heteroallyl,

R11ZA-C1-8the alkyl-, R14Z-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8the alkyl-,

(R11O)(R12O)P(=O)O-C1-8alkyl-ZAZ-C1-8the alkyl-,

(R11O)(R12O)P(=O)O-C1-8alkyl-Z-C1-8the alkyl-,

R11ZA-C1-8alkyl-ZAZ-C1-8the alkyl-, ZAZ-C1-8the alkyl-,

(R13)3N+-C1-8the alkyl-, heterocyclyl, carbocyclic-,

R14SO2C1-8the alkyl and R14SO2NH-, where everyone present Z and a is independently other than a covalent bond. In some embodiments, the implementation of L represents C=O, Q is absent, and R6represents N.

In some embodiments, the implementation of R5represents a C1-6alkyl, R6represents a C1-6alkyl, Q is absent and L is a C=O. In some such embodiments, the implementation of R6represents ethyl, isopropyl, 2,2,2-triptorelin or 2-(methylsulphonyl)ethyl.

In other embodiments, the implementation of L represents C=O, Q is absent, and R6represents a C1-6arylalkyl. In some such embodiments, the implementation of R6selected from 2-phenylethyl, phenylmethyl, (4-methox is phenyl)methyl, (4-chlorophenyl)methyl and (4-forfinal)bromide.

In other embodiments, the implementation of L represents C=O, Q is absent, R5represents a C1-6alkyl, and R6represents aryl. In some such embodiments, the implementation of R6represents a substituted or unsubstituted phenyl.

In some embodiments, the implementation of L represents C=O, Q is absent, and R6selected from heteroaryl and C1-6heteroallyl. In some such embodiments, the implementation of R6is heteroaryl selected from pyrrole, furan, thiophene, imidazole, isoxazol, oxazole, oxadiazole, thiazole, thiadiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine. In some such alternative embodiments, the implementation of R6represents a C1-6heteroaromatic selected from pyrrolidinyl, furylmethyl, thienylmethyl, imidazolidinyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolylmethyl, thiadiazolyl, triazolylmethyl, parasaissetia, pyridylmethyl, personalitie, pyridinylmethyl and pyrimidinylidene.

In some embodiments, the implementation of L represents C=O, Q is absent or represents O, and R6represents carbocyclic-, where M represents a C0-1alkyl. In some embodiments, the OS is supervising R 6is cyclopropyl or cyclohexyl.

In some embodiments, the implementation of L and a are C=O, Q is absent, Z represents O, M represents a C1-8alkyl, preferably methylene, and R6selected from R11ZA-C1-8the alkyl-, R11Z-C1-8the alkyl-, R11ZA-C1-8alkyl-ZAZ-C1-8of alkyl, R11O)(R12O)P(=O)O-C1-8alkyl-ZAZ-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8alkyl-Z-C1-8the alkyl - and ZAZ-C1-8the alkyl-, where everyone present And a is independently other than a covalent bond. In some such embodiments, the implementation of R6represents ZAZ-C1-8alkyl-, where heterocyclyl represents a substituted or unsubstituted oxadiazolyl or N(R16)(R17), where R16and R17together represent a1-6the alkyl-Y-C1-6alkyl, preferably With1-3the alkyl-Y-C1-3alkyl, thereby forming a ring.

In some preferred embodiments, the implementation of L represents C=O, Q is absent, M is a C1-8alkyl, and R6selected from (R11O)(R12O)P(=O)O-C1-8the alkyl-, (R13)2NC1-8of alkyl, R13)3N+C1-8the alkyl - and heterocyclyl-M-. In some such embodiments, the implementation of R6is the Wallpaper (R 13)2NC1-8alkyl or (R13)3N+C1-8alkyl-, where R13represents a C1-6alkyl. In some other such embodiments, the implementation of R6represents heterocyclyl-where heterocyclyl selected from morpholino, piperidino, piperazine derivatives and pyrrolidino.

In some embodiments, the implementation of L represents C=O, R5represents a C1-6alkyl, Q is selected from O and NH, and R6selected from C1-6of alkyl, cycloalkyl-M1-6arylalkyl and C1-6heteroallyl. In other embodiments, the implementation of L represents C=O, R5represents a C1-6alkyl, Q is selected from O and NH, and R6represents a C1-6alkyl, where C1-6alkyl selected from methyl, ethyl and isopropyl. In the following embodiments, the implementation of L represents C=O, R5represents a C1-6alkyl, Q is selected from O and NH, and R6represents a C1-6arylalkyl where arylalkyl represents phenylmethyl. In other embodiments, the implementation of L represents C=O, R5represents a C1-6alkyl, Q is selected from O and NH, and R6represents a C1-6heteroaromatic where heteroaromatic represents (4-pyridyl)methyl.

In some embodiments, the implementation of L is absent or represents C=O, R5and R6together p is establet a 1-6the alkyl-Y-C1-6alkyl, C1-6alkyl-ZA-C1-6alkyl or C1-6alkyl-And where each participant Z and a is independently other than a covalent bond, thereby forming a ring. In some preferred embodiments, the implementation of L represents C=O, Q and Y are absent, and R5and R6together represent a1-3the alkyl-Y-C1-3alkyl. In another preferred embodiment, L and Q are absent, and R5and R6together represent a1-3the alkyl-Y-C1-3alkyl. In another preferred embodiment, L represents C=O, Q is absent, Y is selected from NH and N1-6of alkyl, and R5and R6together represent a1-3the alkyl-Y-C1-3alkyl. In another preferred embodiment, L and Q are absent, and R5and R6represent1-3the alkyl-Y-C1-3alkyl. In another preferred embodiment, L represents C=O, Y is absent, and R5and R6together represent a1-3the alkyl-Y-C1-3alkyl. In another preferred embodiment, L and a are C=O, and R5and R6together represent a1-2alkyl-ZA-C1-2alkyl. In another preferred embodiment, L and a are C=O, and R5and R6together represent the a 2-3alkyl-A.

In some embodiments, the implementation of R7and R8independently selected from hydrogen and C1-6the alkyl. In certain preferred such embodiments, the implementation of R7and R8independently selected from hydrogen and methyl. In preferred such embodiments, the implementation of R7and R8both represent hydrogen.

In some embodiments, implementation of the X represents Oh, R2and R3each independently represents a C1-6arylalkyl, and R1selected from C1-6of alkyl, C1-6hydroxyalkyl,1-6alkoxyalkyl, aryl and C1-6arylalkyl, any of which is optionally substituted by one or more substituents of the amide, amine, carboxylic acid (or its salts), complex ether (including complex1-6alkilany ester, complex With1-5alkilany ether and complex arrowy ester), thiol and simple tiefer.

In some embodiments, the implementation of the stereochemical configuration of the carbon atoms with substituents R1, R2or R3independently represents D or L. In some preferred embodiments, the implementation of the stereochemical configuration at least one of the carbon atoms with substituents R1, R2and R3accordingly, represents a D. some prefer the lnyh such scenarios, the implementation of the stereochemical configuration of the carbon atom, having the substituents R1is a D. In some such embodiments, the implementation of the stereochemical configuration of the carbon atom having the substituents R2is a D. In some such embodiments, the implementation of the stereochemical configuration of the carbon atom having the substituents R3is a D. In some embodiments, the implementation of the stereochemical configuration at least two of the carbon atoms with substituents R1, R2and R3accordingly, represents a D. in another preferred embodiment, the stereochemical configuration of all three of the carbon atoms with substituents R1, R2and R3accordingly, represents a D.

Another aspect of the invention relates to compounds having the structure of formula (IV), or their pharmaceutically acceptable salt,

where is each And independently selected from C=O, C=S and SO2preferably, C=O, or

And does not necessarily represent covalent bond when it is related to present Z;

L is absent or selected from C=O, C=S and SO2preferably, SO2or C=O;

M is absent or represents a C1-12alkyl, preferably With1-8alkyl;

W is selected from SNO IN(OR11)2;

Q is absent or selected from O, NH and N1-6of alkyl;

Y is absent or selected from C=O and SO2;

each Z is independently selected from O, S, NH and N1-6the alkyl, preferably O; or

Z is an optional covalent bond, when it is related to present A;

R2and R3each independently selected from aryl, C1-6arylalkyl, heteroaryl and C1-6heteroallyl;

R4represents N(R5)L-Q-R6;

R5selected from hydrogen, HE, WITH1-6arylalkyl and C1-6the alkyl, preferably, hydrogen;

R6selected from hydrogen, C1-6of alkyl, C2-6alkenyl,2-6the quinil, Ar-Y-, carbocycle, heterocyclyl, N-terminal protective group, aryl, C1-6arylalkyl, heteroaryl,1-6heteroallyl, R11ZAZ-C1-8of alkyl, R14Z-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8alkyl-ZAZ-C1-8the alkyl-, R11ZAZ-C1-8alkyl-ZAZ-C1-8the alkyl-, ZAZ-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8the alkyl-, (R13)2N-C1-12the alkyl-, (R13)3N+-C1-12the alkyl-, heterocyclyl, carbocyclic-, R14SO2C1-8the alkyl and R14SO2NH, preferably, N-capirola group, more preferably tert-butoxycarbonyl or benzyloxycarbonyl is; or

R5and R6together represent a1-6the alkyl-Y-C1-6alkyl, C1-6alkyl-ZAZ-C1-6alkyl, ZAZ-C1-6alkyl-ZAZ-C1-6alkyl, ZAZ-C1-6alkyl-ZAZ or1-6alkyl, thereby forming a ring;

R8selected from hydrogen, C1-6the alkyl and C1-6arylalkyl, preferably, hydrogen;

R9selected from hydrogen, HE, and1-6the alkyl, preferably With1-6of alkyl, and

R10represents the N-terminal protective group;

R11and R12independently selected from hydrogen, metal cation, With1-6of alkyl, C2-6alkenyl,2-6the quinil, aryl, heteroaryl,1-6arylalkyl and C1-6heteroallyl, preferably from hydrogen, metal cation and C1-6the alkyl, or R11and R12together represent a1-6alkyl, thereby forming a ring;

each R13independently selected from hydrogen and C1-6the alkyl, preferably With1-6of alkyl; and

R14independently selected from hydrogen, C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle, heterocyclyl, aryl, heteroaryl,1-6arylalkyl and C1-6heteroallyl;

each R16independently selected from hydrogen and C1-6the alkyl, or two R11together can be a1-6alkyl, thus education is UYa ring together with atoms of boron and oxygen, to which they are attached;

provided that in any case the presence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.

In some embodiments, the implementation of R2selected from C1-6arylalkyl and C1-6heteroallyl. In some such embodiments, the implementation of R2selected from C1-6alkylphenyl,1-6alcyonaria,1-6alkylthiol,1-6alkylaryl and C1-6alkalization, where the alkyl part may contain six, five, four, three, two or one carbon atom, preferably one or two. In some such embodiments, the implementation of R2substituted by one or more substituents selected from hydroxy, halogen, amide, amine, carboxylic acid (or its salts), complex ether (including complex1-6alkilany ester, complex With1-5alkilany ether and complex arrowy ester), thiol, or simple tiefer. In some such embodiments, the implementation of R2replaced by Deputy selected from alkyl, trihalomethyl, alkoxy, hydroxy or cyano. In some embodiments, the implementation of R2selected from C1-6alkylphenyl and C1-6alcyonaria. In certain preferred such embodiments, the implementation of R2chosen from:

where D select the n of N, OMe, O-tert-Bu, HE, CN, CF3and CH3. In some embodiments, the implementation of D is selected from H, OMe, HE, CN, CF3and CH3.

In certain preferred such embodiments, the implementation, where D is attached to the six-membered ring D is attached in position 4 with respect to the place of connection, preferably, excluding cases of implementation, where the position 4 of the ring are occupied by the nitrogen atom of the pyridine ring.

In some embodiments, the implementation of R3selected from C1-6arylalkyl and C1-6heteroallyl. In some cases, the alkyl part may contain six, five, four, three, two or one carbon atom, preferably one or two. In some such embodiments, the implementation of R3substituted by one or more substituents selected from hydroxy, halogen, amide, amine, carboxylic acid (or its salts), complex ether (including complex1-6alkilany ester, complex With1-5alkilany ether or complex arrowy ester), thiol, or simple tiefer. In some such embodiments, the implementation of R3replaced by Deputy selected from alkyl, trihalomethyl, alkoxy, hydroxy or cyano. In some such embodiments, the implementation of R3selected from C1-6alkylphenyl and C1-6alcyonaria. In certain preferred such embodiments, the implementation of R3in the bran from:

where D is selected from H, OMe, O-tert-Bu, HE, CN, CF3and CH3. In some embodiments, the implementation of D is selected from H, OMe, HE, CN, CF3and CH3.

In some embodiments, the implementation of R5represents hydrogen, L represents C=O or SO2, R6is an Ar-Y-, and each Ar is independently selected from phenyl, indolyl, benzofuranyl, naphthyl, chinoline, chinolone, teinila, pyridyl, pirila and the like. In some such embodiments, the implementation of the Ar may be substituted Ar-E-, where E is selected from a direct link, -O - and1-6the alkyl. In some other such embodiments, implementation, when Q represents C1-6alkyl, Q may be substituted, preferably, Ar, such as phenyl.

In some embodiments, the implementation of R5represents hydrogen, Q is absent, L is a C=O or SO2and R6selected from Ar-Y and heterocyclyl. In certain preferred such embodiments, the implementation heterocyclyl selected from chromonica, Romania, morpholino and piperidinyl. In some other preferred such embodiments, the implementation of Ar is selected from phenyl, indolyl, benzofuranyl, naphthyl, chinoline, chinolone, teinila, pyridyl, pirila and the like.

In some embodiments, the implementation of R5represents hydrogen, L p is ecstasy a C=O or SO 2Q is absent, and R6represents a C2-6alkenyl, where C2-6alkenyl represents a substituted vinyl group, where the Deputy is, preferably, aryl or heteroaryl group, more preferably phenyl group, optionally substituted by one to four substituents.

In some embodiments, the implementation of L and Q are absent, and R6selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil,1-6arylalkyl and C1-6heteroallyl. In some such embodiments, the implementation of R5represents a C1-6alkyl, and R6selected from butyl, allyl, propargyl, phenylmethyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.

In other embodiments, the implementation of L represents the SO2Q is absent, and R6selected from C1-6of alkyl and aryl. In some such embodiments, the implementation of R6selected from methyl and phenyl.

In some embodiments, the implementation of L represents C=O, and R6selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil, aryl,

With1-6arylalkyl, heteroaryl,1-6heteroallyl,

R11ZA-C1-8the alkyl-, R14Z-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8the alkyl-,

(R11O)(R12O)P(=O)O-C1-8alkyl-ZAZ-C1-8the alkyl-,

(R11O)(R12OP(=O)O-C 1-8alkyl-Z-C1-8the alkyl-,

R11ZA-C1-8alkyl-ZAZ-C1-8the alkyl-, ZAZ-C1-8the alkyl-,

(R13)2N-C1-8the alkyl-, (R13)2N+-C1-8the alkyl-, heterocyclyl-,

carbocyclic-, R14SO2C1-8the alkyl and R14SO2NH-, where everyone present Z and a is independently other than a covalent bond. In some embodiments, the implementation of L represents C=O, Q is absent, and R6represents N.

In some embodiments, the implementation of R5represents a C1-6alkyl, R6represents a C1-6alkyl, Q is absent and L is a C=O. In some such embodiments, the implementation of R6represents ethyl, isopropyl, 2,2,2-triptorelin or 2-(methylsulphonyl)ethyl.

In other embodiments, the implementation of L represents C=O, Q is absent, and R6represents a C1-6arylalkyl. In some such embodiments, the implementation of R6selected from 2-phenylethyl, phenylmethyl, (4-methoxyphenyl)methyl, (4-chlorophenyl)methyl and (4-forfinal)bromide.

In other embodiments, the implementation of L represents C=O, Q is absent, R5represents a C1-6alkyl, and R6represents aryl. In some such embodiments, the implementation of R6represents a substituted or illegal is ewenny phenyl.

In some embodiments, the implementation of L represents C=O, Q is absent, and R6selected from heteroaryl and C1-6heteroallyl. In some embodiments, the implementation of R6is heteroaryl selected from pyrrole, furan, thiophene, imidazole, isoxazol, oxazole, oxadiazole, thiazole, thiadiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine. In some such alternative embodiments, the implementation of R6represents a C1-6heteroaromatic selected from pyrrolidinyl, furylmethyl, thienylmethyl, imidazolidinyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolylmethyl, thiadiazolyl, triazolylmethyl, parasaissetia, pyridylmethyl, personalitie, pyridinylmethyl and pyrimidinylidene.

In some embodiments, the implementation of L represents C=O, Q is absent or represents O, and R6represents carbocyclic-, where M represents a C0-1alkyl. In some such embodiments, the implementation of R6is cyclopropyl or cyclohexyl.

In some embodiments, the implementation of L and a are C=O, Q is absent, Z represents O, M represents a C1-8alkyl, preferably methylene, and R6selected from R11ZA-C1-8the alkyl-, R14Z-C1-8 the alkyl-, R11ZA-C1-8alkyl-ZAZ-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8alkyl-ZAZ-C1-8the alkyl-, (R11O)(R12O)P(=O)O-C1-8alkyl-Z-C1-8the alkyl - and ZAZ-C1-8the alkyl-, where everyone present And a is independently other than a covalent bond. In some such embodiments, the implementation of R6represents ZAZ-C1-8alkyl-, where heterocyclyl represents a substituted or unsubstituted oxadiazolyl, or N(R16)(R17), where R16and R17together represent a1-6the alkyl-Y-C1-6alkyl, preferably With1-3the alkyl-Y-C1-3alkyl, thereby forming a ring.

