New compounds mimetics and using them

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new compounds of general formula (I):

in the form of a separate stereoisomer or mixed stereoisomers or in the form of its pharmaceutically acceptable salt wherein R1 is indazolyl or substituted indazolyl; R6 is C6aryl or C6-12aryl substituted by halogen, hydroxy, cyano and C1-6alkoxy; or C6heterocyclyl containing 1-2 heteroatoms specified in nitrogen or oxygen; each X2 and X3 independently mean hydrogen, hydroxy or phosphate.

EFFECT: prepared compounds may be used for preparing a drug preparation for treating or preventing cancer, particularly acute myeloid leukemia.

6 cl, 6 tbl, 8 ex, 4 dwg

 

The technical field

The present invention mainly relates to new compounds of the reverse-turn mimetics and their use in the treatment of pathological conditions such as cancer, and to pharmaceutical compositions containing mimetics.

The level of technology

For many years he conducted unsystematic screening molecules for potential activity as therapeutic agents and led to the discovery of a number of important medicines. Although advances in molecular biology and computational chemistry has generated increased interest in what was defined by the concept of "directional design of drugs", such methods were not as fast and reliable as originally expected. Thus, in recent years there has been renewed interest in haphazard screening of drugs and returned to him. In this regard, much progress has been made in new technologies based on the development of libraries combinatorial chemistry and screening such libraries for biologically active members.

Originally libraries combinatorial chemistry were largely confined to members of peptide or nucleotide origin.

Although combinatorial library containing members peptide and nucleotide the origin, are of great importance, yet in this prior art there remains a need in the libraries that contain members of different origin. For example, in classical peptide libraries to get members of the library mostly just varies amino acid sequence. Although it is widely accepted that secondary structure of the peptides are of great importance from the point of view of biological activity, such peptide libraries do not provide their members with a stable secondary structure.

In this regard, some researchers have cyclically peptides via disulfide bridges in an attempt to provide a more stable secondary structure (Tumelty et al., J. Chem. Soc. 1067-68, 1994; Eichler et al., Peptide Res. 7:300-306, 1994). However, such cyklinowanie peptides usually still quite unstable and in a small degree bioavailable and, therefore, achieve only modest success.

Recently been developed ones connections that more mimic the secondary structure of reverse turns, found in biologically active proteins or peptides. For example, U.S. patent No. 5440013 author Kahn and published PCT application no WO 94/03494, WO 01/00210A1 and WO 01/16135A2 author Kahn, each disclose conformationally stable ones compounds that mimic the three-dimensional structure of reverse turns. Additionally, U.S. patent No. 5929237 and its partial continuation of U.S. patent No. 6013458, both authors Kahn, open conformationally stable compounds which mimic the secondary structure regions of reverse turns of biologically active peptides and proteins. Synthesis and identification of conformationally stable reverse-turn mimetics and their use for the treatment of diseases discussed in detail in Obrecht (Advances in Med. Chem., 4, 1-68, 1999).

Although the synthesis and identification of conformationally stable reverse-turn mimetics significant progress has been made, in this prior art there remains a need for small molecules that mimic the secondary structure of peptides. Also in this prior art there is a need for libraries containing such members, as well as methods of synthesis and screening the library members, which is important, especially biological objects, in order to identify biologically active members of the library.

Meanwhile, protooncogen is a normal gene that can become an oncogene due to mutations or increased expression. c-Myc (MYC) is known as one of the proto-oncogene, and dysregulation of c-Myc is considered one of the series of oncogenic events that are required for carcinogenesis in mammals (Pelengaris s, Khan M. The many faces of c-MYC. Arch Biochem Biophys. 2003; 416:129-136). It was also found that the dysregulation of MYC through a lot of the e.g mechanisms, associated with myeloid leukemia (B. Hoffman, A. Amanullah, Shafarenko, M., Liebermann D. A. The proto-oncogene c-Myc in hematopoietic development and leukemogenesis, Oncogene. 2002; 21:3414-3421). In addition, it was found that c-Myc quickly causes acute myeloid leukemia (Hui Luo et al. "c-Myc rapidly dosage acute myeloid leukemia in mice without evidence of lymphoma-associated antiapoptotic mutations, Blood, 1 October 2005, volume 106, Number 7, p. 2452-2461).

Because the expression of c-Myc can be activated in acute myeloid leukemia, investigated the carcinogenic action of c-Myc and studied its exact role in myeloid leukemogenesis. Recently, a scientist found that Myc mainly stimulates the growth of myeloid progenitor cells in methylcellulose, and showed that Myc is a critical downstream effector myeloid leukemogenesis (from the same source).

The discovery of the fact that c-Myc plays a critical role in myeloid leukemogenesis means that by inhibiting the activation of the protein c-Myc is possible to treat or prevent acute myeloid leukemia.

On the other hand, the enzymes of the superfamily of cytochrome P450 (CYP) are the main determinants of half-life and provide the pharmacological effects of many therapeutic drugs. Subfamily of the human cytochrome P450 (CYP) 3A includes CYP3A4, which is most common in human liver (~40%), and metabolizes more than 50% of the Kli is automatic used drugs (Shimada et al. 1994; Rendic and Di Carlo, 1997). Due to the key role of CYP3A4 in the metabolism of drugs significant inactivation of this enzyme could lead to severe pharmacokinetic drug-drug interactions. Inhibition of CYP3A4 can cause severe drug toxicity due to increased exposure to the action of simultaneously introduced drugs (Dresser et al. 2000). For example, if the joint introduction of irreversible inhibitors of CYP3A4, such as erythromycin or clarithromycin with terfenadine, astemizole or pimozidom patients may begin bidirectional tachycardia (life-threatening ventricular arrhythmia associated with QT prolongation) (Spinler et al. 1995; Dresser et al. 2000). Patients with cancer are at times subjected to multiple therapies, which increases the risk of drug-drug interactions, which appear adverse reaction.

Therefore, the development of therapeutic agents, especially when they need to be led in combination with other drugs, there is a need to provide compounds having a weak CYP3A4 inhibitory activity.

The invention

The aim of the present invention is to provide new compounds which mimic the secondary structure regions of reverse turns biologically active is aptidon and proteins have biological activity, such as an anti-cancer effect.

Another purpose of this invention is the provision of new compounds that inhibit Wnt signaling.

Another purpose of this invention is the provision of new compounds that can be used as drugs, in particular those with weak CYP3A4 inhibitory activity (higher IC50).

Another purpose of this invention is the provision of new compounds for the treatment or prevention of acute myeloid leukemia by regulation, reduce the expression of c-Myc.

The present invention relates to a new type of conformationally stable compounds and their derivatives, including prodrugs, which mimic the secondary structure regions of reverse turns of biologically active peptides and proteins. This invention also discloses libraries containing such compounds, and their synthesis and screening. Compounds of the present invention have the following General formula (I):

,

in which E represents a-ZR3- or -(C=O)-, with Z represents CH or N; W represents -(C=O)-, -(C=O)NH-, -(C=O)O-, -(C=O)S-, -S(O)2or a simple bond; and each of R1, R2, R3, R4and R5are the same or different and independently before the represent functional group of the amino acid side chain or a derivative of amino acid side chain. Connection, simulating the reverse rotation may be in the form of a single stereoisomer or mixture of stereoisomers or in the form of their pharmaceutically acceptable salts.

In some embodiments, the implementation of R1compounds of formula (I) represents indazole or substituted indazoles.

Specific examples of R1, R2, R3, R4and R5given in the following detailed description.

In the embodiment, in which E represents CHR3, the compounds of this invention have the following formula (II):

,

in which W represents a group as defined above, and R1, R2, R3, R4and R5defined in the following detailed description.

In some embodiments, the communication in this invention have the following General formula (III):

,

in which R1, R4, R6X1X2and X3defined in the following detailed description.

The present invention also relates to prodrugs using libraries containing one or more compounds of the formula (I). Typically, the prodrug is designed to release the active drug in the body during or after absorption by enzymatic and/or the chemical hydrolysis. Proletarskiy approach is an effective means of improving oral bioavailability or centuries (intravenous) administration of drugs which are poorly soluble in water by chemical receiving derivatives more water-soluble compounds. The most common proletarienne approach to improve the water solubility of drugs containing a hydroxyl group, is the production of esters containing an ionic group; for example, a phosphate group, carboxylate group, alkylamino (Fleisher et al., Advanced Drug Delivery Reviews, 115-130, 1996; Davis et al., Cancer Res., 7247-7253, 2002, Golik et al., Bioorg. Med. Chem. Lett., 1837-1842, 1996).

Examples of functional groups that may be released into the body, may include phosphate,

but can be used with any other functional group, which is usually used as the ionic group in a prodrug.

In some embodiments, the implementation of the prodrugs of the present invention have the following General formula (IV):

,

in which (III) represents the formula (III)as described above; one of R1, R4, R6X1X2and X3associated with R7through Y; Y represents oxygen, sulfur or nitrogen, R1, R4or R6or oxygen is in the X 1X2or X3; and R7is hydroxyalkyl, glycosyl, phosphorylethanolamine, substituted or unsubstituted piperidine carbonyloxy or its salt; or Y-R7represents an amino acid residue, a combination of amino acid residues, phosphate, hemamala, hemisuccinate, dimethylaminoethylacrylate, dimethylaminoacetyl or its salt; and in the case when not associated with R7: R1, R4, R6X1X2and X3are defined in the following detailed description.

In some embodiments, the implementation of the prodrugs of the present invention can serve as a substrate for the phosphatase activity of the carboxylase or other enzymes and to become using them in connection with General formula (III). The present invention also relates to libraries containing one or more compounds of the formula (I)above, as well as methods of synthesis of such libraries and their screening to identify biologically active compounds. In addition, one side aspect of the present invention provides new compounds that have weak CYP3A4 inhibitory activity. The present invention also provides new compounds which have inhibitory activity in relation to the transfer of the Wnt signal. The present invention t is the train provides new connections you can apply for obtaining a medicinal product for the treatment or prevention of acute myeloid leukemia.

The present invention provides new compounds of the reverse-turn mimetics. Compounds of the present invention are more weak CYP3A4 inhibitory activity (higher IC50), which gives the opportunity to use these compounds as potential pharmaceutical agents, especially in the case when you need to enter them in combination with other drugs. Compounds of the present invention showed strong inhibitory activity in relation to the transfer of the Wnt signal. These compounds inhibited the growth of cancer cells AML (acute myeloid leukemia), and it can be used in the treatment or prevention of acute myeloid leukemia.