In some preferred embodiments, the implementation of L represents C=O, Q is absent, M is a C1-8alkyl, and R6selected from (R11O)(R12O)P(=O)O-C1-8the alkyl-, (R13)2NC1-8of alkyl, R13)3N+C1-8the alkyl - and heterocyclyl-M-. In some such embodiments, the implementation of R6represents (R13)2NC1-8alkyl or (R13)3N+C1-8alkyl, where R13represents a C1-6alkyl. In some other such embodiments, the implementation of R6represents heterocyclyl-where heterocyclyl selected from morpholino, piperidino, piperazine derivatives pirrolidone.

In some embodiments, the implementation of L represents C=O, R5represents a C1-6alkyl, Q is selected from O and NH, and R6selected from C1-6of alkyl, cycloalkyl-M1-6arylalkyl and C1-6heteroallyl. In some embodiments, the implementation of L represents C=O, R5represents a C1-6alkyl, Q is selected from O and NH, and R6represents a C1-6alkyl, where C1-6alkyl selected from methyl, ethyl and isopropyl. In the following embodiments, the implementation of L represents C=O, R5represents a C1-6alkyl, Q is selected from O and NH, and R6represents a C1-6arylalkyl where arylalkyl represents phenylmethyl. In other embodiments, the implementation of L represents C=O, R5represents a C1-6alkyl, Q is selected from O and NH, and R6represents a C1-6heteroaromatic where heteroaromatic represents (4-pyridyl)methyl.

In some embodiments, the implementation of L is absent, and R5and R6together represent a1-6the alkyl-Y-C1-6alkyl, C1-6alkyl-ZA-C1-6alkyl or C1-6alkyl-And where each participant Z and a is independently other than a covalent bond, thereby forming a ring. In some preferred embodiments, the implementation of L represents C=O, Q and Y are absent, and R5 and R6together represent a1-3alkyl-ZA-C1-3alkyl. In another preferred embodiment, L and Q are absent, and R5and R6together represent a1-3the alkyl-Y-C1-3alkyl. In another preferred embodiment, L represents C=O, Q is absent, Y is selected from NH and N1-6of alkyl, and R5and R6together represent a1-3the alkyl-Y-C1-3alkyl. In another preferred embodiment, L represents C=O, Y is absent, and R5and R6together represent a1-3the alkyl-Y-C1-3alkyl. In another preferred embodiment, L and a are C=O, and R5and R6together represent a1-2the alkyl-Y-C1-2alkyl. In another preferred embodiment, L and a are C=O, and R5and R6together represent a2-3alkyl-A.

In some embodiments, the implementation of R8selected from hydrogen and C1-6the alkyl. In some preferred embodiments, the implementation of R8selected from hydrogen and methyl. In more preferred embodiments, the implementation of R8represents hydrogen.

In some embodiments, implementation of the X represents Oh, R2and R3each independently represents a C1-6arylalkyl, and R 1selected from C1-6of alkyl, C1-6hydroxyalkyl,1-6alkoxyalkyl, aryl and C1-6arylalkyl, any of which is optionally substituted by one or more substituents of the amide, amine, carboxylic acid (or its salts), complex ether (including complex1-6alkilany ester, complex With1-5alkilany ether and complex arrowy ester), thiol and simple tiefer.

In some embodiments, the implementation of the stereochemical configuration of the carbon atoms with substituents R2and R3is a D or L. In some preferred embodiments, the implementation of the stereochemical configuration at least one of the carbon atoms with substituents R2and R3accordingly, represents a D. In some such embodiments, the implementation of the stereochemical configuration of the carbon atom having the substituents R2is a D. In such scenarios, the implementation of the stereochemical configuration of the carbon atom having the substituents R3is a D. In some embodiments, the implementation of the stereochemical configuration of both of the carbon atoms with substituents R2and R3accordingly, represents a D.

One aspect of the invention relates to inhibitors that preferentially inhibit the activity of immunoplate the soma compared with the activity of the constitutive proteasome. In some embodiments, the implementation of the EU50compounds of any of formulas I-IV to test the activity of constitutive proteasome compared to the EU50the same compounds in the test activity immunoproteasome is above 1. In some such embodiments, the implementation of the ratio EC50above 2, 3, 4 or even 5. In this description describes the appropriate test for determining the activity of constitutive proteasome and activity immunoproteasome (see example 18).

The term "Cx-yalkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including alkyl groups with non-branched chain alkyl groups, branched chain, containing from x to y carbon atoms in the chain, including halogenoalkane groups such as trifluoromethyl and 2,2,2-triptorelin etc.0alkyl means hydrogen, when the group is in the limit position, and means of communication, if the group internal. The term "C2-yalkenyl" and "C2-yquinil" refers to substituted or unsubstituted unsaturated aliphatic groups of similar length and possible substitution to Akilov described above, but which contain at least one double or triple bond, respectively.

The term "alkoxy" refers to an alkyl group having attached thereto atom color is Yes. Representative alkoxygroup include methoxy, ethoxy, propoxy, tert-butoxy and the like. "Plain air" consists of two hydrocarbon covalently linked an oxygen atom. Accordingly, the Deputy of alkyl, which is such a simple alkyl ether, a is an alkoxy, or similar alkoxy.

The term "C1-6alkoxyalkyl" is a C1-6alkyl group substituted by alkoxygroup, thus forming a simple ether.

Used in this description, the term "C1-6arylalkyl" is a C1-6alkyl group, a substituted aryl group.

The term "amine" and "amino" is recognized in this field and applies to both unsubstituted and substituted amines and their salts, for example the group that can be represented by the General formula:

where R9, R10and R10'each independently represents hydrogen, alkyl, alkenyl, -(CH2)m-R8or R9and R10taken together with the N atom to which they are attached, form a heterocycle having from 4 to 8 atoms in the ring structure; R8represents aryl, cycloalkyl, cycloalkenyl, heterocyclyl or polycyclic; and m is 0 or an integer from 1 to 8. In preferred embodiments, the implementation of only one of R9or R10maybe CA is bonila, for example, R9, R10and the nitrogen atom together do not form an imide. In even more preferred embodiments, R9and R10(and optionally R10'each independently represents hydrogen, alkyl, alkenyl or -(CH2)m-R8. In some embodiments, implementation of the amino group is basic in nature, meaning that it has the pKa>7,00. Protonated forms of these functional groups have a pKaabove 7,00.

The term "amide" and "amido", which is recognized in the field as aminosilanes carbonyl, includes a group which can be represented General formula:

where R9and R10have the meanings as described above. Preferred embodiments of the amide will not include imides which may be unstable.

Used in this description, the term "aryl" includes 5-, 6 - and 7-membered substituted or unsubstituted aromatic group with one ring in which each atom of the ring is a carbon. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two connected rings, where at least one of the rings is an aromatic, e.g., the other cyclic rings can be cycloalkyl cycloalkenyl, cycloalkenyl, aryl, heteroaryl and/or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline and the like.

As used in this description, the terms "carbocycle" and "carbocyclic" refers to non-aromatic substituted or unsubstituted ring in which each atom of the ring is a carbon. The term "carbocycle" and "carbocyclic" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two connected rings, where at least one of the rings is a carbocyclic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkenyl, aryl, heteroaryl and/or heterocyclyl.

The term "carbonyl" is recognized in this field and includes such groups, which can be represented General formula:

or

where X is a bond or represents an oxygen atom or sulfur, and R11represents hydrogen, alkyl, alkenyl, -(CH2)m-R8or a pharmaceutically acceptable salt, R11'represents hydrogen, alkyl, alkenyl or -(CH2)m-R8where R8matter, as stated above. When X is predstavljaet an oxygen atom and R 11or R11'is not hydrogen, the formula represents an "ester". When X represents an oxygen atom and R11represents a hydrogen, the formula represents a "carboxylic acid".

Used in this description, the term "enzyme" can be any partially or fully the protein molecule, which carries out a chemical reaction by the catalytic method. Such enzymes can be natural enzymes fused enzymes, proenzymes, apparments, denaturirovannyj enzymes, farnesiani enzymes, ubiquitination enzymes, enzymes, acylated fatty acid, geranygeranylation enzymes, GPI-linked enzymes, lipid-related enzymes, prenisolone enzymes, mutant enzymes of natural origin or obtained by synthesis, enzymes with modifications in the side chain or main chain, enzymes, having a leader sequence, and enzymes, forming a complex with a non-protein substance, such as proteoglycans, proteoliposome. Enzymes can be obtained by any means, including natural expression promoted the expression, cloning, various peptide syntheses based solutions and in the solid phase, and similar methods known to the specialist in the given area.

Used in this description, the term "C1-6heteroaromatic" is a C1-6alkyl group, a substituted heteroaryl group.

The term "heteroaryl" includes substituted or unsubstituted aromatic 5-7 membered ring structures, more preferably, 5 to 6-membered ring, the ring structures include one to four heteroatoms. The term "heteroaryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two connected rings, where at least one of the rings is a heteroaromatic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkenyl, aryl, heteroaryl and/or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, isoxazol, oxazol, oxadiazole, thiazole, thiadiazole, triazole, pyrazole, pyridine, pyrazin, pyridazine, pyrimidine and the like.

Used in this description, the term "heteroatom" means an atom of any element other than a carbon atom or hydrogen. Preferred heteroatoms are nitrogen, oxygen, phosphorus and sulphur.

The terms "heterocyclyl" or "heterocyclic group" refer to substituted or unsubstituted neuromath the ical 3-10-membered ring structures, more preferably, 3-7-membered rings, ring structures which include one to four heteroatoms. The terms "heterocyclyl" or "heterocyclic group" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two connected rings, where at least one of the rings is a heterocyclic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkenyl, aryl, heteroaryl and/or heterocyclyl. Heterocyclic groups include, for example, tetrahydropyran, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

The term "C1-6hydroxyalkyl" is a C1-6alkyl group substituted by a hydroxy-group.

Used in this description, the term "inhibitor" means a description of a compound that blocks or reduces the activity of the enzyme (e.g., inhibits proteolytic cleavage of the standard fluorogenic peptide substrates, such as suc-LLVY-AMC, Box-LRR-AMC and Z-LLE-AMC, inhibits various catalytic activity of the 20S proteasome). The inhibitor can act by competitive, anti-competitive or uncompetitive inhibition. The inhibitor can bind reversibly Il is irreversible, and so the term includes compounds that are detrimental to enzyme substrates. The inhibitor may modify one or more sites (or near) the active site of the enzyme, or it may cause a conformational change in another place of the enzyme.

Used in this description, the term "peptide" includes not only standard amide bond with the standard α-substituents, but also commonly used peptidomimetics, other modified connection, the side chains of non-natural origin and modification of the side chain, as described in detail below.

The term "polycyclic" or "polycyclic" refers to two or more rings (e.g., cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl, heteroaryl and/or heterocyclyl), in which two or more carbons are common to two connected rings, for example, the rings are "condensed ring". Each of the rings polycycle may be substituted or unsubstituted.

The term "prevention" recognize in the field, and when used in connection with a disease state, such as a local recurrence (e.g., pain), a disease such as cancer, multiple syndrome, such as heart failure, or any other painful condition, completely understandable in this field and included the em introduction of the composition, which reduces the frequency or slow the appearance of symptoms of painful conditions in the body of the subject compared to a subject who does not receive the composition. Therefore, the prevention of cancer includes, for example, reducing the number of detectable cancerous tumors in the group of patients receiving prophylactic treatment, relative to not being treated control group and/or slowing down the appearance of detectable cancerous tumors in exposed treatment group compared to not being treated control group, for example, by a statistically and/or clinically significant amount. Prevention of infection includes, for example, reducing the number of diagnoses of infection being treated group compared to not being treated control group and/or slow the appearance of symptoms of the infection being treated group compared to not being treated control group. Prevention of pain includes, for example, reduction in force or, alternatively, delay the pain experienced by the subjects, being treated group compared to not being treated control group.

The term "prodrug" includes compounds which, under physiological conditions become therapeutically active agents. Usual with the persons receiving the prodrug is the inclusion of the selected groups, which are hydrolyzed under physiological conditions to release the desired molecule. In other embodiments, implementation of the prodrug is converted by using the enzymatic activity of an animal host.

The term "prophylactic or therapeutic treatment recognized in this field and includes an introduction into the host organism of one or more of the suggested songs. If you spend an introduction to clinical manifestation of the unwanted painful conditions (e.g., disease or other unwanted state of an animal host), then the treatment is a prophylactic (i.e., it protects the host against developing the unwanted painful condition), whereas if conducted after introduction of undesirable painful condition, the treatment is a therapeutic (i.e., it implies a decrease, reduction or stabilization of existing unwanted painful condition or side effects).

The term "substituted" refers to the fraction of molecules having substituents replacing a hydrogen on one or more carbon atoms of the main chain. It should be understood that "substitution" or "substituted" includes an unconditional condition under which such substitution is in accordance with a permitted valence of the substituted atom and the Deputy is, such a substitution results in a stable connection, which, for example, does not undergo spontaneous transformation, such as rearrangement, cyclization, elimination, etc. Used in this description, the term "substituted" is expected to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, linear and branched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Permissible substituents may be one or more, same or different for the respective organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of the above described organic compounds which satisfy the valences of the heteroatoms. Substituents may include, for example, halogen, hydroxyl, a carbonyl (such as carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as a complex tiefer, thioacetal or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amicin, Imin, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, arylalkyl or aromatic or heteroaromatic gr is polyurethane foam. The person skilled in the art will understand that the substituted hydrocarbon chain groups may themselves be substituted, if appropriate.

"Therapeutically effective amount" of the compound in connection with the method of treatment refers to the amount of compound(s) in the product that, when introduced as part of the required dosing schedules (mammal, preferably a human) alleviates a symptom, eases painful condition, or slows the appearance of painful conditions according to clinically acceptable standards for the disorder or painful condition which is subjected to treatment, or for cosmetic purposes, for example, within a reasonable relationship of benefit/risk, applicable to any therapeutic treatment.

The term "simple thioether" refers to an alkyl group as described above, having attached thereto sulfur-containing fragment. In preferred embodiments, the implementation of "simple tiefer" presents-S-alkyl. A representative group of simple tiefer include methylthio, ethylthio and the like.

Used in this description, the term "being treated" or "treatment" includes the reversibility of the reduction or suppression of symptoms, clinical signs, underlying pathology of the disease condition, in such a way to improve or stabilizer is its state of the subject.

Inhibitors of the enzyme

Biological consequences of inhibiting the proteasome numerous. Inhibition of the proteasome serves as the prevention and/or treatment of a large number of diseases, including, but not limited to, proliferative diseases, neurotoxic/degenerative diseases, ischemic painful conditions, inflammation related to immune diseases, HIV, cancer, rejection of transplanted organ, septic shock, viral and parasitic infections, painful conditions associated with acidosis, macular degeneration, pulmonary painful condition, syndrome, muscle wasting, fibrotic diseases, diseases associated with bone growth and hair.

Inhibitors of the proteasome can be used to treat conditions mediated directly by the proteolytic function of the proteasome, such as muscle wasting, or mediated indirectly via proteins which are processionary proteasome, such as NF-kB. The proteasome is involved in the rapid elimination and post-translational processing of proteins (e.g. enzymes)involved in cellular regulation (for example, cell cycle, gene transcription and metabolic pathways), extracellular communication and immune response (for example, the presentation of the anti-Christ. s).

Reported that after treatment of cells with different proteasome inhibitors on the cellular level is the accumulation polyubiquitinated proteins, cellular morphological changes and apoptosis. It should be noted that commercially available proteasome inhibitors inhibit both constitutive and immuno-form of the proteasome. Even bortezomib, the only FDA approved proteasome inhibitor for the treatment of patients with relapsed multiple myeloma, does not distinguish between these two forms (Altun et al., Cancer Res 65:7896, 2005). So what is known about therapeutic inhibition of proteasomes, based on molecules that inhibit both forms of the proteasome. Accordingly, the compounds of the invention can be useful for reducing the intensity of the side effects associated with molecules that inhibit both forms of the proteasome.

Expression of immunoproteasome occurs mainly in cells and organs, which form the lymphatic system, such as white blood cells (leukocytes), bone marrow and the thymus, spleen and lymph nodes. Although some bodies preferably Express the constitutive proteasome (e.g., heart), others, such as, for example, adrenal gland, liver, lungs and intestines, apparently, Express both forms.

The immune system, white blood cells and lymphoid tissue is toroi play a major role, responsible for the protection of the organism from outside biological influences. In normal operation, they protect the body from bacterial and viral infections. The immune system also protects autologous cells that undergo oncogenic transformation. Intracellular proteolysis generates small peptides for presentation to T-lymphocytes to induce an immune response, mediated MHC I class. The proteasome is a major provider of such precursors of peptides, however, the differences between antigenic peptides observed among cells with different amounts of each form of the proteasome (Cascio et al., EMBO J 20:2357-2366, 2001). In some embodiments implementing the invention relates to a method for inhibiting antigen presentation in a cell, including the effects on the cell a compound of the present invention. In some embodiments implementing the invention relates to a method of changing the set of antigenic peptides produced by the proteasome or other Ntn with polimetallicheskoe activity. For example, if the activity immunoproteasomes proteasome selectively inhibit remaining constitutive proteasome can be produced a different set of antigenic peptides presented in MHC molecules on the surfaces of cells than the set that was producyrovtsa would, presenti who was balsa without any enzyme inhibition.

Several disorders and painful conditions associated with abnormal function of the immune system, refer to this description as related to the immune painful conditions. Probably the most well-known relating to the immune painful condition is an allergic disorders, such as allergies, asthma and the like atopic dermatitis eczema. This happens when the immune system reacts excessively to exposure to antigens in the environment. So the next version of the implementation is a method of suppressing the immune system of a subject comprising administration to the subject an effective amount of compounds of the proteasome inhibitor, the method of the present invention.