Brief description of drawings

Here is the detail will be made reference to the preferred implementation of the present invention, examples of which are illustrated in the drawings accompanying this document. Options for implementation are described below so as to explain the present invention by reference to figures.

Figure 1 presents the General scheme of the synthesis to obtain the reverse-turn mimetics of the present invention.

Figure 2 shows the effect of the investigated compounds is s (Connection A, B and C) on CYP3A4 activity. This graph is based on measuring the IC50for compounds of the present invention in the analysis of inhibition of CYP3A4 in which inhibition of CYP3A4 activity was measured at various concentrations of this compound with the aim of obtaining the values of the IC50. Detailed procedures disclosed in Example 1.

Figure 3 shows the results of measurement IC50connection D for SW480 cells in bioanalysis gene-reporter TopFlash.

Figure 4 shows the inhibition of growth of cancer cells in AML using these compounds depending on the concentrations of these compounds (Compounds A and C).

The preferred embodiment of the invention

As used in this description and the attached claims, unless otherwise specified, the following terms have a specific value.

"Amino" refers to-NH2the radical.

"Amidino" refers to-C(=NH)-NH2the radical. One or both of the hydrogen atom of the amine group amidino can be substituted by one or two alkyl groups, as defined in the context of this document. Alkyl-derivatives amidino radicals are also known as "alkylamino" and "dialkylamino" respectively.

"Cyano" refers to the CN radical.

"Carboxy" refers to the radical COOR, in which R represents hydrogen or alkyl, as defined what about in the context of this document.

"Acyl" refers to-the COR radical in which R represents alkyl, aryl, cycloalkyl, heterocyclyl, as defined in the context of this document. For example, R may be the stands, butanolom, cyclopropyl and the like. The alkyl or aryl may be optionally substituted by the substituents described for the alkyl or aryl group, respectively. Exemplary acyl groups include, without limitation, venilale, bansilal, C1-6acyl (e.g. acetyl), and the like.

"Alkylsulfonyl" refers to-S(O)2-OR radical where R is alkyl, as defined in the context of this document.

"Aminosulfonyl" refers to the radical-OS(O)2-NR2and each R independently represents hydrogen or alkyl. Approximate amidosulfonic include-OS(O)2NH2, -OS(O)2NHMe.

"Aminocarbonyl" refers to the radical-C(O)NR2and each R independently represents hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, alkoxyalkyl, hydroxyalkyl, hydroxyl, alkoxy, arylalkyl, geterotsiklicheskikh, or two R together with the nitrogen atom to which they are attached, form heterocyclyl, as defined in the context of this document. If one R is a hydrogen, the other R represents a C1-4alkyl, aminocarbonyl can be represented "Csub> 1-4alkyltrimethyl".

"N-formamides" refers to the radical-NHC(O)H.

"Phenylsulfonyl" refers to-S(O)2-The R radical in which R represents phenyl, phenyl may be optionally substituted by alkyl or chlorine.

"Phenylsulfonyl" refers to-O-S(O)2-The R radical in which R represents phenyl, phenyl may be optionally substituted by alkyl or chlorine.

"Alkylsulfonyl" refers to-S(O)2-The R radical in which R represents an alkyl, as defined in the context of this document. Approximate alkylsulfonyl radicals include methylsulphonyl.

"Alkylthio" refers to-SR radical, in which R represents an alkyl, as defined in the context of this document.

"Aristeo" refers to-SR radical, in which R represents an aryl, as defined in the context of this document. Aryl group aaltio may be optionally substituted by alkyl or chlorine.

"Aryloxy" refers to an-OR radical where R is aryl as defined in the context of this document. The aryl group may be optionally substituted by alkyl, alkoxy and the like.

"Aryloxyalkyl" refers to-R'-OC(O)-R radical where R is an alkyl, aryl, cycloalkyl, heterocyclyl, as defined in the context of this document; and R' represents alkyl./p>

"Guanidino" refers to-NH-C(=NH)-NH2the radical. One or both of the hydrogen atom of the amine group guanidino can be substituted by one or two alkyl groups, as defined in the context of this document. Alkylated guanidine radicals are also known as "alkylguanine" and "dialkylamino" respectively.

"Nitro" refers to-NO2the radical.

"Alkyl" refers to a radical with a linear or branched hydrocarbon chain consisting solely of carbon atoms and hydrogen. The alkyl may be saturated (containing carbon atoms linked only ordinary bonds) or unsaturated (containing carbon atoms, which are interconnected, at least one double bond or triple bond). Alkyl containing from one to twelve carbon atoms, also referred to as "lower alkyl group" and may be represented by "C1-12by alkyl". In other embodiments, implementation of the alkyl may contain from one to four carbon atoms and can be represented by "C1-4by alkyl". In other embodiments, implementation of the alkyl may contain from two to five carbon atoms and can be represented by "C2-5by alkyl". Alkyl is attached to the rest of the molecule through ordinary communication. Examples of saturated Akilov include without limitation methyl, ethyl,n-propyl, 1-methylethyl (isopropyl),<> n-butyl,npentyl, 1,1-dimethylethyl (tert-butyl), 3-etylhexyl, 2-etylhexyl and the like. Examples of unsaturated Akilov include, without limitation, ethynyl (i.e. vinyl), prop-1-enyl (i.e. allyl), but-1-enyl, Penta-1-enyl, Penta-1,4-dienyl, ethinyl (i.e. acetylenyl), prop-1-inyl and the like.

The alkyl may be a monocyclic or bicyclic hydrocarbon ring radical, which may include a condensed or bridged ring system. Cyclic alkyl also referred to as "cycloalkyl". In some embodiments, the implementation of cycloalkyl may contain from three to six carbon atoms and can be represented by "C3-6cycloalkyl". Examples of monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Unsaturated cycloalkyl contains an internal double bond (i.e. the double bond in the ring). Examples of unsaturated cycloalkyl include cyclohexenyl. Examples of bicyclic cycloalkyl radicals include, for example, norbornyl (i.e. bicyclo[2.2.1]heptyl), 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like.

Unless otherwise stated specifically in this description, it is assumed that the term "alkyl" includes alkyl, and substituted alkyl," which refers to the alkyl radical, in to the or one or more hydrogen atoms substituted by one or more substituents, independently selected from acyl, amidino, alkylamino, dialkylamino, alkoxy, aryl, cyano, cycloalkyl, guanidino, alkylguanine, dialkylamino, halogen, heterocyclyl, hydrazine, hydroxyl, nitro, -OC(O)-R11, -N(R11)2, -C(O)OR11, -C(O)N(R11)2, -N(R11)C(O)OR11, -N(R11)C(O)R11, -N(R11)S(O)tR11(where t represents 1 or 2), -S(O)tOR11(where t represents 1 or 2), -S(O)pR11(where p represents 0, 1 or 2) and-S(O)tN(R11)2(where t represents 1 or 2, each R11independently represents hydrogen, alkyl, aryl, arylalkyl, heterocyclyl or geterotsiklicheskikh, as defined in the context of this document.

"Alkoxy" refers to the radical represented by the formula alkyl-O-, in which alkyl is defined in the context of this document. The alkyl portion may be optionally substituted by one or more halogen. Alkoxygroup can also be represented by the number of carbon atoms in the alkyl group, for example, C1-6alkoxy or C1-3alkoxy.

"Aryl" refers to a radical derived from an aromatic monocyclic or bicyclic ring system by removing a hydrogen atom from a ring carbon atom. Aromatic monocyclic or bicyclic carbon is hydrogen ring system contains from six to twelve carbon atoms (i.e. C6-12aryl), while at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with theory of hukkala. Optional one or two ring atoms of the aryl may be heteroatoms selected from nitrogen, oxygen or sulfur. Examples of aryl radicals include, but are not limited to, phenyl and naphthyl. Unless otherwise stated specifically in this description, it is assumed that the term "aryl" includes aryl and substituted aryl", which refers to the aryl radical, in which one or more hydrogen atoms substituted by one or more substituents, independently selected from alkyl, acyl, amidino, amidosulfonic, alkoxy, aryloxy, cyano, guanidino, alkylguanine, dialkylamino, halogen, hydrazine, hydroxyl, nitro, heterocyclyl, -OC(O)-R11, -N(R11)2, -C(O)OR11, -C(O)N(R11)2, -N(R11)C(O)OR11, -N(R11)C(O)R11, -N(R11)S(O)tR11(where t represents 1 or 2), -S(O)tOR11(where t represents 1 or 2), -S(O)pR11(where p represents 0, 1 or 2) and-S(O)tN(R11)2(where t represents 1 or 2, each R11independently represents hydrogen, alkyl, aryl, arylalkyl, Goethe is iillil or geterotsiklicheskikh.

"Arylalkyl" refers to the alkyl radical in which one or more hydrogen atoms of the alkyl substituted by one or more aryl groups, as defined in the context of this document. In various embodiments, the implementation of arylalkyl include from 7 to 15 carbon atoms and can be represented by C7-15arylalkyl. In some embodiments, the implementation of arylalkyl is arils1-4alkyl, in which C1-4alkyl is substituted with one aryl or two aryl groups, the latter also referred to as "diarylamino" or "bisaillon". Examples arils1-4of alkyl include, but are not limited to, arylmethyl, arylaryl, allpaper, arivall, bizarelly, bizarrely, becerileri, binaryboy. Approximate arylalkyl radicals include without limitation, benzyl, naphthylmethyl, diphenylmethyl, 3,3-biphenyldiol and the like. Unless otherwise stated specifically in this description, it is assumed that the concept of "arylalkyl" includes both arylalkyl and "substituted arylalkyl", in which the alkyl part and/or the aryl portion arylalkyl radical may be substituted as described in the context of this document for an alkyl radical and an aryl radical, respectively.