Immunodeficiency disorders occur when part of the immune system is not properly working or not represented. They can affect b lymphocytes, T lymphocytes or phagocytes and can be either hereditary (for example, IgA deficiency, severe combined immunodeficiency (SCID), thymic dysplasia and chronic granulomatous)or acquired (for example, acquired immunodeficiency syndrome (AIDS), human immunodeficiency virus (HIV) and induced dosed means immunodeficiencies). Strategy dispensing with the use of selective proteasome inhibitors the present invention can be used for treatment related to immune medical conditions, such as immunodeficiency disorders.

In autoimmune disorders, the immune system inappropriately affects healthy tissues and organs of the body so as if they were foreign invaders. An example of autoimmune disease is Sjogren syndrome, which is characterized by infiltration and focal accumulation of lymphocytes in the exocrine glands. The study analyses the level of expression of the proteasome found a significant positive regulation beta (LMP7) exclusively in the salivary glands of SS patients (Egerer et al., Arthritis Rheum 54:1501-8, 2006). Other examples related to immune illnesses include ordinary erythematosus, rheumatoid arthritis, scleroderma, ankylosing spondyloarthritis, dermatomyositis, psoriasis, multiple sclerosis and inflammatory bowel disease (such as ulcerative colitis and Crohn's disease). Rejection of the transplanted tissue/organ occurs when the immune system mistakenly attacks cells that are introduced into the host organism. Disease graft-versus-host (GVHD), which is the outcome of allogeneic transplantation, occurs when T cells from the donor tissue continue to attack and affect the host tissue. In all three cases, autoimmune disease, graft rejection and GVHD, may be the useful modulation of the immune system by treating the subject with a composition of the invention.

Inflammation is the first response of the immune system to infection or irritation. The cellular component of inflammation involves the movement of leukocytes, which Express immunoproteasome of blood vessels in the inflamed tissue. These cells play an important role in the elimination of the irritant, bacteria, parasite or cellular debris. It is already known that inhibitors of the proteasome have anti-inflammatory activity (Meng et al. PNAS 96:10403-10408, 1999). In cases of chronic inflammation, which is characterized by the dominant presence of macrophages, cells that originally served as protective agents begin to release toxins and cytokines, including TNF-α, now become harmful to the body, causing damage to and loss of tissue. In some embodiments implementing the invention relates to a method of treatment of inflammation and inflammatory diseases, comprising the administration to a subject in need of such treatment, an effective amount of compounds of the proteasome inhibitor of the present invention. Inflammatory diseases include acute (e.g., bronchitis, conjunctivitis, pancreatitis and chronic painful conditions (e.g., chronic cholecystitis, bronchiectasis, stenosis of the aortic valve, restenosis, psoriasis, and arthritis), along with painful conditions related vospolenie, such as fibrosis, infection and ischemia.

After tissue damage, including damage due to inflammatory process begins with the development of regeneration and healing. During the stage of regeneration of lost tissue is replaced by proliferation of cells of the same type, which reconstructs the normal spatial location. However, inadequate regeneration of the spatial distribution of tissue can have serious consequences. In some cases, chronic inflammatory liver disease, regenerated tissues abnormal nodular spatial location, which leads to cirrhosis and portal hypertension. The recovery process occurs when the lost tissue is replaced by fibrous scar, which is formed of granulation tissue. Fibrosis represents an excessive and persistent formation of scar tissue resulting from a hyperproliferative growth of fibroblasts and is associated with activation of the transmission signal of TGF-β. Fibrosis is extensive deposition of extracellular matrix and can occur in virtually any tissue or encompass several different tissues. Usually, the level of intracellular protein signaling (Smad), which activates the transcription of target genes after stimulation of TGF-β is regulated by the activity of the proteasome is (Xu et al., 2000). However, acceleration of decomposition of the components of the transmission signal of TGF-β was observed in cases of cancer and other proliferative disease conditions. Therefore, some embodiments of the invention relate to a method of treatment of hyperproliferative disease conditions, such as diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis, IgA nephropathy, cirrhosis, atresia of bile ducts, congestive heart failure, scleroderma, radiation-induced fibrosis, and pulmonary fibrosis (idiopathic pulmonary fibrosis, collagenase vascular disease, sarcoidosis, interstitial lung disease and pulmonary external disturbances). Treatment of burns victims often prevents fibrosis, therefore, in some embodiments implementing the invention relates to local or systemic injection of inhibitors for the treatment of burns. Wound healing after surgery is often associated with the formless scars, which can be prevented by inhibition of fibrosis. Therefore, in some embodiments implementing the invention relates to a method of preventing or decreasing the formation of scars.

Infection with bacteria, parasite or virus, all leads to the initiation of the inflammatory process. When the inflammation takes hold of the whole organism, is the system the syndrome response to inflammation (SIRS). The term sepsis is used when it is the result of infection. I believe that overproduction induced by lipopolysaccharide (LPS), cytokines, such as TNFα, is Central to the processes associated with septic shock. Not surprisingly, LPS also induces an increase in all components of metabolic pathways of MHC-1, including subunit of immunoproteasome LMP2 and LMP7 (MacAry et al., PNAS 98:3982-3987, 2001). In addition, generally accepted that the first stage in the activation of cells LPS represents the binding of LPS with specific membrane receptors. α - and β-subunit complex 20S proteasome identified as LPS-binding proteins, suggesting that LPS-induced signal transduction may be an important therapeutic target in the treatment or prevention of sepsis (Qureshi, N. et al., J. Immun. (2003) 171:1515-1525). Therefore, in some embodiments, the implementation of the described inhibitors of the proteasome can be used for inhibition of TNFα to prevent and/or treat septic shock.

In another embodiment, the proposed composition is used to treat parasitic infections, such as infections caused by protozoan parasites. I believe that the proteasome such parasites are involved mainly in cell differentiation and activity of replication (Paugam et al., Trends Parasitol. 2003, 19(2):55-59). In addition,as shown, what kind of entamoeba loses the ability to incestyoung after exposure to proteasome inhibitors (Gonzales, et al., Arch. Med. Res. 1997, 28, Spec No: 139-140). In some such embodiments, the implementation of the composition of the proteasome inhibitor used to treat parasitic infections in humans caused by the protozoan parasite selected from Plasmodium sps. (including P. falciparum, P. vivax, P. malariae and P. ovale, which cause malaria), Trypanosoma sps. (including T. Cruzi, which causes the disease, Chaga, and T. brucei, which causes African sleeping sickness), Leishmania sps. (including L. amazonesis, L. donovani, L. infantum, L. mexicana, and so on), Pneumocystis carinii (protozoa cause pneumonia in patients with AIDS and other immunosuppressive patients), Toxoplasma gondii, Entamoeba histolytica, Entamoeba invadens and Giardia lamrlia. In some embodiments, implementation of the proposed composition is used to treat parasitic infections in animals and livestock, caused by the protozoan parasite selected from Plasmidium hermani, Criptosporidium sps., Echinococcus granulosus, Eimeria tenella, Sarcocystis neurona, and Neurospora crassa. Other compounds applicable as proteasome inhibitors in the treatment of parasitic diseases, described in WO 9810779, which is included in this description by reference in its entirety.

In some embodiments, the implementation of the composition of the proteasome inhibitor inhibit proteasome activity in parasite without returning to normal, lacots the tov. In some such embodiments, the implementation of the long half-life of blood cells can provide lasting protection, given therapy against repeated impacts of parasites. In some embodiments, the implementation described in this description of the proteasome inhibitors can provide long-lasting protection given chemoprophylaxis against future infection.

Viral infections contribute to the pathology of many diseases. Heart painful conditions, such as the manifestation of myocarditis and common cardiomyopathy associated with Coxsackie virus B3. In comparative analyses of microrad the full genome of infected hearts of mice, all three subunits of immunoproteasome were uniformly activated in the hearts of mice that have been diagnosed with chronic myocarditis (Szalay et al., Am J Pathol 168:1542-52, 2006). Some viruses use the system the ubiquitin-proteasome at the stage of entry of the virus, when the virus is released from endosome in the cytosol. Murine hepatitis virus (MHV) belongs to the family Coronaviridae, which also includes coronavirus severe acute respiratory syndrome (SARS). Yu and Lai (J Viril 79:644-648, 2005) demonstrated that treatment of cells infected with MHV, an inhibitor of the proteasome leads to the reduction of viral replication, correlating with reduced viral titer comparedwith the titer of the untreated cells. Hepatitis a virus In human (HBV), a member of the virus family Hepadnaviridae, is required to distribute the encoded virus protein shell. Inhibition route of degradation in the proteasome causes a significant decrease in the amount of secreted protein shell (Simsek et al., J Virol 79:12914-12920, 2005). In addition to other HBV hepatitis (a, C, D and E) can also use the path of degradation of the ubiquitin-proteasome for secretion, morphogenesis and pathogenesis.

Monocytogenes bacteria Listeria causes painful condition known as listeriosis, forms of which vary from mild (nausea, vomiting, and diarrhea) to severe (septicaemia, meningitis, encephalitis). Quantitative analysis of changes in the subunit composition of proteasomes found that infection of mice with lymphocytic virus choriomeningitis or monocytogenes Listeria leads to almost complete replacement of constitutive proteasomes by immunoproteasomes in the liver within seven days (Khan et al., J Immunol 167:6859-6868, 2001). There are prokaryotes, which is equivalent to the particle of the eukaryotic 20S proteasome. Although the subunit composition of the particles prokaryotes 20S easier than particles eukaryotes, it has the ability to hydrolyze peptide bonds in a similar way. For example, nucleophilic effect on the peptide linkage occurs through the threonine residue at the N-end of the β-subunits. Therefore, an implementation option given the CSOs invention relates to a method of treatment of prokaryotic infections, includes introduction to the subject an effective amount described in this description of the composition of the proteasome inhibitor. Prokaryotic infection can include diseases caused or mycobacteria such as tuberculosis, leprosy or Buruli ulcer)or archebacteria.

Accordingly, in some embodiments implementing the invention relates to a method for the treatment of infections (e.g. bacterial, parasitic or viral), comprising contacting cells (or introduction to the subject with an effective amount of the compounds of the present invention.

Ischemia and reperfusion injury leads to hypoxia, painful condition, which is lack of oxygen delivery to body tissues. This painful condition causes increased degradation of Ik-Bα, which thereby leads to activation of NF-KB (Koong et al., 1994). Of interest is the fact that the factors identified as being able to enhance the expression of immunoproteasome, TNF-α and lipopolysaccharide, also stimulate the activation of NF-KB. Demonstrated that the intensity of the damage, which leads to hypoxia, it is possible to reduce the introduction of proteasome inhibitor (Gao et al., 2000; Bao et al., 2001; Pye et al., 2003). Therefore, some embodiments of the invention relate to a method of treatment of ischemic painful condition or rapper is known damage includes introduction to the subject in need of such treatment, an effective amount of a compound of the proteasome inhibitor of the present invention. Examples of such illnesses or injuries include, but are not limited to, acute coronary syndrome (vulnerable plaques), occlusal lesion artery (occlusion of arteries and blood vessels of the heart, brain, peripheral), atherosclerosis (coronary sclerosis, coronary artery disease), heart attacks, heart failure, pancreatitis, myocardial hypertrophy, stenosis and restenosis.

Cachexia is a syndrome characterized by depletion of skeletal muscle associated with increased proteolysis caused by metabolism ubiquitin-proteasome. Inhibition of the proteasome reduces proteolysis, thereby decreasing as the loss of muscle protein and nitrogen load on the kidneys or the liver (Tawa et al., JCI 100:197-203, 1997). Report that cachexia increased expression of proinflammatory cytokines, TNF-α and IFN-γ, both of which stimulate the expression of subunits of immunoproteasome (Acharyya et al., JCI 114:370-378, 2004). Indeed, most of the types of muscle atrophy shows the increased degradation rate of a protein (Lecker et al., FASEB J 18:39-51, 2004). Muscle exhaustion is evident in several life-threatening diseases, including cancer, sepsis, renal failure, is a PID, exhaustion, denervation atrophy, disorders, diabetes, muscular atrophy with inaction and congestive heart failure. One way of carrying out the invention relates to the treatment of cachexia and diseases with muscle exhaustion. The methods of the invention are useful for the treatment of such illnesses as cancer, chronic infectious diseases, fever, muscle inactivity (atrophy) and denervation, nerve damage, depletion, renal failure, associated with acidosis, and liver failure. See, for example, Goldberg, U.S. patent No. 5340736.

Degradation of some proteins by the proteasome acts on the mechanisms of signal transmission, which in turn act on gene transcription, cell cycle and metabolic pathways. As noted above, the inhibitors of the proteasome block as the degradation and processing ubiquitination NF-kB in vitro and in vivo. The proteasome inhibitors also block the degradation of IkB-a and activation of NF-kB (Palombella, et al., Cell (1994) 78:773-785; Traenckner et al., EMBO J. (1994) 13:5433-5441). One variant of the invention is a method of inhibiting the degradation of IkB-α, comprising contacting cells with a compound of the present invention.

In some embodiments implementing the invention relates to methods of treatment of cyclin-dependent eukaryotic cell cycles, including the impact of the journey of a cell (in vivo or in vitro) of the proteasome inhibitor of the present invention. Cycline represent proteins involved in the control of cell cycle. Proteasome involved in the degradation of tsiklonov. Examples of tsiklonov include mitotic cycline, G1 cycline and cyclin C. Degradation tsiklonov enables cells to complete one phase of the cell cycle (e.g., mitosis) and enter into another (e.g., division). I believe that all cycline associated with protein kinase P34cdc2or similar kinases. Proteolysis of the target signal localized to amino acids 42-RAALGNISEN-50 (Boxing destruction). Obviously, cyclin converted into a form that is vulnerable to ubiquitinate, or that the cyclin-specific ligase is activated during mitosis (Ciechanover, A., Cell (1994) 79:13-21). Inhibition of the proteasome inhibits the degradation cyclina and, consequently, inhibits cell proliferation, for example, in cases of cancer related to cyclina (Kumatori et al., Proc. Natl. Acad. Sci. USA (1990) 87:7071-7075). In some embodiments implementing the invention relates to a method of treating a proliferative disease in a subject (e.g., cancer, psoriasis or restenosis), including introduction to the subject an effective amount of the composition of the proteasome inhibitor by the method of the present invention. The invention also relates to a method of treatment of the subject of the inflammation that is associated with cyclin, including introduction to the subject a therapeutically effective what about the amount of the composition of the proteasome inhibitor by the method of the present invention.

In maturing the reticulocytes and growing fibroblasts, cells deprived of insulin or serum, the rate of proteolysis is almost double that suggests a role of the proteasome in cellular metabolism. In some embodiments implementing the invention relates to methods of reducing the rate of intracellular protein degradation in the cell. Each of these methods includes contacting cells (in vivo or in vitro, for example, muscles of the subject with an effective amount of a pharmaceutical composition containing an inhibitor of proteasomes present invention.

Alzheimer's disease (AD) is a progressive neurodegenerative painful disorder associated with the loss of higher cognitive functions. The pathological hallmarks of the disease include senile amyloid plaques, neurofibrillary tangles, dystrophic neuritis and significant neuronal loss in specific areas of the brain. Microglia, characteristic of macrophages in the brain, releases numerous proinflammatory cytokines, including TNF-α, after activation β42, a peptide associated with trigeminus and vascular amyloid plaques. This microelectroporation inflammatory response contributes to significant neuronal loss. Cell-based studies have demonstrated toshodai cortical neurons, treated with conditioned media from microglial BV2 cells stimulated with either LPS/INS-γ, or confezione β42 peptides, leading to approximately 60% decrease in cell viability (Gan et al., J. Biol. Chem. 279:5565-5572, 2004). Higher expression of immunoproteasome detected in brain tissue of patients with AD than those without dementia in the elderly (Mishto et al., Neurobiol Aging 27:54-66, 2006).

Patients suffering from Huntington disease (HD), another neurodegenerative disorder, demonstrate locomotor dysfunction and deterioration in cognitive abilities over a number of years before his death. After apoptosis can be used to detect the presence of inclusions or intraneuronal aggregates, caused by enhanced mutation Q (also designated as the expansion of CAG triplet repeats), accompanied by significant atrophy in the striatum and parts of the cerebral cortex. By immunohistochemistry detected, which is a significant increase in the expression of immunoproteasome in the striatum and the frontal region of the cerebral cortex of patients with HD compared with values in normal adults of the appropriate age (Diaz-Hernandez et al., J Neurosci 23:11653-1161, 2003). After further analysis found that increased mainly occurs in degenerative neurons. Using mouse models of HD research is the researchers found a selective increase in chymotrypsin-, trypsin-like activities in affected and containing units of the areas of the brain, mainly the cerebral cortex and striatum (Diaz-Hernandez et al., J Neurosci 23:11653-1161, 2003).

Accordingly, some embodiments of the invention relate to the use of compositions of the proteasome inhibitor of the present invention for the treatment of neurodegenerative diseases. Neurodegenerative diseases and painful conditions include, but are not limited to, stroke, ischemic damage to the nervous system, neural trauma (e.g., percussive brain damage, spinal cord injuries and traumatic injury in the nervous system), multiple sclerosis and other immune neuropathy (e.g., syndrome Gulliana-Barr and its variants, acute motor axonal neuropathy, acute inflammatory demyelinated the polyneuropathy, and Fisher syndrome), dementia complex HIV/AIDS, economiy, diabetic neuropathy, Parkinson's disease, Huntington's disease, multiple sclerosis, bacterial, parasitic, fungal and viral meningitis, encephalitis, vascular dementia, dementia due to multiple heart attacks, dementia with calves Levi, the anterior lobe dementia, such as sickness Peak, subcortical dementia (for example, disease Genting is on or progressing supranuclear paralysis), syndromes, focal cortical atrophy (such as primary aphasia), toxic metabolic disease (such as chronic hypothyroidism or B12 deficiency and dementia caused by infections (such as syphilis or chronic meningitis).