"Cycloalkenyl" refers to the alkyl radical in which one or more hydrogen atoms alkylsilane one or more cyclic groups, as defined in the context of this document. In some embodiments, the implementation of cycloalkenyl is cycloalkyl1-2alkyl, such as cycloalkenyl, cycloalkenyl and the like. Approximate cycloalkenyl radicals include without limitation cyclohexylethyl (for example, cyclohexylmethyl and cyclohexylethyl) and cyclopentylamine (for example, cyclopentylmethyl and cyclopentylmethyl) and the like. Unless otherwise stated specifically in this description, it is assumed that the concept of "cycloalkenyl" includes both cycloalkenyl and "substituted cycloalkenyl", in which the alkyl part and/or cycloalkyl part cycloalkylation radical can be substituted as described in the context of this document for the alkyl radical and cycloalkyl radical, respectively.

"Glycosyl" refers to the radical obtained by removing polyacetylenes hydroxyl group of a cyclic form of a monosaccharide (e.g. glucose), disaccharide, oligosaccharide (containing from three to ten monosaccharides or polysaccharides (containing more than ten monosaccharides).

"Halogen" or "halogen" refers to fluorine, chlorine, bromine or iodine radicals.

"Halogenated" refers to the alkyl radical, as defined in the context of this document, which the Deputy is converted by one or more halogen radicals, as defined in the context of this document. Approximate halogenoalkane include, without limitation trifluoromethyl, deformity, trichloromethyl, 2,2,2-triptorelin, 1-vermeil-2-foretel, 3-bromo-2-forproper, 1-methyl bromide-2-bromacil and the like. Alkyl, substituted by one or more fluorine atoms, also called "perfluoroalkyl", for example "pervers1-4alkyl". Alkyl part halogenating radical may be optionally substituted as defined in the context of this document for alkyl groups.

"Heterocyclyl" refers to a stable heterocyclic ring radical that contains from two to eleven carbon atoms and from one to three heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the implementation heterocyclyl contains one or two heteroatoms. Unless otherwise stated specifically in this description, heterocyclyl radical may be a monocyclic or bicyclic ring system, which may include a condensed or bridged ring system. In some embodiments, the implementation heterocyclyl can be 5-, 6 - or 7-membered monocyclic ring. In other embodiments, implementation heterocyclyl can be 8-, 9-, 10-, 11 -, or 12-membered condensed bicyclic ring. Heteroatoms in heterocyclyl radical can be optional is entrusted oxidized. One or more nitrogen atoms, if present, can be optional quaternity. Heterocyclyl radical may be non-aromatic or aromatic (i.e., at least one ring in heterocyclyl radical is delocalized (4n+2) π-electron system in accordance with theory of hukkala). Heterocyclyl can be attached to the rest of the molecule through any atom of the ring(EC). Examples of non-aromatic heterocyclyl radicals include, but are not limited to, DIOXOLANYL, decahydroquinoline, imidazolines, imidazolidinyl, isothiazolinones, isoxazolidine, morpholine, octahedrally, activitiesunder, 2-oxopiperidine, 2-oxopiperidine, 2-oxopyrrolidin, oxazolidinyl, piperidinyl (also called "piperidyl"), piperazinil, 4-piperidinyl, 3-pyrroline, pyrrolidine, pyrazolidine, hinokitiol, diazolidinyl, tetrahydrofuryl, tritional, tetrahydropyranyl, thiomorpholine and thiomorpholine. Examples of aromatic heterocyclyl radicals include, but are not limited to, azepine, acridines, benzimidazolyl, bunzendahl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzisoxazole, benzo[d]thiazolyl, benzothiazolyl, benzo[b][1,4]doxepin, benzo[b][1,4]oxazinyl, 1,4-benzodioxane, benzoxazolyl, benzodioxolyl, benzodioxolyl, benzopyranyl, benzimidazolyl, b is Sourani, benzofuranyl, benzothiazol (benzothiophenes), benzothieno[3,2-d]pyrimidinyl, benzothiazolyl, carbazolyl, chrome, cinnoline, cyclopent[d]pyrimidinyl, dibenzofurans, dibenzothiophenes, furanyl, furanones, furo[3,2-c]pyridinyl, isothiazolin, imidazolyl, indazoles, indolyl, indazoles, isoindolyl, indolinyl, isoindolyl, ethanolic, indolizinyl, isoxazolyl, 5,8-methane-5,6,7,8-tetrahydroquinazoline, naphthyridine, 1,6-naphthyridine, oxadiazole, 2-oxoazetidin, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahedrons[h]hintline, phenazines, phenothiazines, phenoxazines, phthalazine, pteridine, purinol, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl (also called pyridyl), pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, hintline, honokalani, chinoline, ethenolysis, tetrahydroquinoline, 1,2,3,4-tetrahydrocarbazole, 5,6,7,8-tetrahydroquinazoline, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazine-2-yl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl and thiophenyl (i.e. thienyl). Unless otherwise stated specifically in this description, it is assumed that the concept of "heterocyclyl" includes both heterocyclic and "substituted heterocyclyl", which refers to heterocyclyl the radical, substituted by one or more substituents selected is from alkyl, acyl, oxo (e.g., pyridinyl, pyrrolidinyl), aryl, arylalkyl, aryloxyalkyl, amidino, alkoxy, cyano, guanidino, alkylguanine, dialkylamino, halogen, hydrazine, hydroxyl, nitro, -OC(O)-R11, -N(R11)2, -C(O)OR11, -C(O)N(R11)2, -N(R11)C(O)OR11, -N(R11)C(O)R11, -N(R11)S(O)tR11(where t represents 1 or 2), -S(O)tOR11(where t represents 1 or 2), -S(O)pR11(where p represents 0, 1 or 2) and-S(O)tN(R11)2(where t represents 1 or 2, each R11independently represents hydrogen, alkyl, aryl, arylalkyl, heterocyclyl or geterotsiklicheskikh.

"Geterotsiklicheskikh" refers to the alkyl radical in which one or more hydrogen atoms of the alkyl substituted by one or more heterocyclyl groups, as defined in the context of this document. If heterocyclyl represents a nitrogen-containing heterocyclyl, such heterocyclyl can be attached to the alkyl radical at the nitrogen atom. In some embodiments, the implementation of the alkyl part of geterotsiklicheskikh contains 1-4 carbon atoms and may be represented by heterocyclic1-4the alkyl. Examples geterotsiklicheskikh radicals include without limitation morpholinylmethyl, such as morpholinylmethyl, piperidinyl the sludge, such as piperidinomethyl, imidazolylalkyl, such as imidazolidinyl and the like. Additional examples geterotsiklicheskikh radicals, in which heterocyclyl part is aromatic, include, but are not limited to, pyridylmethyl, pyridylethyl, pyridylmethyl, pyridylethyl, hyalinella, jinlinlet, chinolonelor, hinolinovy, indazolinone, indusrial, industryprofile, indazolinone, inspirational, inspirationail, inspirationpro, inspirational, izohinolinove, ethanolinduced, izohinolinove, ethanolinduced, benzotriazolyl, benzothiazolyl, benzotriazolyl, benzothiazolyl and the like. Unless otherwise stated specifically in this description, it is assumed that the concept of "geterotsiklicheskikh" includes both geterotsiklicheskikh and "substituted geterotsiklicheskikh", in which the alkyl part and/or heterocyclyl part geterotsiklicheskikh radical may be substituted as described in the context of this document for the alkyl radical and heterocyclyl radical, respectively.

Compounds or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give the enantiomers, diastereomers, and other stereoisomeric forms, the cat is which can be defined in the framework of absolute stereochemistry, as, for example, (R)- or (S)- or as (D)- or (L)- for amino acids. When the compounds described in the context of this document, contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is assumed that these compounds include both E and Z geometric isomers (e.g., CIS or TRANS). Similarly, it is assumed that also includes all the possible isomers, as well as their racemic and optically pure forms and all tautomeric forms.

It is implied that used in the context of this document, the term "amino acid" includes a natural α-amino acids and/or unnatural amino acids such as β-amino acids and homonegativity. Examples of amino acids include, but are not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, Proline, serine, threonine, tryptophan, tyrosine, valine, phosphoserine, posttraining, phosphotyrosine, 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, gamma carboxyglutamate, hippuric acid, octahedron-2-carboxylic acid, a statin, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, Norvaline beta-alanine, gamma-aminobutyrate acid, citrulline, homocysteine, homoserine, m is kilalanin, pair-benzylpenicillin, phenylglycine, propargylglycine, sarcosin, methanesulfonic,tert-butylglycol, 3,5-dibrominated and 3.5-diyodtirosin.

"Amino acid residue" or "the group of amino acid side chain" refers to part of the amino acid which remains after the release of a molecule of water (or alcohol) by condensation of amino acids with any molecule. Typically, the amino acid is condensed with any molecule, including a compound of any of formulas (I)-(IV), through the formation of peptide bonds. In some embodiments, the implementation of the amine functional group of the amino acids may be condensed with a carboxylic acid group or its equivalent in reactivity (e.g., a carboxylic acid anhydride) in the molecule. In other embodiments, the functional group of carboxylic acid in the amino acid can be condensed with the amino group of the molecule. Usually in the process of formation of the peptide bond is released the water molecule. Examples of "amino acid residue" or "amino acid group on the side chain include, but are not limited to, residues of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, Proline, serine, threonine, tryptophan, tyrosine, valine, Osteria, posttraining, phosphotyrosine, 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, gamma carboxyglutamate, the hippuric acid, octahedron-2-carboxylic acid, statin, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penitsillamin, ornithine, 3-methylhistidine, Norvaline, beta-alanine, gamma-aminobutanoic acid, citrulline, homocysteine, homoserine, methyl-alanine,pair-benzylpenicillin, phenylglycine, propargylglycine, sarcosine, methanesulfonic,tert-butylglycol, 3,5-dibromothiophene, 3,5-diyodtirosina, glycosylated threonine, glycosylated glycosylated serine and asparagine.

Derived from amino acid side chain" refers to a derivative of any group of amino acid side chain described in table 1. In some embodiments, the implementation is derived from the amino acid side chain is an alkyl, acyl, alkoxy, aryl, arylalkyl, heterocyclyl or geterotsiklicheskikh, as defined in the context of this document.

The term "stereoisomer" refers to a compound consisting of the same atoms connected by the same bonds but having different three-dimensional structures which are not interchangeable. Therefore, it is assumed that different stereos the measures and their mixtures include "enantiomers", which belong to two stereoisomers whose molecules are incompatible mirror images of each other.

The concept of "tautomer" refers to proton shift from one atom of a molecule to another atom of the same molecule.

It is implied that the term "prodrug" defines the connection that can turn under physiological conditions or by solvolysis to a biologically active compound that is described in the context of this document. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a patient, but becomes an active connectionin vivofor example, by hydrolysis. Proletarienne compound often offers advantages of solubility, tissue compatibility or delayed release in the body of a mammal (see, Bundgard, H., Design of Prodrugs (1985), p. 7-9, 21-24 (Elsevier, Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems, ACS Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, which are both fully incorporated in the context of this document.

This also implies that the term "prodrug" includes any covalently associated media that h is wait for an active connection in vivowith the introduction of such prodrug to the mammal patient. Prodrugs of the active compounds, as described in the context of this document, can be obtained by modifying functional groups present in the active compound, so that these modifications are split either the standard treatment orin vivoto the primary active compounds. Prodrugs include compounds in which the hydroxyl, amino or mercaptopropyl associated with any group that, with the introduction of prodrugs of the active compounds to the mammal patient, cleaved with the formation of free hydroxyl, free amino, or free mercaptopropyl respectively. Examples of such prodrugs include, but are not limited to, acetate, succinate, phosphate, hemisuccinate, malate, hemamala, formate and benzoate derivative of an alcohol or amine functional groups in the active compounds and the like. Other examples of prodrugs include, but are not limited to, amino acid derivative of an alcohol or amine functional groups in the active compounds and the like.

The present invention is directed to conformationally stable compounds which mimic the secondary structure regions of reverse turns of biological peptides and proteins (also referred to in the context of this documentary is ment by "reverse-turn mimetics"), and also aimed at a chemical library relating to them.

Structure of reverse-turn mimetics of the present invention are used as biologically active agents, including but not limited to) use as diagnostic, prophylactic and/or therapeutic agents. Library structures of reverse-turn mimetics according to this invention is used for the identification of biologically active agents with similar applications. In the practice of the present invention, the data library may contain from tens to hundreds to thousands (or more) individual structures of reverse rotation (also referred to in the context of this document, "members").

In one aspect of the present invention disclosed structure mimetica reverse, having the following formula (I):

,

in which E represents a-ZR3- or -(C=O)-, with Z represents CH or N; W represents -(C=O)-, -(C=O)NH-, -(C=O)O-, -(C=O)S-, -S(O)2- or a bond; and each of R1, R2, R3, R4and R5are the same or different and independently represent a functional group of the amino acid side chain or a derivative of amino acid side chain. Connection mimetic reverse rotation can be represented in the form of individual p is th stereoisomer, or mixture of stereoisomers or in the form of their pharmaceutically acceptable salts.

In some embodiments, the implementation of R1compounds of formula (I) represents indazole or substituted indazoles.

In one embodiment, compounds described in the previous paragraph, R1compounds of formula (I) may be indazole or substituted indazoles having one or more substituents independently selected from C1-7of alkyl, C6-12aryl, C7-15arylalkyl, substituted C7-15arylalkyl, cycloalkenyl, hydroxyalkyl, C1-10acyl, amino, halogen, nitro, C2-10aryloxyalkyl, aminocarbonyl, aminocarbonylmethyl, dialkylaminoalkyl, alkoxycarbonyl, hydroxyalkyl, tsianos1-3of alkyl, morpholinyl1-3of alkyl, alkoxyalkyl and cycloalkylcarbonyl.

In some embodiments, the implementation of R2, R4and R5compounds of formula (I) independently selected from the group consisting of:

C1-12the alkyl or substituted C1-12of alkyl having one or more substituents independently selected from halogen, cyano, C1-6alkoxy, amino, guanidino, C1-4alkylguanine, dis1-4alkylguanine, amidino, C1-4alkylamino, dis1-4alkylamino, C1-5alkylamino, dis1-5alkylamino, aminocarbonyl, morpho is inila, methyl-piperazinil, phenyl and hydroxyl;

C2-12alkenyl or substituted C2-12alkenyl having one or more substituents independently selected from amino, guanidino, C1-4alkylguanine, dis1-4alkylguanine, amidino, C1-4alkylamino, dis1-4alkylamino, C1-5alkylamino, dis1-5alkylamino and hydroxyl;

C6-12aryl or substituted C6-12aryl having one or more substituents independently selected from halogen, amino, guanidino, C1-4alkylguanine, dis1-4alkylguanine, amidino, C1-4alkylamino, dis1-4alkylamino, C1-5alkylamino, dis1-5alkylamino and hydroxyl;

C1-6alkoxy; dis1-5alkylamino;

C6-13geterotsiklicheskikh, which contains 1 to 2 heteroatoms selected from nitrogen, oxygen, or sulfur, or substituted C6-13geterotsiklicheskikh, which has 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur and has one or more substituents independently selected from halogen, C1-6of alkyl, C1-6alkoxy, cyano, and hydroxyl; and

C7-13arylalkyl or substituted C7-13arylalkyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-6Ala is La, C1-6alkoxy, nitro, carboxy, cyano, Sulfuryl, acetylenyl and hydroxyl; and

R3selected from the group consisting of:

hydrogen;

C1-12the alkyl or substituted C1-12of alkyl having one or more substituents independently selected from halogen, cyano, C1-6alkoxy, amino, guanidino, C1-4alkylguanine, dis1-4alkylguanine, amidino, C1-4alkylamino, dis1-4alkylamino, C1-5alkylamino, dis1-5alkylamino and hydroxyl;

C2-12alkenyl or substituted C2-12alkenyl having one or more substituents independently selected from amino, guanidino, C1-4alkylguanine, dis1-4alkylguanine, amidino, C1-4alkylamino, dis1-4alkylamino, C1-5alkylamino, dis1-5alkylamino and hydroxyl;

C6-12aryl or substituted C6-12aryl having one or more substituents independently selected from halogen, amino, guanidino, C1-4alkylguanine, dis1-4alkylguanine, amidino, C1-4alkylamino, dis1-4alkylamino, C1-5alkylamino, dis1-5alkylamino and hydroxyl;

C1-6alkoxy;

C6-13geterotsiklicheskikh, which contains 1 to 2 heteroatoms selected from nitrogen, oxygen, or sulfur, or substituted C6-13geterotsiklicheskikh, which contains from 1 to 2 is heteroatoms, selected from nitrogen, oxygen or sulfur and has one or more substituents independently selected from halogen, C1-6of alkyl, C1-6alkoxy, cyano, and hydroxyl; and

C7-13arylalkyl or substituted C7-13arylalkyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-6of alkyl, C1-6alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl.

In some embodiments, the implementation of R2, R4and R5compounds of formula (I) independently selected from the group consisting of:

aminos2-5of alkyl; guanidines2-5of alkyl, C1-4alkylguanine2-5of alkyl, dis1-4alkylguanine-C2-5of alkyl; amidino2-5of alkyl, C1-4alkylamides2-5of alkyl; dis1-4alkylamides2-5of alkyl, C1-3alkoxy;

C1-12of alkyl, C6-12aryl; C6-12arylalkyl; C2-12alkenyl;

phenyl or substituted phenyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl;

naphthyl or substituted naphthyl having one or Bo is her deputies, independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl;

of benzyl or substituted benzyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl, C1-4of alkyl, acetylenyl and hydroxyl;

biphenylyl or substituted biphenylyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl;

pyridyl or substituted pyridyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl;

pyridyl1-4the alkyl or substituted pyridyl1-4of alkyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, 1-4dialkylamino, halogen, perfors1-4of alkyl, C1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl;

pyrimidyl1-4the alkyl or substituted pyrimidyl1-4of alkyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl;

the triazine-2-ILS1-4the alkyl or substituted triazine-2-ILS1-4of alkyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl;

imidazolyl1-4the alkyl or substituted imidazolyl1-4of alkyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl;

N-amidinopropane-N-C0-4of alkyl, N-amidinopropane1-4of alkyl; and

4-aminocyclohexane0-2of alkyl; and

R3choose from the group SOS is oasa from:

hydrogen; amino2-5of alkyl; guanidines2-5of alkyl, C1-4alkylguanine2-5of alkyl, dis1-4alkylguanine-C2-5of alkyl; amidino2-5of alkyl, C1-4alkylamides2-5of alkyl; dis1-4alkylamides2-5of alkyl, C1-3alkoxy;

C1-12of alkyl, C6-12aryl; C6-12arylalkyl; C2-12alkenyl;

phenyl or substituted phenyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl;

naphthyl or substituted naphthyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl;

of benzyl or substituted benzyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl;

biphenylyl or substituted biphenylyl having one or more for which estately, independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl;

pyridyl or substituted pyridyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl;

pyridyl1-4the alkyl or substituted pyridyl1-4of alkyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl;

pyrimidyl1-4the alkyl or substituted pyrimidyl1-4of alkyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl;

the triazine-2-ILS1-4the alkyl or substituted triazine-2-ILS1-4of alkyl having one or more substituents independently selected from amino, amide is but guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl;

imidazolyl1-4the alkyl or substituted imidazolyl1-4of alkyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl;

N-amidinopropane-N-C0-4of alkyl, N-amidinopropane1-4of alkyl; and

4-aminocyclohexane0-2the alkyl.

In some embodiments, the implementation of R1compounds of formula (I) represents indazole or substituted indazoles having one or more substituents independently selected from methyl; isopropyl; cyclopropylmethyl; hydroxyethyl; cyclopropanecarbonyl; aminocarbonyl; cyanomethyl; morpholinylmethyl; aminocarbonylmethyl; dimethylaminocarbonylmethyl; methoxyethylamine; ethoxycarbonylmethyl; acetoxyethyl; phenyl; benzyl and substituted C7-15arylalkyl having one or more substituents independently selected from amino and nitro.