It is also shown that inhibitors that are associated with the 20S proteasome, stimulate bone formation in cultures of bone bodies. In addition, when such inhibitors administered systemically to mice, some proteasome inhibitors increase bone volume and rate of bone formation by 70% (Garrett, I.R. et al., J. Clin. Invest. (2003) 111:1771-1782), suggesting that the ubiquitin-proteasome mechanisms regulate the differentiation of osteoblasts and bone formation. Therefore, the described composition of the proteasome inhibitor can be used in the treatment and/or prevention of diseases associated with bone loss such as osteoporosis.

Cancer is a General term for diseases characterized by uncontrolled abnormal growth of cells. Many forms of cancer arise through multistage path of metabolism involving the inactivation of proteins of tumor suppressor and oncogenic activation peptides. Cancer cells can spread to other parts of the body through the lymphatic system or the bloodstream. Usually, cancer is classified in accordance with the most significantly involved type the m tissue or cells. As noted earlier, an inhibitor of proteasome already justified as a therapeutic strategy for the treatment of cancer, particularly multiple myeloma. As shown in figure 1, the cells of multiple myeloma have both forms of the proteasome, although the ratio may to some extent be changed. Multiple myeloma is a hematological disorder characterized by excessive numbers of abnormal plasma cells in the bone marrow. Plasma cells develop from b cells, it is not surprising that other malignant b-cells will also to some extent to Express immunoproteasome. With the exception of two cell lines from chronic myelogenous leukemia, heme-similar forms of cancer (e.g., multiple myeloma, leukemias and lymphomas), which, apparently, usually Express immunoproteasome (figure 1). Cancer cells derived from lymphoid cells, Express a 30% or more immunoproteasome. In some embodiments implementing the invention relates to a method of treating cancer, comprising introducing a therapeutically effective amount of the compounds of the present invention. In some preferred embodiments, the implementation of cancer is a disorder associated with gem.

The intrigue that some forms of cancer (such as solid tumor, squamous cell carcinoma is carcinoma head and neck, cervical carcinoma and small cell lung carcinoma), appears to negatively regulate the expression of immunoproteasome (Evans et al., J Immunok 167:5420, 2001; Meissner et al., Clin Cancer Res 11:2552, 2005; Restifo et al., Exp Med 177:265-272, 1993). Apparently, this correlates with the lack of processing of the antigen and may be a strategy used by tumor cells to escape from immune surveillance. The cell treatment with INF-γ can induce the expression of immunoproteasome. Therefore, some embodiments of the invention relate to a method of treating cancer comprising the administration to a subject in need of such treatment, an effective amount of INF-γ or TNF-α and connection of the proteasome inhibitor of the present invention.

Introduction

The compounds obtained as described herein, can be introduced in various forms, depending on the disorder being treated and the age, medical conditions and body weight of the patient, as is well known in this field. For example, when connections are intended for oral administration, they can be in the form of tablets, capsules, granules, powders or syrups, or parenteral administration can be by injection (intravenous, intramuscular or subcutaneous), drugs for drip infusion or suppositories. For the introduction of ophthalmic way is through the membrane of the mucosa, they can be in the form of eye drops or eye ointments. Such preparations can be obtained in a common manner, and, if required, the active ingredient can be mixed with any conventional additive or excipient, such as a binder, disintegrity agent, lubricant, corrigent, solubilizers agent, auxiliary agent for suspension, emulsifying agent, the covering agent, cyclodextrin and/or a buffer. Although the dose will vary depending on symptoms, age and body weight of the patient, the nature and intensity of the disorder being treated or avoidance, route of administration and the form of the medicinal product, usually, for adult patients, the recommended daily dose of from 0.01 to 2000 mg of the compound and can be entered in a single dose or in divided doses. The amount of active ingredient which can be combined with the substance of the media to produce a single dosage form will generally constitute such number of connections that causes therapeutic effect.

The precise time of administration and/or amount of a composition which will give the most effective results from treatment efficacy for a particular patient will depend upon the activity, pharmacokinetics and bioavailability of a particular compound, physiological condition of the patient (VK is UCA age, gender, type of disease and stage, General physical condition, sensitivity to the dose and type of medication), route of administration, etc. But the above methodological recommendations can be used as the basis for a precise regulation of treatment, such as determining the optimal time and/or amount of administration, which will require no more than routine experiment, including the monitoring of the subject and the establishment of dose and/or synchronization.

Used in this description, the phrase "pharmaceutically acceptable" refers to ligands, substances, compositions and/or dosage forms which are, within reasonable medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable ratio of benefit/risk.

Used in this description, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable substance, composition or environment, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating substance. Each carrier must be "acceptable" in the sense of compatibility with other ingredients of the drug and not detrimental to the patient. Some ol the measures substances, which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch, potato starch, and substituted or unsubstituted β-cyclodextrin; (3) cellulose, and its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; (4) powdered tragakant; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and waxes for suppositories; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as etiloleat and tillaart; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical preparations. In some embodiments, the implementation of the pharmaceutical compositions of the present invention represent a pyrogen-free, i.e. does not cause a significant temperature increase with the introduction of the patient.

The term "Pharma is efticiency acceptable salt" refers to a relatively non-toxic additive salts of the inhibitor(s) with inorganic and organic acid. Such salts can be obtained in situ during the final isolation and purification of the inhibitor(s) or separately, the interaction of purified inhibitor(s) in free base form with a suitable organic or inorganic acid and allocation educated so of salt. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naftilan, mesilate, glucoheptonate, lactobionate, laurylsulphate salts and amino acid salts and the like (see, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66: 1-19).

In other cases, the inhibitors used in the methods of the present invention may contain one or more acidic functional groups, therefore, capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these examples relate to relatively non-toxic additive salts of the inhibitor(s) with inorganic and organic base. These salts can likewise be obtained in situ during the final isolation and purification of the inhibitor(s) or separately, the interaction of purified inhibitor(s) in the form of the free acid with a suitable base, such ka is the hydroxide, the carbonate or bicarbonate pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include salts of lithium, sodium, potassium, calcium, magnesium, aluminum and the like. Representative organic amines used for the formation of additive salts with base include ethylamine, diethylamine, Ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, for example, Berge et al., as indicated above).

Moisturizing agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, corrigentov and agents, perfumes, preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, bottled hydroxyanisol (BHA), bottled hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol and the like; and (3) agents, chelating a metal, such as citric acid, e is lindemulderalyssa acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.

Preparations suitable for oral administration may be in the form of capsules, sachets, pills, tablets, pellets (using the basics of corrigenda, usually sucrose and acacia Arabian or tragakant), powders, granules, or in the form of a solution or suspension in aqueous or non-aqueous liquid, or in the form of a liquid emulsion of the type oil-in-water or water in oil, or as an elixir or syrup, or as pastilles (using an inert matrix, such as gelatin and glycerin, or sucrose and acacia Arabia) and/or liquids for rinsing mouth, and the like, each of which contains a predetermined amount of inhibitor(s) as an active ingredient. The composition can also be entered in the form of a bolus, electuary or paste.

In solid dosage forms for oral administration (capsules, tablets, pills, coated tablets, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or with any of the following: (1) fillers or diluents, such as starch, cyclodextrin, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyle alidon, sucrose and/or acacia Arabia; (3) humectants, such as glycerol; (4) dezinfeciruyuhimi agents such as agar-agar, calcium carbonate, potato starch or tapioca starches, alginic acid, certain silicates and sodium carbonate; (5) agents to slow the dissolution such as paraffin; (6) absorption accelerators, such as Quaternary ammonium compounds; (7) wetting agents such as, for example, acetylcoenzyme alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugars, as well as polyethylene glycols of high molecular weight and the like.

The tablet can be manufactured by extrusion or molding, optionally with one or more accessory ingredients. Molded tablets can be made using a binder (such as gelatin or hydroxypropyl what ethylcellulose), the lubricant, inert diluent, preservative, dezintegriruetsja agent (for example, glycolate, sodium starch or cross-linked carboximetilzellulozu sodium), surface-active or dispersing agent. Molded tablets can be made by molding in a suitable device is a mixture of powdered inhibitor(s), moistened with an inert liquid diluent.

Tablets and other solid dosage forms such as tablets, capsules, pills and granules, may not necessarily be with the notch or obtained with coatings and shells, such as intersolubility coatings and other coatings well known in the manufacture of pharmaceuticals. They can also produce such a way as to provide slow or controlled release of the active ingredients using, for example, hydroxypropylmethylcellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They can be sterilized, for example, by filtration through a retaining bacteria filter or the introduction of sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use. Such compositions n is necessarily may also contain fogging agents and can be a composition, one where they release only the active ingredient(s) or, preferably, in a certain part of the gastrointestinal tract, it is not necessarily a slow way. Examples of embedded compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulating form, if appropriate, with one or more of the abovementioned excipients.

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

Besides inert diluents, the oral compositions can also contain adjuvants, such as wetting agents, emulsifying and suspendresume AG is, for example, sweeteners, flavors, corrective, dye, and preservative agents.

Suspensions, in addition to the active inhibitor(s)may contain suspendresume agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylenated and esters sorbitan, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant and mixtures thereof.

Preparations for rectal or vaginal injection can be presented in the form of a suppository, which can be obtained by mixing one or more inhibitors of one or more suitable a non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, which is a solid at room temperature, but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active agent.

Drugs that are suitable for vaginal administration, also include pessaries, tampons, creams, gels, pastes, foams or spray preparations containing such media are known in the field as appropriate.

Dosage forms for local or percutaneous injection of inhibitor(s) include powders, sprays, ointments, pastes, creams, lotions, gels, R is the sampling sites patches and forms for inhalation. The active ingredient can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.

Ointments, pastes, creams and gels may contain, in addition to the inhibitor(s), excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragakant, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures thereof.

Powders and sprays can contain, in addition to the inhibitor(s), excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures thereof. Sprays can additionally contain customary propellants such as chlorofluorocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

The inhibitor(s) can alternatively be entered using the aerosol. This is achieved by making an aqueous aerosol, liposomal preparation or solid particles containing the composition. You can apply a non-aqueous suspension (for example, the fluorocarbon propellant). Acoustic dispensers are preferred because they minimize the impact on the agent shear stress, which can lead to degradation of the connection.

Typically, water spray the floor is up by preparing an aqueous solution or suspension of the agent together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements for a particular composition, but typically include nonionic surfactants (twins, pluronic, esters sorbitan, lecithin, crematory), pharmaceutically acceptable cosolvent, such as polyethylene glycol, non-toxic proteins like serum albumin, oleic acid, amino acids such as glycine, buffers, salts, sugars, sugar alcohols. Aerosols are usually obtained from isotonic solutions.

Transdermal patches have the added advantage of providing controlled delivery of the inhibitor(s) in the body. Such dosage forms can be produced by dissolving or dispersing agent in an appropriate environment. You can also use amplifiers absorption to increase the penetration of the inhibitor(s) through the skin. The speed of such penetration can be adjusted either by the provision of controlling the speed of the membrane or by dispersing the inhibitor(s) in a polymer matrix or gel.

The pharmaceutical compositions of this invention suitable for parenteral administration contain one or more inhibitors in combination with one or more pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile item is Rostami, which can be restored into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, antimicrobial agents, dissolved substances, which make the drug isotonic with the blood of the intended recipient, or suspendresume or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which can be used in pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable complex organic esters, such as etiloleat. The corresponding liquid state can be maintained, for example, the use of covering materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surface-active substances.

Such compositions may also contain adjuvants such as preservatives, moisturizing agents, emulsifying agents and dispersing agents. Preventing exposure of microorganisms can be ensured by inclusion of various antibacterial and antifungal agents such as parabens, chlorobutanol, fenolcarbonove acid and the like. Also can potreboval is by inclusion in the composition of agents to establish toychest, such as sugars, sodium chloride, and the like. In addition, prolonged absorption of the injectable pharmaceutical form can be made by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

In some cases, in order to prolong the action of drugs, you want to slow down the absorption of the drug from subcutaneous or intramuscular injection. For example, delayed absorption of parenteral entered medicines reach the dissolution or suspendirovanie medicines in oily environments.

Form injectable depot is prepared by forming a matrix for microencapsulation inhibitor(s) in biodegradable polymers such as polylactide-polyglycolide. Depending on the relationship of drug to polymer and the nature of the used special polymer, it is possible to regulate the rate of release of the drug. Examples of other biodegradable polymers include complex poly(orthoevra) and poly(anhydrides). In addition, drugs injectable depot get hold of the drug in liposomes or microemulsions that are compatible with body tissues.

Drugs agents can be administered orally, parenterally, topically or rectally. Of course, they are introduced in the armah, suitable for each route of administration. For example, they are administered in tablets or in the form of a capsule by injection, inhalation, eye lotion, ointment, suppository, infusion; topical by lotion or ointment and rectal by suppositories. It is preferable to oral administration.

Used in this description, the phrases "parenteral administration" and "put parenteral" means the routes of administration other than enteral or local injection, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, through the trachea, subcutaneous, under the cuticle, intra-articular, subcapsular, subarachnoid, intraspinal and epigastric injection and infusion.

Used in this description, the phrase "system introduction, injected systemically", "peripheral introduction" and "put perifericheskie" means the introduction of a ligand, drug or other substance other than directly into the Central nervous system, so that it is logged in the patient and, therefore, was subject to metabolism and other like processes, for example, subcutaneous administration.

Such inhibitors can enter people and other animals DL the treatment by any suitable introduction, including oral, nasal, for example, in the form of a spray, rectally, vnutrivaginalno, parenteral, intracisternally and topically in the form of powders, ointments or drops, including buccal and sublingual.

Regardless of the chosen route of administration, the inhibitor(s), which can be used in a suitable hydrated form, and/or pharmaceutical compositions of the present invention are pharmaceutically acceptable dosage forms by using common methods known to the expert in this field.

The actual dosing levels of active ingredients in the pharmaceutical compositions of this invention can be modified in such a way as to obtain the amount of active ingredient which is effective to achieve a desired therapeutic response for an individual patient, compositions and mode of administration, and non-toxic for the patient.

The concentration of the compounds of the present invention in a pharmaceutically acceptable mixture will vary depending on several factors, including the dose of the compound for administration, the pharmacokinetic characteristics of the used connection(s) and route of administration. Typically, the compositions of this invention can be provided in an aqueous solution containing about 0.1-10% wt./about. compounds of the present invention, among draganescu for parenteral administration. Typical intervals dose is from about 0.01 to 50 mg/kg of body weight per day, administered in 1-4 separate doses. Each separate dose may contain the same or different compounds of the invention. The dose will be an effective amount depending on several factors including the overall health of the patient and the drug and route of administration selected connection(s).

Another aspect of the invention is a joint therapy, in which one or more therapeutic agents are administered with an inhibitor of the proteasome. This combined treatment can be achieved by sequential, simultaneous or separate dosing of the individual components of the treatment.

In some embodiments, the implementation of the connection of the invention jointly administered with one or more other inhibitors of the proteasome.

In some embodiments, the implementation of the connection of the invention jointly administered with the chemotherapeutic agent. Suitable chemotherapeutic agents may include natural substances, such as Vinca alkaloids (i.e. vinblastine, vincristine and vinorelbine), paclitaxel, epileptogenesis (i.e. etoposide, teniposide), antibiotics (dactinomycin (actinomycin D) daunorubicin, doxorubicin and idarubitsin), anthracyclines, mitoxantrone, bleomycin, plicamycin (Mitra is Itin) and mitomycin, enzymes (L-asparaginase which systemically metabolizes L-asparagine and produces the deprivation of cells that lack the ability to synthesize their own asparagine); antiplatelet agents; antiproliferative/antimitoticescoe alkylating agents, such as derivatives of nitrogen mustard (mechlorethamine, cyclophosphamide and analogs, melphalan, chlorambucil), ethylenimines and methylmelamine (hexamethylmelamine, thiotepa), alkyl sulphonates (busulfan), nitrosoanatabine (carmustin (BCNU) and analogs, streptozocin), trazeni-dacarbazine (DTIC); antiproliferative/antimitoticescoe antimetabolites, such as analogs of folic acid (methotrexate), analogues of pyrimidine (fluorouracil, floxuridine and cytarabine), purine analogues and similar inhibitors (mercaptopurine, tioguanin, pentostatin and 2-chlorodeoxyadenosine); aromatase inhibitors (anastrozole, exemestane and letrozole); coordination complexes of platinum (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutetimid; hormones (i.e. estrogen) and hormone agonists, such as agonists hormone releasing luteinizing hormone (LHRH) analogues (goserelin, leuprolide and triptorelin). Other chemotherapeutic agents may include mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, navelbine or any analog or derivative is a variant of the above agent.

In some embodiments, the implementation of the connection of the invention jointly administered with the steroid. Suitable steroids may include, but are not limited to, 21-acetoxyphenyl, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortisol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, flashcart, fluchloralin, flumetazon, flunisolide, fluotsinolon acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, flaperon acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, farmacita, halcinonide, halobetasol propionate, halobetasol, hydrocortisone, loteprednol etabonate, mazipredon, Madison, meprednisone, methylprednisolone, mometazon furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone nutrifaster, prednisone, prednesol, prednisone, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetone, triamcinolone hexacetonide and their salts and/or derivatives.

In some embodiments, the implementation of the connection of the invention in conjunction injected with immunotherapy agent. Appropriate immunotherapy agents may include, but is not limited icehouse them cyclosporine, thalidomide, and monoclonal antibodies. Monoclonal antibodies can be either as such or conjugated, for example, rituximab, has ended, alemtuzumab, epratuzumab, ibritumomab tiuxetan, gemtuzumab ozogamicin, bevacizumab, cetuximab, erlotinib and trastuzumab.

Explanation of examples

Scheme 1: synthesis of compounds of example 1

Synthesis of compounds (A)

To a solution of Cbz-Trp-OH (10 g, 29 mmol) in DMF (DMF) (150 ml) was added dropwise Me-Im (25,2 ml, 458 mmol). The solution was allowed to mix for 10 minutes, followed by addition of TBSCl (23.9 g, 158 mmol). The resulting solution was allowed to mix overnight. Then added water (100 ml) and the mixture was extracted with EtOAc (3×50 ml). The combined organic layers were washed with water (3×50 ml) and saturated salt solution (50 ml), dried over MgSO4, filtered and concentrated under reduced pressure, to obtain the oil, which was dissolved in a mixture of water/THF 1:1 (200 ml), and to the solution was added K2CO3(440 mg, 0,031 mmol). The resulting solution was allowed to mix overnight. Then the organic solvent was removed under reduced pressure and brought the pH to 2 using 1 N. HCl. The resulting solution was extracted with EtOAc (3×75 ml) and the combined organic is a mini layers were dried over MgSO 4, filtered and concentrated under reduced pressure, to obtain the compounds (A).

Synthesis of compound (C)

To a solution of hydrochloride dimethylhydroxylamine (3.6 g, 36,9 mmol) in DCM (20 ml) at 0 ° C was added dropwise diisopropylethylamine (DIEA) (5 ml, 54,7 mmol). The resulting solution was allowed to mix for 20 minutes.

To a solution of the compound (A) in DCM (20 ml) at 0 ° C was added dropwise isobutylparaben (IBCF) (5 ml, of 51.5 mmol), followed by adding dropwise N-methylmorpholine (NMM) (4,0 ml of 56.7 mmol). The resulting solution was allowed to mix for 10 minutes before adding it to the previously obtained solution of the hydrochloride dimethylhydroxylamine/DIEA. The mixture was allowed to mix for 3 h at 0OC, followed by the addition of water (50 ml). The layers were separated and the aqueous layer washed with DCM (3×15 ml). The combined organic layers were washed 1 N. HCl (3×20 ml) and saturated salt solution (20 ml), dried over MgSO4, filtered and concentrated under reduced pressure, to obtain the oil, which was purified flash chromatography, using as eluent a mixture of from 20 to 40% EtOAc/hexane, to obtain the compounds (B).

Synthesis of compound (C)

To a solution of the compound (In) (6,82 g, 14.4 mmol) in THF solution (40 ml) at -20 ° C was added a solution of isopropylacrylamide (90 ml, 0.5m wtgf), while maintaining the inside of the reaction mixture temperature below-5ºC. The solution was allowed to mix for 3 h at 0OC, followed by the addition of 1 N. HCl (20 ml). The solution was filtered through celite 521 and the filter cake washed with EtOAc. Then the organic solvent was removed under reduced pressure and the remaining aqueous solution was extracted with EtOAc (3×20 ml). The combined organic layers were washed a feast upon. NaHCO3(3×15 ml) and saturated salt solution (15 ml), dried over MgSO4, filtered and concentrated under reduced pressure, to obtain the oil, which was purified flash chromatography, using as eluent a mixture of from 10 to 20% EtOAc/hexane, to obtain the compound (C).

The synthesis of compounds (D) and (E)

To a solution of the compound (C) (a 3.06 g of 6.75 mmol) in Meon (40 ml) and THF (40 ml) was added Cl3·7H2O (of 3.64 g, 9,77 mmol). The resulting mixture was allowed to mix until until it becomes homogeneous. Then the solution was cooled to 0 ° C and was added NaBH4(369 mg, of 9.75 mmol) for 10 minutes. The solution was allowed to mix for 1 hour followed by addition of Asón (5 ml) under continuous stirring for 20 minutes. The solvent is evaporated under reduced pressure, the obtained residue was diluted with water (30 ml) and was extracted with EtOAc (3×10 ml). The combined organic with the ois washed with water (3×10 ml) and saturated salt solution (10 ml), dried over MgSO4, filtered and concentrated under reduced pressure, to obtain a mixture of compounds 4/1 (D) and (E).

The synthesis of compounds (F) and (G)

To a solution of compounds (D) and (E) in DCM (90 ml) at 0OC was added VO(acac)2(63 mg, 0.23 mmol), after stirring for 5 minutes was added dropwise tert-BuOOH (2.25 ml, 6.0 M in decane). The resulting solution was allowed to mix for 2 h, then filtered through celite 521 and the filter cake washed with DCM (20 ml). The combined organic layers were washed a feast upon. NaHCO3(3×20 ml) and saturated salt solution (20 ml), dried over MgSO4, filtered and concentrated under reduced pressure, to obtain a mixture of compounds (F) and (G) 4/1.

Synthesis of compound (H)

To a solution of periodinane Dess-Martin (6.75 g, 15.9 mmol) in DCM (75 ml) at 0 ° C was added dropwise a solution of compounds (F) and (G) in DCM (35 ml). The solution was allowed to warm to room temperature and was stirred overnight. Then the solvent was concentrated under reduced pressure and the residue was diluted with EtOAc (20 ml) and feast upon. NaHCO3(20 ml). The resulting mixture was filtered through celite 521 and the filter cake washed with EtOAc (20 ml). The layers were separated and the organic layer was washed with water (3×10 ml) and saturated salt solution (10 ml), dried over MgSO4, filtered and concentrated under reduced pressure, the floor is the group of mixtures of compounds (H) and (I) (4/1), which was purified flash chromatography, using as eluent a mixture of from 15 to 40% EtOAc/hexane, to obtain the compound (H).

Synthesis of compounds 1

To a solution of compound (H) (50 mg, 1.06 mmol) in TFOC (5 ml) was added Pd/C (14 mg, 10%). The resulting mixture was allowed to mix at a pressure of H21 atmosphere for 2 h, followed by dilution with DCM (10 ml). The filtrate was concentrated under reduced pressure, the obtained residue was diluted with DCM (10 ml) and concentrated under reduced pressure again. The residue was placed in a high vacuum for 2 h to obtain compound 1.

Scheme 2: synthesis of compounds of example 2

Synthesis of compound (J)

To a solution of Fmoc-Trp(Boc)-OH (2.4 mmol, 1.0 g) in DCM (20 ml) were added Me-Im (6.7 mmol, 0,370 ml) and the mixture was stirred until then, until the solution is homogeneous, in that moment, was added 1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole (MSNT) (2.9 mmol, 0,870 g). As soon as MSNT was dissolved, the reaction mixture was added to the resin NMRV-VNA (0.8 mmol, 1.25 g) and the resulting solution was allowed to shake things up within 45 minutes. The resin was filtered and washed with DMF (50 ml), Meon (50 ml) and DCM (50 ml). Then the resin was allowed to air dry, to obtain the compound (J).

Synthesis of compound (K)

To the compound (J) (0.40 mmol who, of 0.62 g) was added to a mixture of 20% piperidine/DMF (10 ml) and the resulting heterogeneous solution was allowed to shake things up within 20 minutes. The mixture was filtered, the resin washed with DMF (20 ml), Meon (20 ml) and DCM (20 ml) and allowed to air dry, and then was subjected to the above reaction conditions for the second time, to obtain the compound (K).

Synthesis of compounds (L)

To the compound (K) (0.40 mmol) was added DMF (20 ml), Cbz-D-Ala-OH (0.40 mmol, 0,090 g), DIEA (1.6 mmol, 0,12 ml), NAWT (0.64 mmol, 0,062 mg) and the THIEF (0.64 mmol, 0,178 g) and the reaction mixture was allowed to shake things up within 45 minutes. The reaction mixture was filtered, the resin washed with DMF (40 ml), Meon (40 ml) and DCM (40 ml) and allowed to air dry, to obtain the compound (L).

Synthesis of compound (M)

To the compound (L) (0.08 mmol) was added 5% TFWC/DCM (2 ml) and the mixture was allowed to shake things up within 20 minutes. The reaction mixture was filtered and the resin washed with DCM (10 ml). Volatiles were removed under reduced pressure, the resulting oil was diluted with DCM (10 ml) and evaporated in the end three times, to obtain the compounds (M).

Synthesis of compounds (N)

To a stirred solution of the compound (M) (0.11 mmol, 0,019 g) in MeCN (4 ml) and DMF (1 ml) was added the compound (M) (0.1 mmol), DIEA (2.9 mmol, 0.5 ml), NAWT (0.2 mmol, 0,032 g) and HBTU (0.23 mmol, 0,087 g) and the mixture was stirred at ControlTemplate during the night. The reaction mixture was diluted feast upon. NaHCO3(15 ml) and was extracted with EtOAc. The organic layer was washed a feast upon. NaHCO3and saturated salt solution, dried over MgSO4and volatile compounds were removed under reduced pressure. The crude substance was purified flash chromatography, using as eluent a mixture of from 20 to 40% EtOAc/hexane, to obtain the compound (N).

The synthesis of compounds 2

To a stirred solution of the compound (N) (0.1 mmol) in pyridine (1.5 ml) and THF (3.0 ml) at 0 ° C was added dropwise a solution of HF/pyridine. The solution was allowed to mix for 2 hours at 0 ° C before addition of water (5.0 ml) and extraction with EtOAc. The combined organic layers were washed a feast upon. NaHCO3and saturated salt solution, dried over MgSO4was filtered and the volatile compounds were removed at high pressure. The crude substance was purified flash chromatography, using as eluent a mixture of from 30 to 60% EtOAc/hexane, to obtain the compound 2 (4.2 mg).

Scheme 3: synthesis of compounds of example 3

Synthesis of compounds (A)

To a solution of Fmoc-Tyr(Me)-OH (1.9 mmol, 0,80 g) in DCM (20 ml) was added IU-Im (6.7 mmol, 0,370 ml). When the solution became homogeneous, add MSNT (2.9 mmol, 0,870 g) and the mixture was stirred to dissolve the MSNT, at this point, the resin NMRV-VNA (0,64 m is ol, to 1.00 g) and the resulting solution was allowed to shake things up within 45 minutes. The resin was filtered and washed with DMF (50 ml), Meon (50 ml) and DCM (50 ml) and then the resin was allowed to air dry, to obtain the compound (O).

Synthesis of compound (P)

To the compound (O) (0.40 mmol, of 0.62 g) was added to a mixture of 20% piperidine/DMF (10 ml) and the resulting heterogeneous solution was allowed to shake things up within 20 minutes. The mixture was filtered, the resin washed with DMF (20 ml), Meon (20 ml) and DCM(20 ml) and allowed to air dry. Then the resin was subjected to the above reaction conditions for the second time, to obtain the compounds (R).

Synthesis of compound (Q)

To the compound (P) (0.40 mmol) was added DMF (20 ml), Cbz-D-Ala-OH (0.40 mmol, 0,090 g), DIEA (1.6 mmol, 0,12 ml), NAWT (0.64 mmol, 0,062 mg) and the THIEF (0.64 mmol, 0,178 g) and the reaction mixture was allowed to shake things up within 45 minutes. The reaction mixture was filtered, the resin washed with DMF (40 ml), Meon (40 ml) and DCM (40 ml) and allowed to air dry, to obtain the compound (Q).

Synthesis of compound (R)

To the compound (Q) (0.08 mmol) was added 5% NFA/DCM (2 ml) and the mixture was allowed to shake things up within 20 minutes. The reaction mixture was filtered and the resin washed with DCM (10 ml). Then the volatile compounds were removed under reduced pressure, the resulting oil was diluted with DCM (10ml) and evaporated in the end three times, obtaining connection (R).

The synthesis of the compound (S)

To a stirred solution of compound 1 (0.11 mmol, 0,019 g) in MeCN (4 ml) and DMF (1 ml) was added the compound (R) (0.1 mmol), DIEA (2.9 mmol, 0.5 ml), NAWT (0.2 mmol, 0,032 g) and HBTU (0.23 mmol, 0,087 g) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted feast upon. NaHCO3(15 ml) and was extracted with EtOAc. The organic layer was washed a feast upon. NaHCO3and saturated salt solution, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting substance was purified flash chromatography, using as eluent a mixture of from 20 to 40% EtOAc/hexane, to obtain the compound (S).

Synthesis of compound 3

To a stirred solution of the compound (S) (0.1 mmol) in pyridine (1.5 ml) and THF (3.0 ml) at 0 ° C was added dropwise a solution of HF/pyridine. The solution was allowed to mix for 2 hours at 0 ° C, followed by addition of water (5.0 ml) and extraction with EtOAc. Then the organic layer was washed a feast upon. NaHCO3saturated salt solution, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting substance was purified flash chromatography, using as eluent a mixture of from 30 to 60% EtOAc/hexane, to obtain compound 3 (6,7 mg).

Scheme 4: synthesis of compound of example 4

Synthesis of compound (U)

To a solution of hydrochloride dimethylhydroxylamine (18,4 g, 226,3 mmol) in DCM (400 ml) at 0 ° C was added dropwise DIEA (from 25.8 ml, 282 mmol). The resulting solution was allowed to mix for 20 minutes.

To a solution of Cbz-Phe-OH (50 g, 169 mmol) in DCM (400 ml) at 0 ° C was added dropwise IBCF (24,4 ml, 266 mmol), followed by adding dropwise NMM (20.7 ml, 293 mmol). The resulting solution was allowed to mix for 10 minutes, then add the previously obtained solution of the hydrochloride dimethylhydroxylamine/DIEA. The mixture was allowed to mix for 3 h at 0OC, followed by the addition of water (250 ml). Then the layers were separated and the aqueous layer washed with DCM (3×100 ml). The combined organic layers were washed 1 N. HCl (3×100 ml) and saturated salt solution (100 ml), dried over MgSO4, filtered and concentrated under reduced pressure, to obtain the oil, which was purified flash chromatography, using as eluent a mixture of from 20 to 40% EtOAc/hexane, to obtain the compound (U).

Synthesis of compound (V)

To a solution of the compound (U) (47 g, 145 mmol) in THF solution (400 ml) at -20 ° C was added a solution of isopropylacrylamide (800 ml, 0.5m in THF), while maintaining the inside temperature of the solution below-5ºC. The solution was allowed to mix for 3 h at 0OC, followed add is the group of 1 N. HCl (200 ml). The solution was filtered through celite 521 and the filter cake washed with EtOAc. Then the organic solvent was removed under reduced pressure and the remaining aqueous solution was extracted with EtOAc (3×200 ml). The combined organic layers were washed a feast upon. NaHCO3(3×150 ml) and saturated salt solution (150 ml), dried over MgSO4, filtered and concentrated under reduced pressure, to obtain the oil, which was purified flash chromatography, using as eluent a mixture of from 20 to 40% EtOAc/hexane, to obtain the compound (V).

The synthesis of compounds (W) and (X)

To a solution of compound (V) (30,03 g, 92.0 mmol) in Meon (500 ml) and THF (500 ml) was added CeCl3·7H2O (48,04 g, 130 mmol). The resulting solution was allowed to mix until until it becomes homogeneous. Then the solution was cooled to 0 ° C and was added NaBH4(4,90 mg, 129 mmol) over a 10 minute period. The solution was allowed to mix for 1 h, followed by addition of Asón (70 ml) under continuous stirring for 20 minutes. The mixture is then concentrated under reduced pressure, the obtained residue was diluted with water (400 ml) and was extracted with EtOAc (3×130 ml). The combined organic layers were washed with water (3×130 ml) and saturated salt solution (130 ml), dried over MgSO4, filtered and concentrated under reduced pressure, with the teachings of the mixture of compounds (W) and (X) 5/1.

The synthesis of compounds (Y) and (Z)

To a solution of compound (W) and (X) in DCM (500 ml) at 0OC was added VO(acac)2(900 mg, 3,26 mmol), after stirring for 5 minutes was added dropwise tert-BuOOH (30 ml, 6.0 M in decane). The resulting solution was allowed to mix for 2 h, then filtered through celite 521 and the filter cake washed with DCM (200 ml). Then the filtrate was washed a feast upon. NaHCO3(3×200 ml) and saturated salt solution (200 ml), dried over MgSO4, filtered and concentrated under reduced pressure, to obtain a mixture of compounds (Y) and (Z) 5/1.

Synthesis of compound (AA)

To a solution of periodinane Dess-Martin (40 g, was 94.2 mmol) in DCM (300 ml) at 0 ° C was added dropwise a solution of compounds (Y) and (Z) in DCM (100 ml). Then the solution was allowed to warm to room temperature and was stirred overnight. Then the reaction mixture was concentrated under reduced pressure and the residue was diluted with EtOAc (120 ml) and feast upon. NaHCO3(120 ml). The resulting mixture was filtered through celite 521 and the filter cake washed with EtOAc (120 ml). The layers were separated and the organic layer was washed with water (3×60 ml) and saturated salt solution (60 ml), dried over MgSO4, filtered and concentrated under reduced pressure, to obtain the oil, which was purified flash chromatography, using as eluent a mixture of from 15 to 40% EtOAc/hexane, poluchenierazreshenija (AA).

The synthesis of compounds 4

To a solution of compound (AA) (50 mg, 1.06 mmol) in TFOC (5 ml) was added Pd/C (14 mg, 10%). The resulting mixture was allowed to mix at a pressure of H21 atmosphere for 2 h and then diluted with DCM (10 ml). The mixture was filtered through celite 521 and the filter cake washed with DCM (10 ml). Then the filtrate was concentrated under reduced pressure and the residue was diluted with DCM (10 ml) and concentrated under reduced pressure again. The residue was placed in a high vacuum for 2 h to obtain compound 4.

Scheme 5: synthesis of compound of example 5

Synthesis of compounds (SS)

To the compound (IV) (0.06 mmol) was added DMF (2 ml), Cbz-D-Abu-OH (0.12 mmol, 0,032 g), DIEA (0,256 mmol, 0.075 ml), NOT (is 0.102 mmol, 0,010 mg) and the THIEF (is 0.102 mmol, 0.075 g) and the reaction mixture was allowed to shake things up within 45 minutes. Then the reaction mixture was filtered, the resin washed with DMF (4 ml), Meon (4 ml) and DCM (4 ml) and allowed to air dry, to obtain the compounds (SS).