In some embodiments, the implementation of R1compounds of formula (I) are selected from the group consisting of 2-ethyl-2H-indazole, 1-methyl-1H-indazole, 3-cyclopropanecarbonyl-1H-indazole, 1-hydroxyethyl-1H-indazole, 1H-indazole, 2-cyclopropylmethyl-2H-indazole, 3-amino-1H-indazole, 1-benzyl-1H-indazole, 3-chloro-1H-indazole, 6-chloro-1H-indazole, 3-phenyl-1H-indazole, 1-benzyl-3-phenyl-1H-indazole, 1-nitrobenzyl-1H-indazole, 1-aminobenzyl-1H-indazole, 2-methyl-3-cyclopropanecarbonyl-2H-indazole, 1-methyl-3-aminocarbonyl-1H-indazole, carbonyl-indazole, 2-isopropyl-2H-indazole, 2-aminocarbonylmethyl-2H-indazole, 1-cyanomethyl-3-cyclopropanecarbonyl-1H-indazole, 2-cyanomethyl-3-cyclopropanecarbonyl-2H-indazole, 1-morpholinyl-N-ethyl-1H-indazole, 2-morpholinyl-N-ethyl-2H-indazole, 2-dimethylaminocarbonylmethyl-2H-indazole, 2-methoxyethylamine-2H-indazole, 1-ethoxycarbonylmethyl-1H-indazole, 2-ethoxycarbonylmethyl-2H-indazole and 1-acetoxyethyl-1H-indazole.

In some embodiments, the implementation of R2, R4and R5compounds of formula (I) independently selected from the group consisting of:

C1-12the alkyl or substituted C1-12of alkyl having one or more substituents independently selected from acyl, carboxy, alkylthio, aminocarbonyl, morpholinyl, methyl-piperazinil, phenyl, cyano, C1-5alkylamino, dis1-5alkylamino, hydroxyl, C1-6alkoxy and phenylsulfonyl;

C2-12alkenyl or substituted C2-12

substituted C6-12aryl, substituted aminosulfonates;

arils1-4the alkyl or substituted aryls1-4of alkyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, C3-6cycloalkyl, halogen, perfors1-4of alkyl, C1-6of alkyl, acetylenyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl, hydroxyl, C1-6alkoxyl1-6acyl, morpholinyl1-6of alkyl, aryl, aryloxy, (alkyl)(arylalkyl)amino, heterocyclyl, acyl, amidosulfonic, aminocarbonyl, alkylsulfonate, alkylsulfonyl, alkylthio, aaltio, vinylsulfonate, phenylsulfonyl, morpholinyl1-3alkoxy,Nformamide and pyrrolidinyl;

heterocyclyl or substituted heterocyclyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-6of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl;

heterocyclic1-4the alkyl or substituted heterocyclic1-4of alkyl having one or more substituents independently selected from amino, amidino guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, C3-6cycloalkyl, halogen, perfors1-4of alkyl, C1-6of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl, hydroxyl, C1-6alkalosis1-6acyl, morpholinyl1-6of alkyl, arylalkyl, aryl, heterocyclyl, acyl, phenylsulfonyl, cycloalkenyl, aryloxyalkyl, aminocarbonyl and C1-4alkyltrimethyl;

cycloalkyl or substituted cycloalkyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl; and

cycloalkenyl or substituted cycloalkenyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl; and

R3selected from the group consisting of:

hydrogen;

C1-12the alkyl or substituted C1-12of alkyl having one or more substituents independently selected from acyl, carboxy, alkylthio and phenylsulfonyl;

C2-12alkenyl or substituted C2-12alkenyl, and housego one or more substituents, independently selected from acyl, carboxy, alkylthio and phenylsulfonyl;

substituted C6-12aryl, substituted aminosulfonates;

arils1-4the alkyl or substituted aryls1-4of alkyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, C3-6cycloalkyl, halogen, perfors1-4of alkyl, C1-6of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl, hydroxyl, C1-6alkalosis1-6acyl, morpholinyl1-6of alkyl, aryl, aryloxy, (alkyl)(arylalkyl)amino, heterocyclyl, acyl, amidosulfonic, aminocarbonyl, alkylsulfonate, alkylsulfonyl, alkylthio, aaltio, vinylsulfonate, phenylsulfonyl, morpholinyl1-3alkoxy,Nformamide and pyrrolidinyl;

heterocyclyl or substituted heterocyclyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl;

heterocyclic1-4the alkyl or substituted heterocyclic1-4of alkyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino is, C3-6cycloalkyl, halogen, perfors1-4of alkyl, C1-6of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl, hydroxyl, C1-6alkalosis1-6acyl, morpholinyl1-6of alkyl, arylalkyl, aryl, heterocyclyl, acyl, phenylsulfonyl, cycloalkenyl, aryloxyalkyl, aminocarbonyl and C1-4alkyltrimethyl;

cycloalkyl or substituted cycloalkyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl; and

cycloalkenyl or substituted cycloalkenyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-4of alkyl, C1-4of alkyl, C1-3alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl.

In one embodiment, compounds described in the preceding paragraph, arils1-4alkyl represents a benzyl, acetylenylmethyl, C1-4alkoxybenzyl, hydroxybenzyl, biphenylyl, naphthylmethyl or 3.3-biphenyldiol; and heterocyclic1-4alkyl represents benzotriazolyl1-4alkyl, benzimidazolyl1- alkyl, indazoles1-4alkyl, ethanolic1-4alkyl, benzothiazolyl1-4alkyl, fineliners1-4alkyl, imidazolines1-4alkyl, teenies1-4alkyl, tetrahydrofuranyl1-4alkyl, pyridinyl1-4alkyl, benzimidazolyl1-4alkyl or indolyl1-4alkyl.

In this embodiment, in which E represents CHR3the connection of the reverse-turn mimetic according to this invention has the structure of formula (II):

,

in which W represents -(C=O)-, -(C=O)NH-, -(C=O)O-, -(C=O)S-, -S(O)2- or a bond; and each of R1, R2, R3, R4and R5are the same or different and independently represent a functional group of the amino acid side chain or a derivative of amino acid side chain.

In some embodiments, the implementation of R1compounds of the formula (II) represents indazole or substituted indazoles, and it can be indazole or substituted indazoles having one or more substituents independently selected from C1-7of alkyl, C6-12aryl, C7-15arylalkyl, substituted C7-15arylalkyl, cycloalkenyl, hydroxyalkyl, C1-10acyl, amino, halogen, nitro, C2-10aryloxyalkyl, aminocarbonyl, aminocarbonylmethyl, dialkylaminoalkyl, is alkoxycarbonylmethyl, hydroxyalkyl, tsianos1-3of alkyl, morpholinyl1-3of alkyl, alkoxyalkyl and cycloalkylcarbonyl;

R2, R4and R5independently selected from the group consisting of:

C1-12the alkyl or substituted C1-12of alkyl having one or more substituents independently selected from halogen, cyano, C1-6alkoxy, amino, guanidino, C1-4alkylguanine, dis1-4alkylguanine, amidino, C1-4alkylamino, dis1-4alkylamino, C1-5alkylamino, dis1-5alkylamino, aminocarbonyl, morpholinyl, methyl-piperazinil, phenyl and hydroxyl;

C2-12alkenyl or substituted C2-12alkenyl having one or more substituents independently selected from amino, guanidino, C1-4alkylguanine, dis1-4alkylguanine, amidino, C1-4alkylamino, dis1-4alkylamino, C1-5alkylamino, dis1-5alkylamino and hydroxyl;

C6-12aryl or substituted C6-12aryl having one or more substituents independently selected from halogen, amino, guanidino, C1-4alkylguanine, dis1-4alkylguanine, amidino, C1-4alkylamino, dis1-4alkylamino, C1-5alkylamino, dis1-5alkylamino and hydroxyl;

C1-6alkoxy; dis1-5alkylamino;

C6-13geterotsiklicheskikh which has from 1 to 2 gets is of Rotanov, selected from nitrogen, oxygen, or sulfur, or substituted C6-13geterotsiklicheskikh, which has 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur and has one or more substituents independently selected from halogen, C1-6of alkyl, C1-6alkoxy, cyano, and hydroxyl; and

C7-13arylalkyl or substituted C7-13arylalkyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-6of alkyl, C1-6alkoxy, nitro, carboxy, cyano, Sulfuryl, C1-4of alkyl, acetylenyl, hydroxyl, phosphate, diethylaminoacetate, dimethylaminoethylacrylate and diethyl-phosphono-acetamido; and

R3selected from the group consisting of:

hydrogen;

C1-12the alkyl or substituted C1-12of alkyl having one or more substituents independently selected from halogen, cyano, C1-6alkoxy, amino, guanidino, C1-4alkylguanine, dis1-4alkylguanine, amidino, C1-4alkylamino, dis1-4alkylamino, C1-5alkylamino, dis1-5alkylamino and hydroxyl;

C2-12alkenyl or substituted C2-12alkenyl having one or more substituents independently selected from amino, guanidino, C1-4alkylguanine, dis1-4alkylguanine, and ideno, C1-4alkylamino, dis1-4alkylamino, C1-5alkylamino, dis1-5alkylamino and hydroxyl;

C6-12aryl or substituted C6-12aryl having one or more substituents independently selected from halogen, amino, guanidino, C1-4alkylguanine, dis1-4alkylguanine, amidino, C1-4alkylamino, dis1-4alkylamino, C1-5alkylamino, dis1-5alkylamino and hydroxyl;

C1-6alkoxy;

C6-13geterotsiklicheskikh, which has 1 to 2 heteroatoms selected from nitrogen, oxygen, or sulfur, or substituted C6-13geterotsiklicheskikh, which has 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur and has one or more substituents independently selected from halogen, C1-6of alkyl, C1-6alkoxy, cyano, and hydroxyl; and

C7-13arylalkyl or substituted C7-13arylalkyl having one or more substituents independently selected from amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfors1-6of alkyl, C1-6alkoxy, nitro, carboxy, cyano, Sulfuryl and hydroxyl.