Synthesis of compound (DD)

To the compound (SS) (0.08 mmol) was added 50% TFWC/DCM (2 ml) and the mixture was allowed to shake things up within 20 minutes. The reaction mixture was filtered and the resin washed with DCM (10 ml). Then the solution was concentrated under reduced pressure, the resulting oil was diluted with DCM (10 ml) and evaporated in the end three times, with the floor is the group of compounds (DD).

Synthesis of compound 5

To a stirred solution of compound 4 (0.11 mmol, 0,019 g) in CN (4 ml) and DMF (1 ml) was added the compound (DD) (0.1 mmol), DIEA (2.9 mmol, 0.5 ml), NAWT (0.2 mmol, 0,032 g) and HBTU (0.23 mmol, 0,087 g) and the mixture was stirred at room temperature overnight. Then the reaction mixture was diluted feast upon. NaHCO3(15 ml) and was extracted with EtOAc. The organic layer was washed a feast upon. NaHCO3and saturated salt solution, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting substance was purified flash chromatography, using as eluent a mixture of from 25 to 55% EtOAc/hexane, to obtain the compound 5 (12.0 mg).

Scheme 6: synthesis of compound of example 6

Synthesis of compounds (HER)

To the compound (IV) (0.06 mmol) was added DMF (2 ml), Cbz-D-Leu-OH (0.12 mmol, 0,032 g), DIEA (0,256 mmol, 0.075 ml), NOT (is 0.102 mmol, 0,010 mg) and the THIEF (is 0.102 mmol, 0.075 g) and the reaction mixture was allowed to shake things up within 45 minutes. Then the reaction mixture was filtered and the filter cake washed with DMF (4 ml), Meon (4 ml) and DCM (4 ml) and allowed to air dry, to obtain the compounds (HER).

Synthesis of compounds (FF)

To the compound (IT) (0.08 mmol) was added 50% TFWC/DCM (2 ml) and the mixture was allowed to shake things up within 20 minutes. The reaction mixture was filtered and the resin p is washed by DCM (10 ml). Volatile compounds were removed under reduced pressure, the resulting oil was diluted with DCM (10 ml) and evaporated in the end three times, to obtain the compounds (FF).

Synthesis of compound 6

To a stirred solution of compound 4 (0.11 mmol, 0,019 g) in MeCN (4 ml) and DMF (1 ml) was added the compound (FF) (0.1 mmol), DIEA (2.9 mmol, 0.5 ml), NAWT (0.2 mmol, 0,032 g) and HBTU (0.23 mmol, 0,087 g) and the mixture was stirred at room temperature overnight. Then the reaction mixture was diluted feast upon. NaHCO3(15 ml) and was extracted with EtOAc. The organic layer was washed a feast upon. NaHCO3and saturated salt solution, dried over MgSO4, filtered and concentrated under reduced pressure. Then the resulting material was purified flash chromatography, using as eluent a mixture of from 25 to 55% EtOAc/hexane, to obtain compound 6 (of 14.0 mg).

Scheme 7: synthesis of the compound of example 7

Synthesis of compound 7

To a stirred solution of compound 4 (0.11 mmol, 0,019 g) in MeCN (4 ml) and DMF (1 ml) was added the compound (R) (0.1 mmol), DIEA (2.9 mmol, 0.5 ml), NAWT (0.2 mmol, 0,032 g) and HBTU (0.23 mmol, 0,087 g) and the mixture was stirred at room temperature overnight. Then the reaction mixture was diluted feast upon. NaHCO3(15 ml) and was extracted with EtOAc. The organic layer was washed a feast upon. NaHCO3and saturated salt solution, dried over MgSO4, who was intervali and concentrated under reduced pressure. The resulting substance was purified flash chromatography, using as eluent a mixture of from 25 to 55% EtOAc/hexane, to obtain compound 7 (10.5 mg).

Scheme 8: synthesis of the compound of example 8

Synthesis of compound (HH)

To a solution of hydrochloride dimethylhydroxylamine (331 mg, 3.4 mmol) in DCM (20 ml) at 0OC was added drop wise addition of triethylamine (343 mg, 3.4 mmol). The resulting solution was allowed to mix for 20 minutes.

To a solution of Cbz-HomoPhe-OH (1.0 g, 3.2 mmol) in DCM (100 ml) at 0 ° C was added dropwise IBCF (460 mg, 3.35 mmol), followed by adding dropwise NMM (343 mg, 3.4 mmol). The resulting solution was allowed to mix for 10 minutes and then added to the previously obtained solution dimethylhydroxylamine HCl/TAE. The resulting mixture was stirred at 0 ° C for 3 h, followed by addition of water (50 ml). The layers were separated and the aqueous layer was extracted with DCM (3×100 ml). The combined organic layers were washed 1 N. HCl (30 ml) and saturated salt solution (30 ml), dried over MgSO4, filtered and concentrated under reduced pressure. Then the resulting material was purified flash chromatography, using as eluent a mixture of EtOAc/hexane (1:3), to obtain the intermediate compound (LV) (0,92 g).

Synthesis of compound (II)

To a solution connect the wetlands (NN) (920 mg, 2.6 mmol) in THF (50 ml) at -20 ° C was added a solution of isopropylacrylamide (26 ml, 12.9 mmol, 0.5 M in THF). The resulting solution was allowed to mix at 0 ° C for 6 hours, followed by addition of 1 N. HCl (10 ml). The resulting mixture was filtered through celite 521 and the filter cake was washed with ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed a feast upon. NaHCO3(30 ml) and saturated salt solution (30 ml), dried over MgSO4, was filtered and was concentrated under high pressure. The resulting substance was purified flash chromatography, using as eluent a mixture of EtOAc/hexane (1:3), to obtain compound (II) (700 mg).

The synthesis of compounds (JJ) and (KK)

To a solution of compound (II) (700 mg, 2.1 mmol) in DCM (50 ml) at 0 ° C was added sequentially CeCl3·7H2O (942 mg, 2,52 mmol) and NaBH4(98 mg, 2,52 mmol). The solution was stirred at room temperature overnight, followed by addition of Asón (5 ml). The mixture was concentrated under reduced pressure and then diluted with EtOAc (100 ml) and feast upon. NaHCO3(50 ml). Then the aqueous layer was extracted with EtOAc (2×50 ml) and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a yellow oil, which was purified flash chromatography, using the UYa as eluent a mixture of EtOAc/hexane (1:3), obtaining compounds (JJ) and (KK) in the ratio of 5/1.

The synthesis of compounds (LL) and (MM)

To a solution of compounds (JJ) and (KK) in THF (50 ml) at 0 ° C was added sequentially VO(ASAS)2(18 mg, of 0.066 mmol) and tert-BuOOH (0.9 ml, 6.0 M in decane). The resulting solution was stirred at room temperature for 10 hours, then filtered through celite 521 and the filter cake washed with EtOAc (100 ml). The combined organic layers were washed a feast upon. NaHCO3(10 ml) and saturated salt solution (10 ml), dried over MgSO4, filtered and concentrated under reduced pressure, to obtain the compounds (LL) and (MM) (585 mg) in a ratio of 5/1.

Synthesis of compounds (NN)

To a solution of periodinane Dess-Martin (1.40 g, 3.3 mmol) in DMSO (20 ml) at 0 ° C was added the compound (LL) and (MM) (585 mg) in DMSO (10 ml). The solution was stirred at room temperature for 6 hours and then diluted with EtOAc (100 ml) and feast upon. NaHCO3(50 ml), then aqueous phase was extracted with EtOAc (2×50 ml) and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a yellow oil, which was purified flash chromatography, using as eluent a mixture of EtOAc/hexane (2:3), to obtain the compounds (NN) (465 mg).

Synthesis of compound 8

To a solution of compound (NN) (290 mg, 0.82 mmol) in TFOC (5 ml) was added Pd/C (14 mg, 10%). The resulting mixture is allowed to mix at a pressure of H 21 atmosphere for 2 h and then diluted with DCM (10 ml). The mixture was filtered through celite 521 and the filter cake washed with DCM (10 ml). The resulting solution was concentrated under reduced pressure, the residue was diluted with DCM (10 ml) and concentrated under reduced pressure. The obtained residue was placed in a high vacuum for 2 h to obtain compound 8.

Scheme 9: synthesis of the compound of example 9

The synthesis of the compound (PA)

To the compound (K) (0.06 mmol) was added DMF (2 ml), Cbz-Ala-HE (0.12 mmol, 0,032 g), DIEA (0,256 mmol, 0.075 ml), NOT (is 0.102 mmol, 0,010 mg) and the THIEF (is 0.102 mmol, 0.075 g) and the reaction mixture was allowed to shake things up within 45 minutes. Then the reaction mixture was filtered, the resin washed with DMF (4 ml), Meon (4 ml) and DCM (4 ml) and allowed to air dry, to obtain the compound (PA).

Synthesis of compounds (PP)

To the compound (PA) (0.08 mmol) was added 50% TFWC/DCM (2 ml) and the mixture was allowed to shake things up within 20 minutes. Then the reaction mixture was filtered and the resin washed with DCM (10 ml). Volatiles were removed under reduced pressure, the resulting oil was diluted with DCM (10 ml) and evaporated in the end three times, to obtain the compounds (PP).

Synthesis of compound (9)

To a stirred solution of compound 8 (0.11 mmol, 0,019 g) in MeCN (4 ml) and DMF (1 ml) was added the compound (PP) (0.1 mmol), DIEA (2 mmol, 0.5 ml), NAWT (0.2 mmol, 0,032 g) and HBTU (0.23 mmol, 0,087 g) and the mixture was stirred at room temperature overnight. Then the reaction mixture was diluted feast upon. NaHCO3(15 ml) and was extracted with EtOAc. Then the organic layer was washed a feast upon. NaHCO3and saturated salt solution, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting substance was purified flash chromatography, using as eluent a mixture of from 25 to 55% EtOAc/hexane, to obtain compound (9) (7.8 mg).

Scheme 10: synthesis of the compound of example 10

Synthesis of compounds (QQ)

To a solution of Cbz-Asp (t-Bu)-OH (0.32 mmol, 108 mg) in DMF (2 ml) at 0OC was added NOWT (0.51 mmol, 78 mg), HBTU (0.51 mmol, 194 mg) and DIEA (1.2 mmol, 0.2 ml). As soon as the mixture became a homogeneous solution was added to the resin Phe-HMPB-BHA (0.13 mmol, 200 mg) and the resulting reaction mixture was allowed to shake things up at 0-4ºC overnight. The resin was filtered and washed with DMF (3×5 ml) and DCM (3×5 ml). The resin was allowed to air dry, to obtain the compounds (QQ).

Synthesis of compounds (RR)

To the compound (QQ) (0.13 mmol) was added TFWC/DCM (5 ml, 5:95) and gave the opportunity to the mix to shake things up at 0-4ºC for 30 minutes. Then the reaction mixture was filtered and the resin washed with DCM (3×10 ml). Flying is soedineniya was removed under reduced pressure at 0 ° C, obtaining connection (RR).

Synthesis of compounds (SS)

To a solution of compound (RR) (0.13 mmol) and 4 (0.12 mmol) in THF (5 ml) at 0OC was added NOWT (0.18 mmol, 31 mg), HBTU (0.18 mmol, 76 mg) and DIEA (0.6 mmol, 0.1 ml) and the resulting reaction mixture was stirred at 0-4ºC overnight. Then the reaction mixture was diluted with EtOAc (100 ml) and feast upon. NaHCO3and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a yellow oil, which was purified HPLC, elwira a mixture of MeCN/aq. NH4Oac, to obtain the compounds (SS).

Synthesis of compound 10

To a solution of compound (SS) in DCM (5 ml) was added dropwise TFOC (5 ml) and the resulting solution was stirred for 3 h Then the reaction mixture was concentrated under reduced pressure and the obtained residue was purified HPLC, elwira a mixture of MeCN/aq. NH4Oac, receiving of the connection 10.

Scheme 11: synthesis of the compound of example 11

Synthesis of compounds (TT)

To a solution of Z-Ala-OH (0.32 mmol, 71 mg) in DMF (2 ml) at 0OC was added HOBT (0.51 mmol, 78 mg), HBTU (0.51 mmol, 194 mg) and diisopropylethylamine (1.2 mmol, 0.2 ml). Once the mixture has become homogeneous, added Phe(4-MeO)-Wang-resin (0.13 mmol, 200 mg) and the resulting reaction mixture was allowed to shake things up in ECENA night. Then the resin was filtered and washed with DMF (3×5 ml) and DCM (3×5 ml). The resulting resin was allowed to air dry, to obtain the compounds (TT).

Synthesis of compounds (UU)

To the compound (TT) (0.13 mmol) was added 50% TFWC/DCM (5 ml) and the mixture was allowed to shake things up within 30 minutes. Then the reaction mixture was filtered and the resin washed with DCM (3×10 ml). Volatile compounds were removed under reduced pressure, to obtain the compounds (UU).

Synthesis of compound (11)

To a solution of compound (UU) (0.13 mmol) and 4 (0.12 mmol) in THF (5 ml) at 0OC was added HOBT (0.18 mmol, 31 mg), HBTU (0.18 mmol, 76 mg) and DIEA (0.6 mmol, 0.1 ml). The resulting reaction mixture was stirred at 0-4ºC overnight, with further dilution with EtOAc (100 ml) and feast upon. NaHCO3. Then the aqueous phase was extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a yellow oil, which was purified HPLC, elwira a mixture of MeCN/aq. NH4Oac, to obtain compound (11).

Scheme 12: synthesis of the compound of example 12

The synthesis of compounds 12

To a solution of compound (VV) (0.18 mmol, 50 mg) and 4 (0.12 mmol) in THF (5 ml) at 0OC was added NOWT (0.18 mmol, 31 mg), HBTU (0.18 mmol, 76 mg) and DIEA (0.6 mmol, 0.1 ml). The resulting reaction mixture was stirred at 0-4ºC within n the Chi, with further dilution with EtOAc (100 ml) and feast upon. NaHCO3. Then the aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a yellow oil, which was purified HPLC, elwira a mixture of MeCN/aq. NH4Oac, receiving of the connection 12.

Scheme 13: synthesis of the compound of example 13

Synthesis of compounds (WW)

To a solution of Fmoc-O-tert-butyl-L-tyrosine (6.4 mmol, 2,94 g) in DCM (22 ml) was added 1-Mei (4.8 mmol, 0,380 ml) and the mixture was stirred until then, until the solution is homogeneous, in that moment, was added 1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole (MSNT) (6.4 mmol, 1.9 g). As soon as MSNT dissolved, the reaction mixture was added to the resin NMRV-VNA (1.28 mmol, 2 g) and the mixture was allowed to shake things up within 45 minutes. The resin was filtered and washed with DMF (50 ml), Meon (50 ml) and DCM (50 ml). Then the resin was allowed to air dry, to obtain the compounds (WW).

Synthesis of compound (XX)

To the compound (XX) (0.40 mmol, of 0.62 g) was added to a mixture of 20% piperidine/DMF (50 ml) and the resulting mixture was allowed to shake things up within 20 minutes. The mixture was filtered, the resin washed with DMF (20 ml), Meon (20 ml) and DCM (20 ml) and allowed to dry on vozduha.pri fact, as it was subjected to the above reaction conditions for the second time.

To the resulting resin was added DMF (64 ml), Fmoc-Ala-OH (32 mmol, of 1.05 g), DIEA (12.8 mmol, 2.2 ml), NAWT (5,12 mmol, 692 mg) and HBTU (5,12 mmol, 1,94 g) and the reaction mixture was allowed to shake things up within 45 minutes. The reaction mixture was filtered, the resin washed with DMF (40 ml), DCM (40 ml), Meon (40 ml), N2O (40 ml), Meon (40 ml), N2O (40 ml), Meon (40 ml) and DCM (40 ml) and allowed to air dry, to obtain the compound (XX).

Synthesis of compounds (YY)

To the compound (XX) (0,192 mmol, 0.3 g) was added to a mixture of 20% piperidine/DMF (10 ml) and the resulting mixture was allowed to shake things up within 20 minutes. The mixture was filtered, the resin washed with DMF (20 ml), Meon (20 ml) and DCM (20 ml) and allowed to air dry before it was subjected to the above reaction conditions for the second time.

To the resulting resin was added DMF (12 ml), morpholinomethyl acid (0.48 mmol, 70 mg), DIEA (1.92 mmol, 334 μl), NOT (0,768 mmol, 104 mg) and HBTU (0,768 mmol, 291 mg) and the reaction mixture was allowed to shake things up within 45 minutes. The reaction mixture was filtered, the resin washed with DMF (40 ml), DCM (40 ml), Meon (40 ml), N2O (40 ml), Meon (40 ml), N2O (40 ml), Meon (40 ml) and DCM (40 ml) and allowed to air dry, to obtain the compounds (YY).

Synthesis of compound (ZZ)/p>

To the compound (YY) (0,192 mmol) was added 5% TFWC/DCM (10 ml) and the mixture was allowed to shake things up within 10 minutes at 0OC. The reaction mixture was filtered and the resin washed with DCM (10 ml). Volatile compounds were removed under reduced pressure, the resulting oil was diluted with DCM (10 ml) and evaporated in the end three times, to obtain the compound (ZZ).

Synthesis of compound 13

To a stirred solution of compound (ZZ) (0,192 mmol, 83 mg) in MeCN (6 ml) and DMF (2 ml) was added 4 (0.384 mmol, 79 mg), DIEA (0,768 mmol, 133 μl), NAWT (0.3 mmol, 41 mg) and HBTU (0.3 mmol, 116 mg) and the mixture was stirred at 0OC for 2 hours. The reaction mixture was diluted feast upon. NaHCO3(15 ml) and was extracted with EtOAc (3×). The organic layer was washed a feast upon. NaHCO3and saturated salt solution, dried over MgSO4, filtered and concentrated under reduced pressure. The crude substance was purified flash chromatography, using as eluent EtOAc, then EtOAc/MeOH/TEA (98/1/1), with compound 13 as a white solid, which was characterized by LC/MS (LCRS(MH) m/z: 623,80).