In one embodiment, compounds described in the preceding paragraph, R1compounds of the formula (II) may constitute indazole or substituted indazoles having one or more which of amestitelj, independently selected from methyl; isopropyl; cyclopropylmethyl; hydroxyethyl; cyclopropanecarbonyl; aminocarbonyl; cyanomethyl; morpholinylmethyl; aminocarbonylmethyl; dimethylaminocarbonylmethyl; methoxyethylamine; ethoxycarbonylmethyl; acetoxyethyl; phenyl; benzyl and substituted C7-15arylalkyl having one or more substituents independently selected from amino and nitro, and specific examples R1may include, but are not limited to,

2-methyl-2H-indazole, 1-methyl-1H-indazole, 3-cyclopropanecarbonyl-1H-indazole, 1-hydroxyethyl-1H-indazole, 1H-indazole, 2-cyclopropylmethyl-2H-indazole, 3-amino-1H-indazole, 1-benzyl-1H-indazole, 3-chloro-1H-indazole, 6-chloro-1H-indazole, 3-phenyl-1H-indazole, 1-benzyl-3-phenyl-1H-indazole, 1-nitrobenzyl-1H-indazole, 1-aminobenzyl-1H-indazole, 2-methyl-3-cyclopropanecarbonyl-2H-indazole, 1-methyl-3-aminocarbonyl-1H-indazole, carbonyl-indazole, 2-isopropyl-2H-indazole, 2-aminocarbonylmethyl-2H-indazole, 1-cyanomethyl-3-cyclopropanecarbonyl-1H-indazole, 2-cyanomethyl-3-cyclopropanecarbonyl-2H-indazole, 1-morpholinyl-N-ethyl-1H-indazole, 2-morpholinyl-N-ethyl-2H-indazole, 2-dimethylaminocarbonylmethyl-2H-indazole, 2-methoxyethylamine-2H-indazole, 1-ethoxycarbonylmethyl-1H-indazole, 2-ethoxycarbonylmethyl-2H-indazole and 1-acetoxyethyl-1H-indazole.

In one embodiment, the Khujand is to establish connections, described in the preceding paragraph, R2and R5independently represents a C1-12alkyl, C6-12aryl, C7-12arylalkyl, C6-11geterotsiklicheskikh, hydroxybenzyl or substituted benzyl having substituents selected from phosphate, diethylaminoacetate, (2-dimethylamino-ethyl)carbamate and diethyl-phosphono-acetamido;

R3represents hydrogen or C1-12alkyl; and

R4represents a C1-12alkyl, C7-12arylalkyl or C2-12alkenyl.

These compounds can be obtained by using a suitable molecule of the original components (hereinafter called "components"). Briefly, the synthesis of structures that mimic reverse turns, having the formula (I), patterns that mimic reverse turns, of the formula (I) can be obtained by sequential interaction of individual components or Paladino in solution or by solid-phase synthesis, as is widely practiced in solid-phase peptide synthesis, followed by cyclization to obtain structures that mimic the reverse rotation, according to this invention. Alternatively, the first and second components interact with the formation of a joint intermediate the first and second, if necessary, the third and/or fourth components interact with on the education of the combined intermediate third or fourth (or, if it is commercially available, it is possible to use intermediate third), then the combined intermediate the first and second combined intermediate third or fourth (or third intermediate) interact with obtaining the intermediate of the first-second-third-fourth (or intermediate of the first-second-third), which cyclizes obtaining structures that mimic the reverse rotation, according to this invention.

Specific components and their combination to obtain the compounds of the present invention is illustrated in figure 1. For example, the first composite component can have the following formula S1:

,

in which R1represents a group as defined above, and R is a protective group suitable for use in peptide synthesis, this protective group can be attached to a polymeric substrate, which enables solid-phase synthesis. Suitable R groups include alkyl groups, and in a preferred embodiment, R is a methyl group. In figure 1 one of the R groups is a polymer (solid) substrate, indicated on the figure of the "Pol". Similar to the first composite components can be easily synthesized by reductive amination H 2N-C-R1using the CH(OR)2-CHO or through a substitution reaction between the H2N-C-R1and CH(OR)2-CH2-LG (where LG is a leaving group such as halogen (Hal) group).

"The second composite component can have the following formula S2:

,

in which P represents an amino protective group suitable for use in peptide synthesis, L1represents a hydroxyl or activated carboxyl group, and R2represents a group as defined above. Preferred protective groups includetert-butyldimethylsilyl (TBDMS),tert-butyloxycarbonyl (BOC), methyloxycarbonyl (MOC), 9H-fluorenylmethoxycarbonyl (FMOC) and allyloxycarbonyl (Alloc). N-Protected amino acids are commercially available; for example FMOC amino acids can be purchased in many sources. To the second compound component is reacted with the first component, L1is carboxyl-activated group, and converting the carboxyl group into an activated carboxyl group can be easily achieved by way of activating carboxyl groups, known in the prior art. Suitable activated carboxylic acid group include acid halides, in which L 1is a halide, such as chloride or bromide, acid anhydrides, in which L1represents an acyl group such as acetyl, reactive esters, such as N-hydroxysuccinimide esters and pentafluorophenyl esters, and other activated intermediates, such as the active intermediate formed during the reaction of the compounds with the use of a carbodiimide, such as dicyclohexylcarbodiimide (DCC). Accordingly, commercially available N-protected amino acids can be converted into activated carbon form using methods known to the person skilled in the technical field.

In the case of azido derived amino acid that serves as a second component, such compounds can be obtained from the corresponding amino acids by the reaction disclosed Zaloom et al. (J. Org. Chem. 46:5173-76, 1981).

"Third component" may have the following formula S3:

,

in which R4E and L1represent groups defined above. Suitable third components are commercially available from many sources, or they can be obtained by methods well known in organic chemistry.

Figure 1 illustrates the formation of compounds of formula (I).

Thus, as illustrated above, with the organisations of the reverse-turn mimetics of formula (I) can be synthesized by the reaction of the first component with the second component with obtaining joint intermediate the first and second, and then there occurs a reaction of the joint intermediate the first and second and third components of obtaining joint intermediate the first-second-third-fourth, and then cyclization of this intermediate with obtaining a structure that mimics a reverse turn.

The synthesis of typical components in this invention are described in the examples received.

Patterns that mimic reverse turns, formulas (I) and (II) can be obtained by methods analogous to the synthesis of modular components, opened higher, but with appropriate modifications in the component parts.

Patterns that mimic reverse turns, according to the present invention are used as biologically active agents, such as diagnostic, prophylactic and therapeutic agents. For example, patterns that mimic reverse turns, according to the present invention can be used to modulate related peptides transcription factor cell signaling in warm-blooded animal by a method that includes introduction to the animal an effective amount of the compounds of formula (I).

In addition, patterns imitating reverse turns, according to the present invention can also be effective in the inhibition of the binding of the peptide with PTB domains in Teplocom the CSOs of the animal; when the modulation associated with G-protein receptor (GPCR) and ion channel in a warm-blooded animal; when the modulation of cytokines in a warm-blooded animal.

It was found that the compounds of formula (I), especially compounds of the formula (III), are effective for the inhibition or treatment of disorders modulated by Wnt signaling pathway, such as cancer.

The above-shown formula (III), in which each of R1, R4and R6are the same or different and independently represent a functional group of the amino acid side chain or a derivative of amino acid side chain, X1can be a hydrogen, hydroxyl or halogen, and X2and X3can independently represent hydrogen, hydroxyl, or any group that can make this compound a prodrug, such as phosphate, carboxylate, carbamate and substituted amine.

In some embodiments, the implementation of the compounds of the formula (III)

R1represents indazole or substituted indazoles having one or more substituents independently selected from C1-7of alkyl, C6-12aryl, C7-15arylalkyl, substituted C7-15arylalkyl, cycloalkenyl, hydroxyalkyl, C1-10acyl, amino, halogen, nitro, C2-10aryloxyalkyl, aminocarbonyl, and is indocarbocyanine, dialkylaminoalkyl, alkoxycarbonyl, hydroxyalkyl, tsianos1-3of alkyl, morpholinyl1-3of alkyl, alkoxyalkyl and cycloalkylcarbonyl, and specific examples of the substituents can be methyl; isopropyl; cyclopropylmethyl; hydroxyethyl; cyclopropanecarbonyl; aminocarbonyl; cyanomethyl; morpholinylmethyl; aminocarbonylmethyl; dimethylaminocarbonylmethyl; methoxyethylamine; ethoxycarbonylmethyl; acetoxyethyl; phenyl; benzyl and substituted C7-15arylalkyl having one or more substituents independently selected from amino and nitro;

R4represents a C1-6alkyl, C1-6alkoxy, C2-6alkenyl or perftools1-6alkyl;

R6represents a C6-12aryl or substituted C6-12aryl having one or more substituents independently selected from the group consisting of halogen, hydroxyl, cyano, C1-6of alkyl, acetylenyl and C1-6alkoxy; or C5-12heterocyclyl or substituted C5-12heterocyclyl having one or more substituents independently selected from halogen, hydroxyl, cyano, C1-6the alkyl and C1-6alkoxy;

X1represents hydrogen, hydroxyl or halogen; and

each of X2and X3independently represents hydrogen, hydroxyl, phosphate, dimethylaminoacetyl, (2-dimethylamino-ethyl)-carbama is, diethyl-phosphono-acetamido or halogen.

In one embodiment, compounds described in the preceding paragraph,

R1selected from the group consisting of 2-methyl-2H-indazole, 1-methyl-1H-indazole, 3-cyclopropanecarbonyl-1H-indazole, 1-hydroxyethyl-1H-indazole, 1H-indazole, 2-cyclopropylmethyl-2H-indazole, 3-amino-1H-indazole, 1-benzyl-1H-indazole, 3-chloro-1H-indazole, 6-chloro-1H-indazole, 3-phenyl-1H-indazole, 1-benzyl-3-phenyl-1H-indazole, 1-nitrobenzyl-1H-indazole, 1-aminobenzyl-1H-indazole, 2-methyl-3-cyclopropanecarbonyl-2H-indazole, 1-methyl-3-aminocarbonyl-1H-indazole, carbonyl-indazole, 2-isopropyl-2H-indazole, 2-aminocarbonylmethyl-2H-indazole, 1-cyanomethyl-3-cyclopropanecarbonyl-1H-indazole, 2-cyanomethyl-3-cyclopropanecarbonyl-2H-indazole, 1-morpholinyl-N-ethyl-1H-indazole, 2-morpholinyl-N-ethyl-2H-indazole, 2-dimethylaminocarbonylmethyl-2H-indazole, 2-methoxyethylamine-2H-indazole, 1-ethoxycarbonylmethyl-1H-indazole, 2-ethoxycarbonylmethyl-2H-indazole and 1-acetoxyethyl-1H-indazole; and

R4represents a C1-3alkyl or allyl; and

R6represents phenyl or substituted phenyl having one or more substituents independently selected from halogen, hydroxyl, cyano, C1-6of alkyl, acetylenyl and C1-6alkoxy; or pyridyl or substituted pyridyl, which within one or more substituents, independently selected from halogen, hydroxyl, cyano, C1-6the alkyl and C1-6alkoxy.

In another aspect of the present invention disclosed are prodrugs derived from compounds having General formula (I). These prodrugs generally increase the solubility and thus bioavailability of the compounds having General formula (I). In some embodiments, the implementation of the prodrugs of the present invention have the following General formula (IV):

,

in which one of R1, R4, R6X1X2and X3associated with R7through the Y, thus:

Y represents oxygen, sulfur or nitrogen, R1, R4or R6or oxygen in the X1X2or X3; and

R7is hydroxyalkyl, glycosyl, phosphorylethanolamine, substituted or unsubstituted piperidine, carbonyloxy or salt; or Y-R7represents an amino acid residue, a combination of amino acid residues, phosphate, hemamala, hemisuccinate, dimethylaminoethylacrylate, dimethylaminoacetyl or its salt; and

if it is not related to R7: R1, R4, R6X1X2and X3are defined as they appear in the formula (III).

In another aspect of the present invention disclosed library containing structure, mitrousis reverse turns, according to the present invention. It is possible to screen libraries of the present invention, as soon as they are laid out, to identify individual members possessing biological activity. This screening libraries on the subject of biologically active members may include, for example, the binding activity of the members of the library or the assessment of the effect the members library on functional analysis. Screening is usually done by binding members of the library (or a subset of library members with interest the target, such as, for example, antibody, enzyme, receptor or cell line. Library members who are able to communicate with this interest target are called in the context of this document, "biologically active library members" or "biologically active mimetics". For example, biologically active mimetic may be a member of the library, which is able to communicate with any antibody or receptor, or that can inhibit the activity of any enzyme, or which may cause or anlagenservice functional response associated with, for example, the cell line. In other words, screening libraries of the present invention identifies those library members that are able to communicate the one or more interest biological targets. Moreover, when there is an interaction, then among the members of the library can be identified biologically active mimetic or mimetics). Identification of a single (or limited number) of biologically active mimetica(s) from this library provides patterns that mimic reverse turns, which are themselves biologically active, and thus, are used as diagnostic, prophylactic or therapeutic agents, and, in addition, can be used in significantly improved identification of the leading connections in these areas.

Synthesis of peptide mimetics library of the present invention can be performed using known methods for peptide synthesis in combination with the first, second and third components of the present invention. More specifically, the N-end and/or C-Termini of conformationally stable mimetica reverse rotation, you can add any amino acid sequence. So, the mimetics can be synthesized on a solid substrate (such as resin PAH (polycyclic aromatic hydrocarbons)) by known methods (see, e.g., John M. Stewart and Janis D. Young, Solid Phase Peptide Synthesis, 1984, Pierce Chemical Comp., Rockford, III.) or silloway resin by alcohol accession (see Randolph et al., J. Am Chem. Soc. 117:5712-14, 1995).

In addition, for C the importance of peptide mimetics of this invention can use a combination of techniques as solid-phase synthesis, and synthesis in solution. For example, the solid substrate can be applied for the synthesis of the linear peptide sequence up to the moment when the sequence is added conformationally stable reverse rotation. Suitable conformationally stable structure that mimics a reverse rotation, which was previously synthesized by methods of synthesis in solution, can then be added as the next amino acids in solid-phase synthesis (i.e conformationally stable reverse-turn mimetic, which has as the N-end and C-end, can be used as following amino acid that must be added to the linear peptide). When enabled, conformationally stable structures that mimic the reverse rotation, in this sequence you can then add additional amino acids to complete the peptide associated with the solid substrate. Alternatively, linear, protected from N-Terminus and C-Terminus of the peptide sequence can be synthesized on a solid substrate, to separate from the substrate, and then connect with conformationally stable structures that mimic reverse turns, in solution, by means of known methods of binding.

In one aspect of the present invention are disclosed methods of forming the libraries. Traditional is by methods of combinatorial chemistry (see, for example, Gallop et al., J. Med. Chem. 37:1233-1251, 1994) provide a wide range of compounds that can quickly get through the serial connection of reagents to the basic molecular skeleton. Combinatorial methods were used to generate peptide libraries derived from natural amino acids. For example, if you take 20 mixtures of 20 secured in a suitable manner or other amino acids and connect with each one of the 20 amino acids, there is formed a library of 400 (i.e. 202) dipeptides. Repeat this procedure seven times results in a peptide library consisting of about 26 billion (i.e. the 208) octapeptides.

In particular, the synthesis of peptide mimetics for the library of the present invention can be performed using known methods for peptide synthesis, for example, the General Scheme of the Library of Reverse-Turn Mimetics below:

Synthesis of peptide mimetics of the libraries of the present invention was carried out using the reactor block FlexChem, which has a 96-hole plates, by known methods. In the diagram above, 'Pol' is bromatology resin (Advanced ChemTech), and the detailed procedure is illustrated below.

Stage 1

Bromatology resin (37 mg, 0.98 mmol/g) and a solution of R1-amine in DMSO to 1.4 ml) were placed in a block Robbins (FlexChem), includes 96-well plates. The reaction mixture was shaken at 60°C, using a rotary kiln [Robbins Scientific], within 12 hours. The resin is washed with DMF, MeOH, and then DHM.

Stage 2

A solution of commercially available Fmoc-NH-CH(R2)-COOH (4 equiv.), PyBob (4 equiv.), HOAt (4 equiv.) and DIEA (12 equiv.) in DMF was added to the resin. After this the reaction mixture was shaken for 12 hours at room temperature, the resin washed with DMF, MeOH, and then DHM.

Stage 3

To the resin swollen in DMF before the reaction, was added 25% piperidine in DMF and the reaction mixture was shaken for 30 min at room temperature. This phase of removing the protective groups repeated again, and the obtained resin was washed with DMF, methanol, and then DHM. To the resulting resin solution was added hydrazine powered acid (4 equiv.), HOBt (4 equiv.) and DIC (4 equiv.) in DMF and the reaction mixture was shaken for 12 hours at room temperature. The obtained resin was washed with DMF, MeOH, and then DHM.

Stage 4

The resin obtained in stage 3, was treated with formic acid (1.2 ml per well) for 18 hours at room temperature. After the resin was separated by filtration, the obtained filtrate are condensed under reduced pressure using a vacuum system SpeedVac [SAVANT] to obtain the product as oil. The resulting product is abbasli 50% mixture of water/acetonitrile, and then after freezing was liofilizovane.

Key intermediates hydrazine powered acid to obtain data block libraries were synthesized in accordance with the procedure illustrated in the Example of obtaining 1.

Table 2 shows the connections that get in accordance with the present invention, a typical way to obtain them is given in the Examples received.

Below is a NMR data of some of the compounds obtained in accordance with the above procedure:

(6S,9aS)-8-((1H-indazol-7-yl)methyl)-2-allyl-N-benzyl-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide (Compound No. 3 in Table 2)

1H NMR (CDCl3, 300 MHz) δ of 8.09 (s, 1H), δ 7,73 (d, J=3.0 Hz, 1H), δ 7,37-7,22 (m, 5H), δ 7,11-7,03 (m, 2H), δ of 6.90 (d, J=9.0 Hz, 1H), δ 6,74 (d, J=6.0 Hz, 1H), δ to 6.57 (d, J=6.0 Hz, 2H), δ 5,65-4,56 (m, 1H), δ 5,48 to 5.35 (m, 1H), δ 5,31 (t, J=3.0 Hz, 1H), δ 5,16-of 4.95 (m, 3H), δ 4,55 (d, J=to 15.0 Hz, 1H), δ 4,40-4,12 (m, 2H), δ 3.46 in is 3.23 (m, 8H)

(6S,9aS)-2-allyl-N-benzyl-6-(4-hydroxy-benzyl)-8-((1-(3-nitrobenzyl)-1H-indazol-7-yl)methyl)-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide (Compound No. 20 in Table 2)

1H NMR (CDCl3, 300 MHz) δ 8,24 (s, 1H), δ of 8.09 (d, J=9.0 Hz, 1H), δ 7,83 for 7.12 (m, 3H), δ 7,10 (t, J=9.0 Hz, 1H), δ 7,32-7,17 (m, 4H), δ 7,10 (t, J=9.0 Hz, 1H), δ 6,92-6,83 (m, 3H), δ is 6.61 (d, J=9.0 Hz, 1H), δ 5,79-of 5.68 (m, 1H), δ 5,41 and 5.36 (m, 1H), δ 5,12-4,88 (m, 4H), δ the 4.65 (d, J=18,0 Hz, 1H), δ 4,28-4,18 (m, 2H), δ 3,55 is 3.40 (m, 4H), δ 3.25 to of 3.07 (m, 3H), δ 2,85 (DD, J=3.0 Hz, J=12.0 Hz, 1H)

(6S,9aS)-2-allyl-8-((1-(3-aminobenzyl)-1H-indazol-7-yl)methyl)-N-benzyl-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide (Compound No. 6 in Table 2)

1H NMR (CDCl3, 300 MHz) δ of 8.09 (s, 1H), δ 7,73-to 7.68 (m, 1H), δ 7,38-7,21 (m, 5H), δ 7,11 (t, J=9.0 Hz, 1H), δ 7,00-to 6.95 (m, 4H), δ 6,69-only 6.64 (m, 3H), δ 6,44 (d, J=9.0 Hz, 1H), δ 6,23-6,18 (m, 2H), δ 5,71 (s, 2H), δ 5,59-5,49 (m, 1H), δ 5,41-of 5.34 (m, 1H), δ 5,18-5,13 (m, 2H), δ 5,04 (d, J=9.0 Hz, 1H), δ 4,84 (t, J=15,0 Hz, 2H), δ 4,45-of 4.25 (m, 2H), δ 3,44-up 3.22 (m, 6H), δ 2,99-2,95 (m, 2H)

4-(((6S,9aS)-8-((1H-indazol-7-yl)methyl)-2-allyl-1-(benzylcarbamoyl)-4,7-dioxaoctyl-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl)phenylphosphate sodium (Compound No. 23 in Table 2)