Scheme 14: synthesis of the compound of example 14

Synthesis of compounds (AAA)

A suspension of BOC-Tyr(Me)-OH (10 g) in anhydrous dichloromethane (450 ml) was cooled

-5 º C in a bath of ice/acetone. To the resulting suspension were added triethylamine (94 ml, 67.8 mmol) and DMAP (600 mg). Then was added dropwise a solution of benzylbromide (5.7 ml, to 40.6 mmol) in dichloromethane (50 ml). The resulting solution was allowed to mix at 5 º C for three hours and then was allowed to warm to room temperature. Then the solution was added saturated aqueous sodium bicarbonate solution (200 ml). The organic layer was separated and the aqueous layer washed with dichloromethane (200 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel using a mixture of 80% hexane/20% ethyl acetate, obtaining 11,43 g of a white solid (88% yield)which was characterized by LC/MS (LCRS (MH) m/z: 386,42).

BOC-Tyr(Me)-AFP (2 g, 5.2 mmol) was dissolved in dichloromethane (15 ml) and cooled to 0OC, and then adding dropwise TFOC (15 ml). The reaction mixture was allowed to warm to room temperature and was stirred for 2 hours. The solvents were removed under reduced pressure, to obtain the compounds (AAA) as a clear oil (1.4 g, 95% yield)which was characterized by LC/MS (LCRS (MH) m/z: 286,42) and used without further purification.

Synthesis of compounds (BBB)

To a solution of Boc-Ala-OH (70 mg, 3.9 mmol), H-Tyr(Me)-AFP (950 mg, 3.3 mmol), NOT (712 mg, 5.3 mmol) and HBTU (2.0 g, 5.3 mmol) in acetonitrile (60 ml) and DMF (6 ml) was added dropwise N,N-diisopropylethylamine (2.3 ml). The mixture was stirred at 0°C for 2 hours, then was diluted with ethyl acetate (300 ml) and washed with saturated aqueous sodium bicarbonate (2×100 ml) and saturated salt solution (100 ml). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure, to obtain an opaque oil which was purified column chromatography on silica gel using a mixture of 50% hexane/50% ethyl acetate, to obtain 600 mg of the compound (BBB) as a white foam (40% yield), which was characterized by LC/MS (LCRS (MH) m/z: 457,52).

Synthesis of compounds (CCC)

To a solution of compound (BBB) (5.9 g, 12.9 mmol) in tetrahydrofuran (120 ml) at 0° was added 10% Pd/C (1.2 g) and the mixture was allowed to mix with the hydrogen pressure is 1 atmosphere for 2 hours. Then the mixture was filtered through celite-545 and the filter cake was washed with tetrahydrofuran. Then the organic filtrate was concentrated under reduced pressure and placed in conditions of high vacuum, obtaining a 4.53 g (95% yield) of the compound (CCC), which was used without further purification.

Synthesis of compounds (DDD)

To a solution of compound (CCC) (4 g, 10.9 mmol), compound 4 (2,23 is, 10.9 mmol), NOT (2,36 g of 17.4 mmol) and HBTU (6.6 g, to 17.4 mmol) in acetonitrile (200 ml) and DMF (5 ml) at 0°C was added N,N-diisopropylethylamine (7,6 ml) and the mixture was stirred at 0°C for 2 hours. Then was diluted with ethyl acetate (400 ml) and washed with saturated aqueous sodium bicarbonate (2×100 ml) and saturated salt solution (100 ml). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified HPLC (aqueous ammonium acetate (0.02 M) and acetonitrile), to obtain the compounds (DDD) (4,47 g, 74% yield), as characterized by LC/MS (LCRS (MH) m/z: 554,79).

Synthesis of compounds (EEE)

To a solution of compound (DDD) (2 g, 3.6 mmol) in dichloromethane (32 ml) at 0°C was added triperoxonane acid (8 ml) and the resulting solution was stirred at the same temperature for another one hour. Then the solution was concentrated under reduced pressure and placed in conditions of high vacuum, to obtain the compounds (EEE), as confirmed by LC/MS (LCRS (MH) m/z: 454,72), which was used without further purification.

Synthesis of compound 14

To a solution of compound (EEE), morpholine-4-luxusni acid (1,048 g, 7.22 mmol), NOT (780 mg, USD 5.76 mmol) and HBTU (2.2 g, USD 5.76 mmol) in acetonitrile (60 ml) and DMF (3 ml) at 0°C was added dropwise N,N-diisopropylethylamine (2.5 ml). The mixture was stirred at 0°C for 2 cha is s, then was diluted with ethyl acetate (300 ml) and washed with saturated aqueous sodium bicarbonate (2×100 ml) and saturated salt solution (100 ml). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified HPLC (aqueous ammonium acetate (0.02 M) and acetonitrile), to obtain compound 14 (620 mg, 29% yield)which was characterized by LC/MS (LCRS (MH) m/z: 581,83).

Scheme 15: synthesis of the compound of example 15

To a solution of compound (EEE) (65 mg, 0.144 mmol), hydrochloride (2R,6S)-2,6-dimethylmorpholine-4-luxusni acid (FFF) (50 mg, in 0.288 mmol), NOT (32 mg, 0.23 mmol) and HBU (88 mg, 0.23 mmol) in acetonitrile (15 ml) and DMF (1 ml) at 0°C was added dropwise N,N-diisopropylethylamine (100 μl) and the mixture was stirred at 0°C for 2 hours. Then was diluted with ethyl acetate (30 ml) and washed with saturated aqueous sodium bicarbonate (2×15 ml) and saturated salt solution (15 ml). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain residue, which was purified HPLC (aqueous ammonium acetate (0.02 M) and acetonitrile), to obtain compound 15 (32 mg, 36% yield), as characterized by LC/MS (LCRS (MH) m/z: 609,83).

Scheme 16: synthesis of the compound of example 16

To a solution of compound EEE) (0,62 mg, 0.14 mmol), (2-methyl-1,3-thiazol-5-yl)acetic acid (GGG) (25 mg, 0.15 mmol), NOT (30 mg, 0.22 mmol) and HBTU (84 mg, 0.22 mol) in acetonitrile (15 ml) and DMF (1 ml) at 0°C was added dropwise N,N-diisopropylethylamine (143 μl) and the resulting mixture was stirred at 0°C for 2 hours. Then was diluted with ethyl acetate (30 ml) and washed with saturated aqueous sodium bicarbonate (2×15 ml) and saturated salt solution (15 ml). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain residue, which was purified HPLC (aqueous ammonium acetate (0,02M) and acetonitrile), to obtain compound 16, which was characterized by LC/MS (LCRS (MH) m/z: 593,72).

Scheme 17: synthesis of the compound of example 17

Synthesis of compound (III)

To a solution of compound (IUU) (2 g, 5.9 mmol), 4 (2,44 g, 11,89 mmol), NOT (1.28 g, 9.5 mmol) and HBTU (3.6 g, 9.5 mmol) in acetonitrile (180 ml) and DMF (10 ml) at 0°C was added dropwise N,N-diisopropylethylamine (4,14 ml) and the mixture was stirred at 0°C for 2 hours. Then was diluted with ethyl acetate (200 ml) and washed with saturated aqueous sodium bicarbonate (2×50 ml) and saturated salt solution (50 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain residue, which was purified HPLC (aq is th ammonium acetate (0,02M) and acetonitrile), obtaining compound (III) (1.5 g, 50% yield), as characterized by LC/MS (LCRS (MH) m/z: 524,71).

Synthesis of compounds (JJJ)

To a solution of compound (III) (60 mg, 0.1 mmol) in dichloromethane (2 ml) at 0°C was added triperoxonane acid (0.5 ml) and the resulting solution was stirred at the same temperature for another one hour. Then the solution was concentrated under reduced pressure and placed in conditions of high vacuum, to obtain the compounds (JJJ), as confirmed by LC/MS (LCRS (MC) m/z: 424,51), which was used without further purification.

Synthesis of compound 17

To a solution of compound (JJJ), (2,4-dimethyl-1,3-thiazol-5-yl)acetic acid (40 mg, 0.23 mmol), NOT (25 mg, 183 mmol) and HBTU (70 mg, 0,183 mmol) in acetonitrile (6 ml) and DMF (1 ml) at 0°C was added dropwise N,N-diisopropylethylamine (80 ál). Then the mixture was stirred at 0°C for 2 hours. Then was diluted with ethyl acetate (50 ml) and washed with saturated aqueous sodium bicarbonate (2×10 ml) and saturated salt solution (10 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain residue, which was purified HPLC (aqueous ammonium acetate (0.02 M) and acetonitrile), to obtain compound 17 (29 mg, 44% yield), which was characterized by LC/MS (LCRS (MH) m/z: 577,86).

Example 18: tested to determine inhib the dominant advantages

There are three types of tests that can be applied to determine inhibits or not the molecule is predominantly constitutive or immunoproteasome CT-L activity. In enzymatic kinetic tests, such as described in the application U.S. No. 09/569748, example 2, and Stein et al., Biochem. (1996), 35, 3899-3908, using drugs selected 20S proteasome with more than 90% of the constitutive subunits of the proteasome or subunits immunoproteasome. Inhibitory advantage molecules, therefore, based on the EU50regarding chymotrypsinogen activity of constitutive proteasome activity of immunoproteasome (20S).

Alternatively, EU50to evaluate CT-L compounds can be determined using the 26S proteasome in the context of cell lysate. The connection is added to the lysate formed from cells that are either predominantly Express the constitutive proteasome (for example, NT)or immunoproteasome (for example, TNR). Besides, again, the inhibitory advantage based on the EU50(lisatoe ratio).

Finally, you can apply an approach based on a larger number of cells. Cells expressing an approximately equivalent amount of immuno - and constitutive proteasome (e.g., RPMI-8226), treated with the test compound, followed by application of the method the op is adelene activity of the proteasome inhibitor, as described in application No. 11/254541. EU50obtained in the test, based on the ELISA method, using β5 antibody and LMP7 antibodies (ELISA) provides the basis for determining the inhibition of the advantages of the tested compounds. In all examples, the ratio of 1 indicates that the molecule works equally well with the inhibition of CT-L activity of both forms of the proteasome. In all three trials the ratio less than one means that the molecule inhibits the CT-L activity of constitutive proteasome better than immunoproteasome. Relationship above one means that the molecule inhibits chymotrypsinogen activity immunoproteasome better than the activity of constitutive immunoproteasome.

Example 19: an analysis using ELISA method

Suitable analysis method ELISA can be found in the patent application U.S. No. 11/254541 included in this description by reference in its entirety. Briefly, cells RPMI-8226 were treated with 0.1-1 μm inhibitor of the proteasome. Then the samples were washed in phosphate buffered saline (PBS) and literally in hypotonic buffer (20 mm Tris pH 8.5 mm EDTA), (Tris-HCl and EDTA are available from Teknova, Inc., Hollister, CA). Cellular debris was removed by centrifugation at 14000 rpm in microcentrifuge (4°C) for 2 minutes, the Supernatant was transferred into a clean test tube was rapidly frozen in liquid nitrogen and kept the at -80°C. After thawing on ice, the samples (30 µl for analysis (three repetitions) were treated with 500 nm of inhibitor And for 1 h at room temperature. After inhibitor treatment And the lysate was denaturiruet adding seven volumes of 1% SDS (210 μl) (available from BIO-RAD, Hercules, CA) and heated at 99°C With vigorous shaking for 5 minutes the Sample was allowed to cool and added two volume (60 μl) of 10% Triton X-100 (available from BIO-RAD, Hercules, CA).

Granules streptavidine (6,5 μl/per well) (available from Amersham Biosciences, Piscataway, NJ) were washed three times with 1 ml PBS (available from ediatech, Inc., Herndon, VA) in test tubes microcentrifuge. Granules resuspendable in ELISA buffer type washing/blocking (PBS+0,1% Tween 20+1% bovine serum albumin; 20 μl/per well) and transferred to the wells of 96-well pad filtration (PSA available from Sigma, St. Louis, MO; Tween available from Calbiochem, San Diego, CA). Denatured whole blood or lysates RVMS who were treated with inhibitor 3, was added to the wells for titration containing granules streptavidine (each sample was analyzed three times) and incubated for 1 hour at room temperature with shaking (MultiScreen-DV opaque tablets duraperidol membrane with low-binding protein, available from Millipore, Billerica, MA). Unbound substances is soft deleted by filtration and the pellets were washed six times with ELISA buffer type washing/blocking (200 μl each).

Primary antibodies to subunit β5 20S proteasome human (rabbit polyclonal antibody, available from Biomol, Plymouth Meeting, PA) or subunit LMP7 20S immunoproteasome human (rabbit polyclonal antibody, available from Affinity BioReagents, Golden, CO) diluted 1:1000 in ELISA buffer type washing/blocking, was added to the granules (100 µl/well) and incubated for 1 hour at room temperature on an orbital shaker. Pellets were washed six times with ELISA buffer type washing/blocking with a soft filter. Processing secondary antibodies (1:5000) and washing were performed as described for the primary antibody (conjugate goat anti-rabbit antibody-HRP, available from Biosource, Camarillo, CA). Then the granules resuspendable 100 μl of the reagent for chemiluminescent detection (Super Signal Pico Chemiluminescent SubstrateTMavailable from Pierce, Rockford, IL) and the luminescence was read on a tablet reader Tecan.

Filling the active sites of the proteasome peptide epoxyketone inhibitor leads to the reduction of such chymotryptic activity and decrease in binding of the biotinylated probe (inhibitor). These data suggest that based on the ELISA analysis using biotinylated probe accurately reflects the inhibitory activity of the inhibitor Century

Illustrative feature of PD analysis of the foundations of the frame on ELISA, is that it allows differentiation between inhibition of constitutive proteasome (β5) and inhibition of immunoproteasome (LMP7), because it uses specific for subunit antibodies.

Using another probe of the active site (inhibitor) extends the applicability based on ELISA analysis for the measurement of several constitutive (β5, β1, β2) and immunoproteasome (LMP7, LMP2) active sites in cell lines 8226 multiple myeloma, which coexpressed both forms of the proteasome. Advanced analysis of the active site can be used to measure the relative selectivity of the inhibitor between both immuno-and constitutive proteasomes, as well as among the three active sites of the proteasome. In addition, based on ELISA analysis is able to determine the effectiveness and selectivity of other classes of proteasome inhibitors, including peptide inhibitors based on Bronevoy acid.

To conduct pharmacodynamic evaluation of inhibitor of whole blood and samples RVMS collected before dosing and at several time points after dosing. Received lysates and tested protein concentration to be standardized for total protein in each lysate. The level of binding of the inhibitor with subunits β5 and LMP7 in General Inoi blood and PBMCRPMI-8226 cells, respectively, were determined by the above method streptavidine fill ELISA. Standard curves of purified constitutive proteasome and immunoproteasome used to ensure linearity/dynamic analysis interval and to turn the chemiluminescent signal in the absolute amount (µg) binding subunit. EU50obtained in the analysis based on ELISA, using β5 antibody and LMP7 antibodies (ELISA) provides the basis for determining the inhibition of the advantages of the tested compounds. The above inhibitor (C) has a ratio above 20, therefore, it is much more selective in the inhibition chymotrypsinogen activity associated with immunoproteasomes.

To determine the level of proteasome inhibition for a given patient number β5 or LMP7, detektirovanie in the sample after dosing, compared with the sample before the introduction of the dose. Proteasome inhibition was determined after a single dose or after the dispensing cycle or used to monitor inhibition immediately after dosing, and to monitor the recovery of proteasome activity after dosing.

Example 20: the biological results

Example 21: the Use of immunoproteasome inhibitor in models of rheumatoid arthritis

The effect of compound 14 on the development of the disease has been evaluated in 2 mouse models of rheumatoid arthritis (figure 2). On the latter models antibodies, which induce disease introduction anticollagen antibodies and lipopolysaccharide (LPS) (Terato et al., J Immunol 148:2103-2108, 1992), the connection 14 inhibits the development of disease dependent on dose (figure 2(A)). Rheumatoid arthritis was induced on day 0 females Balb/c mice by the introduction of IV anti-type II collagen antibodies, followed by the introduction of 3 days LPS. Compound X was injected IV 3 times a week for 2 weeks starting from day 4, the first day of the animals showed the symptom of the disease. Each paw of the mouse was measured in the course of the disease scale 0-4 and have established a total clinical score for each animal (maximum is 16). Introduction 6 mg/kg of compound 14 reduced the intensity of the disease by about 50%, at the same time, the dose level of 20 mg/kg inhibited the disease by more than 75%.

The effect of the introduction of the connection 14 to the development of the disease was also evaluated on an alternative mouse model for RA, in which the disease is detected on a 21-30 day after immun is implementing a type II bovine collagen (Kagari et al., J Immunol 169:1459-1466, 2002). Introduction 6 or 20 mg/kg of compound 14 starting after the first symptoms inhibited the development of the disease compared with the control medium (figure 2(C)). The disease was again measured using the total clinical assessment paws of the mouse. As shown above, increasing the number of connection 14 leads to an increased reduction in the intensity of the disease.

Equivalents

Specialists in this field will be obvious or will they be able to ascertain using no more than routine experimentation, numerous equivalents to the compounds and methods of use thereof described in this specification. I believe that such equivalents are included in the scope of this invention and are covered by the following claims.

All the above-cited references and publications hereby incorporated in this description by reference in its entirety.

1. The compound having the structure of formula (I)or its pharmaceutically acceptable salt,

where the term aryl, as specified below, as the aromatic group is a phenyl, optionally substituted by methyl, methoxy, hydroxy, CF3CN, tert-utilname or tert-butoxy groups, and as a heteroaromatic group is an indole, optionally substituted methyl is, methoxy, hydroxy, CF3CN, tert-utilname or tert-butoxy groups;
In none;
L is absent or represents C=O;
M is absent or represents a C1-12alkyl;
Q is absent or represents NH;
X represents O;
Y is absent;
R1selected from H, -C1-6alkyl, aryl and C1-6arylalkyl;
R2and R3each independently selected from aryl, C1-6arylalkyl and C1-6heteroallyl, each of which may be optionally substituted as indicated below;
R4represents N(R5)-L-Q-R6;
R5represents H;
R6selected from the N-terminal protective group, aryl and heterocyclyl,
R7and R8represent H;
R15represents a C1-6alkyl.

2. The compound according to claim 1, where R15represents methyl or ethyl.

3. The compound according to claim 1, where L and Q are absent.

4. The compound according to claim 1, where R6represents the N-terminal protective group.

5. The compound according to claim 4, where R6selected from tert-butoxycarbonyl and benzyloxycarbonyl.

6. The compound according to claim 1, where the carbon having substituent R1has the stereochemical configuration D.

7. The compound according to claim 1, where R1selected from C1-6alkyl and C1-6arylalkyl.

8. The connection according to claim 7, where R1selected from methyl,ethyl, the isopropyl, carboxymethyl and benzyl.

9. The compound according to claim 1, where R2selected from C1-6arylalkyl and C1-6heteroallyl.

10. The compound according to claim 1, where R3selected from C1-6arylalkyl and C1-6heteroallyl.

11. The compound according to claim 1, where the EU50, connection to test the activity of constitutive proteasome compared to the EU50connection to test the activity of immunoproteasome higher than 1.0.

12. Connection claim 11, where the EU50higher than a 3.0.

13. The compound according to claim 1, where R6represents heterocyclyl-.

14. The connection indicated in paragraph 13, where R6represents heterocyclyl-and heterocyclyl fragment represents morpholino.

15. The connection 14, where L represents C=O, Q is absent and M is a C1-6alkyl.

16. The Union, representing

or its pharmaceutically acceptable salt.

17. Treatment-related immune disease, comprising introducing the compound according to any one of claims 1 to 15 or its pharmaceutically acceptable salt.

18. The method according to 17, where related to the immune disease is an inflammatory bowel disease.

19. The method according to p, where inflammatory bowel disease is a Crohn's disease or ulcerative to the it.

20. A method of treating cancer, comprising introducing the compound according to any one of claims 1 to 15 or its pharmaceutically acceptable salt.

21. A method of treating inflammation, comprising introducing the compound according to any of claims 1 to 15 or its pharmaceutically acceptable salt.

22. A method for the treatment of infections involving the introduction of a compound according to any one of claims 1 to 15 or its pharmaceutically acceptable salt.

23. A method of treating a proliferative disease, comprising introducing the compound according to any one of claims 1 to 15 or its pharmaceutically acceptable salt.

24. A method of treating neurodegenerative diseases, comprising introducing the compound according to any one of claims 1 to 15 or its pharmaceutically acceptable salt.

25. A method of treating asthma, comprising introducing the compound according to any one of claims 1 to 15 or its pharmaceutically acceptable salt.

26. Treatment-related immune disease, comprising introducing the compound according to clause 16 or its pharmaceutically acceptable salt.

27. A method of treating cancer, comprising introducing the compound according to clause 16 or its pharmaceutically acceptable salt.

28. A method of treating inflammation, comprising introducing the compound according to clause 16 or its pharmaceutically acceptable salt.

29. A method for the treatment of infections involving the introduction of a compound according to item 16 or its pharmaceutically acceptable salt.

30. A method of treating proliferative diseases include the s introduction connections P16 or its pharmaceutically acceptable salt.

31. A method of treating neurodegenerative diseases, comprising introducing the compound according to clause 16 or its pharmaceutically acceptable salt.

32. A method of treating asthma, comprising introducing the compound according to clause 16 or its pharmaceutically acceptable salt.

33. Pharmaceutical composition having inhibitory activity against 20S proteasome containing a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound according to any one of claims 1 to 15.

34. Pharmaceutical composition having inhibitory activity against 20S proteasome containing a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of the compound according to clause 16.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: in claim described are organic compounds of formula I where radicals are given in description, which are applicable for elimination, prevention or alleviation of one or more symptoms, associated with HCV disorders.

EFFECT: obtaining pharmaceutical composition which possesses inhibiting activity with respect to NS3-4 HCV serinprotease, including formula I compound and pharmaceutically acceptable carrier.

30 cl, 25 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the application of a biologically active peptide which represents the amino acid sequence SEQ ID No.1.

EFFECT: preparation of a drug for modulation of at least one of the following conditions: fatigue, liver glycogen level and blood lactic acid level.

30 tbl, 14 ex

FIELD: chemistry; biochemistry.

SUBSTANCE: invention relates to bioengineering and specifically to obtaining biologically active substances of peptide nature, which have growth factor activity towards fibroblast proliferation and can be used in medicine. An oligopeptide of formula A-X1-X2-X3-X4-X5-B is obtained through in silico construction, where A is F; X1 is E, or Q, or S; X2 is N, or Q, or A, or G; X3 is K, or R, or T; X4 is K, or E, or is absent, X5 is K, or L, or is absent and B is OMe - methyl.

EFFECT: invention enables obtaining an oligopeptide with transformation growth factor (TGF-β) and oncostatin M (OSM) towards fibroblast proliferation, and expansion of the range of effective therapeutic agents with wound-healing effect, which take part in closing wounds during inflammation and cicatrisation.

4 dwg, 2 ex

FIELD: chemistry; biochemistry.

SUBSTANCE: invention relates to bioengineering and specifically to obtaining biologically active substances of peptide nature, which have growth factor activity towards collagen synthesis stimulation and can be used in medicine. An oligopeptide of general formula A-X1-X2-X3-X4-X5-B (I) is obtained through in silico construction, where A is Ac - acetyl; X1 is G or A or is absent; X2 is P or I, or L, or V, or A; X3 is G; X4 is P or I, or L, or V, or A; X5 is G or A, or is absent and B is OMe - methyl.

EFFECT: invention enables obtaining an oligopeptide with acidic (aFGF) and transformation (TGF-β) growth factor activity towards stimulation of collagen biosynthesis, and expansion of the range of effective therapeutic agents with wound-healing effect, which speed up regeneration of damaged tissue and cicatrisation.

4 dwg, 2 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention refers to bioactive compounds of formula (Ic) , pharmaceutical compositions and application at cancer treatment, where R2-R7, X2, R, Q, G, J, L and M represent values estimated in invention formula and description.

EFFECT: production of compounds which can be used for anticancer medical product.

55 cl, 19 ex

FIELD: biochemistry.

SUBSTANCE: invention relates to method for tripeptide production of formulae Ac-D-2Nal-D-4ClPhe-D-3Pal-OH and Boc-D-2Nal-D-4ClPhe-D-Pal-OH, which represent intermediates for synthesis of LHRH analogs in combination with acceptable heptapeptides in particular P1-Ser(P2)-NMeTyr(P3)-D-Lys(Nic)-Leu-Lys(iPr,P4)-Pro-D-AlaNH2 and P1-Ser(P2)-NMeTyr(P3)-D-Asn-Leu-Lys(iPr,P4)-Pro-D-AlaNH2 heptapeptides.

EFFECT: new synthetic intermediates for LHRH antagonists.

7 cl, 8 ex

FIELD: biotechnology, medicine, oncology.

SUBSTANCE: invention proposes peptide of the structure Tyr-Ser-Leu and a pharmaceutical composition based on thereof that is used for stimulating antitumor immune response. Also, invention proposes methods for treatment of mammal and for modulation of the immune response. Proposed inventions expand assortment of agents used in treatment of cancer diseases.

EFFECT: valuable medicinal properties of peptide and pharmaceutical composition.

20 cl, 48 tbl

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention provides 1,5-benzothiazepines of general formula I (formulae presented below), in which Rv and Rw are independently selected from hydrogen and C1-C5-alkyl; one of Rx and Ry represents hydrogen or C1-C6-alkyl and the other hydroxy or C1-C6-alkoxy; Rz is selected from halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-C6-alkyl, and other residues indicated in claim 1 of invention; v is a number from 0 to 5; one of R4 and R5 represents group of general formula IA; R3 and R6 and the second from R4 and R5 are independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-C6-alkyl, and other residues indicated in claim 1; R3 and R6 and the second from R4 and R5 being optionally substituted by one or several R16 groups at their carbon atoms; D represents -O-, -N(Ra)-, -S(O)b- or -CH(Ra)-, wherein Ra is hydrogen or C1-C6-alkyl; and b=0-2; ring A represents aryl or heteroaryl and is optionally substituted by one or several substituents selected from R17; R7 represents hydrogen, C1-C4-alkyl, carbocyclyl, or heterocyclyl and is optionally substituted by one or several substituents selected from R18; R8 represents hydrogen or C1-C4-alkyl; R9 represents hydrogen or C1-C4-alkyl; R10 represents hydrogen or C1-C4-alkyl, carbocyclyl, or heterocyclyl and is optionally substituted by one or several substituents selected from R19; R11 represents carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORc)(ORd), -P(O)(OH)(ORc), -P(O)(OH)(Rd), or -(O)(ORc)(Rd), wherein Rc and Rd are independently selected from C1-C6-alkyl; or R11 represents group of general formula IB, in which X is -N(Rq)-, N(Rq)C(O)-, -O-, or -S(O)a, wherein a=0-2; and Rq is hydrogen or C1-C4-alkyl; R12 represents hydrogen or C1-C4-alkyl; R13 and R14 are independently selected from hydrogen, C1-C4-alkyl, carbocyclyl, heterocyclyl, or R23, of which C1-C4-alkyl, carbocyclyl, heterocyclyl, or R23 can be optionally independently substituted by one or several substituents selected from R20; R15 represents carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), -P(O)(OH)(Re), or -P(O)(ORe)(Rf), wherein Re and Rf are independently selected from C1-C6-alkyl; or R15 represents group of general formula IC, in which R24 is selected from hydrogen and C1-C4-alkyl; R24 is selected from hydrogen, C1-C4-alkyl carbocyclyl, heterocyclyl, and R27, of which C1-C4-alkyl, carbocyclyl, heterocyclyl, or R27 can be optionally independently substituted by one or several substituents selected from R28; R26 is selected from carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORg)(ORh), -P(O)(OH)(ORg), -P(O)(OH)(Rg), or -P(O)(ORg)(Rh), wherein Rg and Rg are independently selected from C1-C6-alkyl; p=1-3; wherein meanings for R13 can be the same or different; q=0-1; r=0-3; wherein meanings for R14 can be the same or different; m=0-2; wherein meanings for R10 can be the same or different; n=1-3; wherein meanings for R7 can be the same or different; z=0-3; wherein meanings for R25 can be the same or different; R16, R17, and R18 are independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, sulfamoyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkanoyl, C1-C4-alkanoyloxy, N-(C1-C4-alkyl)amino, N,N-(di-C1-C4-alkyl)amino, C1-C4-alkyl-S(O)a (wherein a=0-2), C1-C4-alkoxycarbonyl, N-(C1-C4-alkyl)sulfamoyl, and N,N-(di-C1-C4-alkyl)sulfamoyl; wherein R16, R17, and R18 can be optionally independently substituted by one or several of R21 at their carbon atoms; R19, R20, R23, R27, and R28 are independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, sulfamoyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkanoyl, C1-C4-alkanoyloxy, N-(C1-C4-alkyl)amino, N.N-(di-C1-C4-alkyl)amino, C1-C4-alkanoylamino, N-(C1-C4-alkyl)carbamoyl, N,N-(di-C1-C4-alkyl)carbamoyl, C1-C4-alkyl-S(O)a (wherein a=0-2), C1-C4-alkoxycarbonyl, N-(C1-C4-alkyl)sulfamoyl, N,N-(di-C1-C4-alkyl)sulfamoyl, carbocyclyl, heterocyclyl, sulfo, sulfino, amidino, phosphono, -P(O)(ORa)(ORb), -P(O)(OH)(ORa), -P(O)(OH)(Ra), or -P(O)(ORa)(Rb), wherein Ra and Rb are independently selected from C1-C6-alkyl and wherein R19, R20, R23, R27, and R28 can be optionally independently substituted by one or several of R22 at their carbon atoms; R21 and R22 are independently selected from halogen, hydroxy, cyano, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl; or pharmaceutically acceptable salt thereof, solvate, or salt solvate. Described are also method for preparing compounds of formula I, pharmaceutical compositions based on compounds I, and a method for achieving inhibiting effect relative to interscapular brown adipose tissue (IBAT), and intermediates. (I), (IA), (IB), (IC).

EFFECT: expanded synthetic possibilities in the 1,5-benzothiazepine series.

36 cl, 121 ex

The invention relates to a series peptidergic heterocyclic compounds, intermediates used in their receiving and containing pharmaceutical compositions

FIELD: medicine, pharmaceutics.

SUBSTANCE: in claim described are organic compounds of formula I where radicals are given in description, which are applicable for elimination, prevention or alleviation of one or more symptoms, associated with HCV disorders.

EFFECT: obtaining pharmaceutical composition which possesses inhibiting activity with respect to NS3-4 HCV serinprotease, including formula I compound and pharmaceutically acceptable carrier.

30 cl, 25 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the application of a biologically active peptide which represents the amino acid sequence SEQ ID No.1.

EFFECT: preparation of a drug for modulation of at least one of the following conditions: fatigue, liver glycogen level and blood lactic acid level.

30 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to production of biologically active substances of peptide nature, having cartilage-derived morphogenetic protein CDMP-1 activity on chondrocyte proliferation. Through in silico construction, an oligopeptide of general formula I is obtained: X1-X2-X3-X4 (I), where X1 denotes M; X2 denotes A or G; X3 denotes W; X4 denotes W or is absent.

EFFECT: invention enables to obtain an oligopeptide having cartilage-derived morphogenetic protein CDMP-1 activity on chondrocyte proliferation, thereby widening the range of effective therapeutic agents which accelerate regeneration of cartilage tissue of joints.

5 dwg, 1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to α',β'-epoxides of peptides of formulae (III) and (IV) which inhibit chymotrypsin-like activity of 20S proteasome.

EFFECT: increased effectiveness of the compounds.

19 cl, 29 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention refers to bioactive compounds of formula (Ic) , pharmaceutical compositions and application at cancer treatment, where R2-R7, X2, R, Q, G, J, L and M represent values estimated in invention formula and description.

EFFECT: production of compounds which can be used for anticancer medical product.

55 cl, 19 ex

FIELD: medicine; pharmacology.

SUBSTANCE: offered are compositions of formula 1 , where PG represents hydrogen or formyl group. R1 and R2 together with nitrogen atom to which they are attached, form heterocycle chosen from piperidine or morpholine and their pharmaceutically acceptable salts.

EFFECT: high haemostatic activity.

8 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention describes heterocyclic compounds represented by the general formula (I): and possessing elastase-inhibitory activity, and intermediate compounds for synthesis of such compounds. In the formula (I) R1 represents heterocyclic group represented by the formula (II): wherein A represents presence or absence of benzene ring; X represents oxygen atom, sulfur atom or -NH; Y represents nitrogen atom or -CH. Indicated heterocyclic group can be substituted with 1-3 substitutes that can be similar or different and they are chosen from group consisting of lower alkyl, lower alkoxy group and phenyl that can be optionally substituted with halogen-containing lower alkyl, lower alkoxy group or halogen atom; each among R2 and R3 represents hydrogen atom or hydroxyl, or R2 and R3 can be combined to form oxo group under condition that both are not hydrogen atoms.

EFFECT: valuable biochemical property of compounds.

8 cl, 7 tbl

FIELD: medicine, biochemistry.

SUBSTANCE: invention describes compounds that inhibit function of NS3-protease encoded by hepatitis C virus.

EFFECT: valuable medicinal properties of inhibitors.

6 cl, 2 tbl, 472 ex

The invention relates to compounds of formula (1), where X and Y Is N or O; R1substituted alkyl, substituted arylalkyl or cycloalkyl; R2and R3Is h or alkyl; And a Is-C(O)-, -OC(O)-, -S(O)2-; R4- alkyl, cycloalkyl or (C5-C12)aryl; compounds of the formula (2), where X and Y are O, S or N; R1- alkyl, optionally substituted arylalkyl; R2and R3Is h or alkyl;- C(O)-; R6- Deputy, including the condensed heterocyclic rings; and compounds of the formula (3), where X and Y are O, S or N; R1- alkyl, alkylsilane, (C5-C12)arylalkyl, (C5-C12)aryl; R2and R3Is h or alkyl; R2' and R3' - N; R11, R12and E together form a mono - or bicyclic ring which may contain heteroatoms

The invention relates to new derivatives of Proline, and more specifically to individual forms new derivative of 1-substituted N-[2-methyl-1-(TRIFLUOROACETYL)- propyl]pyrrolidin-2-carboxamide, which are inhibitors of elastase of human leukocytes (ALC), also known as elastase human neutrophils (ANC), which are important, for example, as a means of research work in pharmacological, diagnostic and related studies and in the treatment of diseases of mammals, which also involved ALC

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula

, where X1, X2, Y, R1a, R1b, R2a, R2b, A1, A2, A3 and A4 have the values specified in the description, which are vanilloid receptor subtype 1 (VR1) antagonists.

EFFECT: preparing a pharmaceutical composition on the basis of the compounds of formula 1 and developing methods of managing pain, neurotic pain, allodynia, inflammation or inflammatory disease associated pain, inflammatory hyperalgesia, bladder hyperactivity and urine incontinence.

22 cl, 21 ex

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