1H NMR (CDCl3, 300 MHz) δ 8,08 (s, 1H), δ 7,72 (t, J=6.0 Hz, 1H), δ 7,34-to 7.09 (m, 6H), δ 7,00-6,92 (m, 3H), δ 5,56-vs. 5.47 (m, 1H), δ 5.40 to and 5.36 (m, 1H), δ is 5.18 (t, J=6.0 Hz, 1H), δ 4,92-of 4.57 (m, 5H), δ 4,33-to 4.14 (m, 2H), δ 3,61-of 3.48 (m, 2H), δ 3,28-3,14 (m, 5H)

Benzolamide (6S,9aS)-2-allyl-6-(4-hydroxy-benzyl)-8-(1H-indazol-4-ileti is)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid (Compound No. 2 in Table 2)

1H NMR (CDCl3, 300 MHz) δ 9,23 (s, 1H), 8,10 (s, 1H), 7,80 (t, J=6.3 Hz, 1H), 7,17-of 7.48 (m, 8H), 6,85 (t, J=8,4 Hz, 3H), of 6.65 (d, J=8,4 Hz, 2H), 5,72 is 5.77 (m, 1H), are 5.36-5,41 (DD, J=3,6 Hz, 10.8 Hz, 1H), 4,89-5,09 (m, 5H), with 4.64 (d, J=15 Hz, 1H), 4,13-4,22 (m, 2H), 3,39-of 3.60 (m, 2H), 3,02-of 3.25 (m, 8H)

(6S,9aS)-2-allyl-N-benzyl-6-(4-hydroxy-benzyl)-8-((2-methyl-2H-indazol-7-yl)methyl)-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide (Compound No. 18 in Table 2)

1H NMR (CDCl3, 300 MHz) δ 7,88 (s, 1H), δ to 7.59 (d, J=9.0 Hz, 1H), δ 7,38-7,22 (m, 4H), δ 7,12-7,03 (m, 2H), δ 6,94 (d, J=9.0 Hz, 2H), δ of 6.71 (t, J=6.0 Hz, 1H), δ to 6.58 (d, J=6.0 Hz, 2H), δ 5,61-5,49 (m, 2H), δ to 5.35 (t, J=6,0 Hz, 1H), δ 5,11-4,91 (m, 1H), δ 4,40-4,34 (m, 2H), δ 4,17 (s, 3H), δ 3,40-of 3.25 (m, 6H)

Benzolamide (6S,9aS)-2-allyl-6-(4-hydroxy-benzyl)-8-(1-methyl-1H-indazol-4-ylmethyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid (Compound No. 19 in Table 2)

1H NMR(CDCl3, 300 MHz) δ 8,08 (s, 1H), 7,21-7,38 (m, 8H), of 6.99 (d, J=8,4 Hz), 6.89 in-6,94 (m, 1H), 6,62-6,69 (m, 3H), 5.40 to-5,59 (m, 2H), of 5.34 (t, J=5.4 Hz, 1H), 5,17-5,23 (m, 1H), 5,07 (d, J=10.5 Hz, 1H), 4,67-4,96 (m, 2H), 4.26 deaths is 4.45 (m, 1H), 4,08 (s, 3H), 3,23-3,44 (m, 9H)

The disodium salt of mono-{4-[(6S,9aS)-2-allyl-1-benzylcarbamoyl-8-(1-methyl-1H-indazol-4-ylmethyl)-4,7-dioxo-octahydro-pyrazino[2,1-c][1,2,4]triazine-6-ylmethyl]-phenyl}ester of phosphoric acid (Compound No. 30 in Table 2)

1H NMR (D2O, 300 MHz) δ to 7.99 (s, 1H), 7,09-7,44 (m, 12H), 6,91 (d, J=6.3 Hz, 1H), 5,58-5,61 (m, 2H), 5,32 (t, J=6.3 Hz, 1H), 4,96-free 5.01 (m, 2H), 4,63-of 4.77 (m, 2H), 4,23-to 4.46 (m, 2H), 3,98 (s, 3H), 3,52-3,82 (m, 3H), 3.25 to 3,37 (m, 6H)

Benz is lame (6S,9aS)-2-allyl-8-(2-cyclopropylmethyl-2H-indazol-7-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid (Compound No. 14 in Table 2)

1H NMR (CDCl3): δ 8,041 (s, 1H), 7,641-7,599 (d, J=12,6 Hz, 1H), 7,371-6,957 (m, 9H), 6,723-6,669 (t, J=12.3 Hz, 1H), 6,613-6,585 (d, J=8,4 Hz, 2H), 5,652-5,561 (dt, J=3,9 Hz, J=10.5 Hz, 2H), 5,162-4,853 (m, 4H), 4,444-4,287 (dt, J=6.0 Hz, J=15,0 Hz, 2H), 4,266 photo-4,242 (d, J=7.2 Hz, 2H), 3,682-3,537 (m, 8H)

The disodium salt of mono-{4-[(6S,9aS)-2-allyl-1-benzylcarbamoyl-8-(2-cyclopropylmethyl-2H-indazol-7-ylmethyl)-4,7-dioxo-octahydro-pyrazino[2,1-c][1,2,4]triazine-6-ylmethyl]-phenyl}ester of phosphoric acid (Compound No. 31 in Table 2)

1H NMR (D2O): δ 8,179 (s, 1H), 7,629-7,604 (d, J=7.5 Hz, 1H), 7,341-7,002 (m, 11H), 5,666-5,433 (m, 2H), 5,298-5,257 (t, J=6,6 Hz, 1H), 5,070-5,019 (d, J=15.3 Hz, 1H), 4,834-4,723 (m, 1H), 4,517-4,460 (d, J=17,1 Hz, 1H), 4,419-4,367 (d, J=15.6 Hz, 1H), 4,245-4,136 (m, 3H), of $ 3.656-3,598 (d, J=17,4 Hz, 1H), 3,539-3,463 (t, J=11.7 Hz, 1H), 3,384-at 3,151 (m, 6H), 1,330-1,239 (TT, J=7.5 Hz, J=2.4 Hz, 1H), 0,546-0,323 (m, 4H)

The disodium salt of mono-{4-[(6S,9aS)-2-allyl-1-benzylcarbamoyl-8-(1H-indazol-4-ylmethyl)-4,7-dioxo-octahydro-pyrazino[2,1-c][1,2,4]triazine-6-ylmethyl]-phenyl}ester of phosphoric acid(Compound No. 33 in Table 2)

1H NMR(D2O, 300 MHz) δ 8,18 (s, 1H), to 7.67 (d, J=8.7 Hz, 1H), 7,31-7,52 (m, 6H), 7,06-7,14 (m, 6H), of 5.53-the 5.65 (m, 2H), of 5.34 (t, J=5,1 Hz, 1H), 5,01-5,16 (m, 2H), 4,67-of 4.90 (m, 3H), 4,28-4,47 (m, 2H), 3,57 of 3.75 (m, 2H), 3,32-of 3.43 (m, 7H)

Benzolamide (6S,9aS) 2-allyl-8-(3-amino-1H-indazol-7-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid (Compound No. 5 in Table 2)

1Η NMR (CDCl3, 300 MHz) δ of 7.60 (d, J=8,1 Hz, 1H), δ 7,53-7,25 (m, 5H), δ 7,13 (d, J=6,9 Hz, 1H), δ 7,01 (who, J=7.5 Hz, 1H), δ at 6.84 (d, J=8.1 Hz, 2H), δ of 6.65 (t, J=5.7 Hz, 1H), δ to 6.57 (d, J=8.1 Hz, 2H), δ 5,70-5,61 (m, 1H), δ 5,28 (t, J=5.7 Hz, 1H), δ to 5.21 (d, J=10,2 Hz, 1H), δ 5,09 (d, J=17,1 Hz, 1H), δ 4,95-4,91 (m, 2H), δ 4,55 (d, J=14.4 Hz, 1H), δ of 4.45 (DD, J=6.3 Hz, J=14,7 Hz, 1H), δ 4,34 (DD, J=6.0 Hz, J=to 15.0 Hz, 1H), δ 3,52-of 3.27 (m, 7H)

2-{7-[(6S,9aS)-2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyrazino[2,1-c][1,2,4]triazine-8-ylmethyl)-indazol-1-yl}-ethyl ester acetic acid (Compound No. 11 in Table 2)

1H NMR (CDCl3, 300 MHz) δ with 8.05 (s, 1H), 7,71 (d, J=8,1 Hz, 1H), 7,22-7,38 (m, 6H), 7,12 (t, J=7.2 Hz, 1H), 6,97-7,03 (m, 3H), 6,68-of 6.71 (m, 3H), and 5.30-5.56mm (m, 4H), 4,99-of 5.06 (m, 2H), 4.75 V-4,88 (m, 3H), 4,27-4,47 (m, 4H), 3.25 to-3,47 (m, 9H), 1.91 a (s, 3H)

Benzolamide (6S,9aS)-2-allyl-6-(4-hydroxy-benzyl)-8-[1-(2-hydroxy-ethyl)-1H-indazol-7-ylmethyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4)triazine-1-carboxylic acid (Compound No. 17 in Table 2)

1H NMR (CDCl3, 300 MHz) δ of 8.04 (s, 1H), of 7.70 (d, J=7.8 Hz, 1H), 7,21-7,38 (m, 5H), 6,99 for 7.12 (m, 5H), 6,66-6,69 (m, 3H), 5,44-of 5.55 (m, 3H), 5,35 (t, J=5,1 Hz, 1H), 4,90-free 5.01 (m, 2H), 4,56-of 4.77 (m, 3H), 4,24-of 4.44 (m, 2H), 4,03-4,11 (m, 2H), 3,17-of 3.48 (m, 8H), to 3.02 (t, J=5.7 Hz, 1H)

Benzolamide (6S,9aS)-2-allyl-8-(3-chloro-1H-indazol-7-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid (Compound No. 15 in Table 2)

1H NMR (CDCl3): δ 11,506 (s, 1H), 7,697-7,670 (d, J=8,1 Hz, 1H), 7,392-7,096 (m, 8H), 6,912-6,884 (d, J=8,4 Hz, 2H), 6,738-6,698 (t, J=6.0 Hz, 1H), 6,556-6,529 (d, J=8,4 Hz, 2H), 5,682-5,549 (dt, J=6.3 Hz, J=10,2 Hz, 1H), 5,366-5,291 (m, 2H), 5,187-5,153 (d, J=10,2 Hz, 1H), 5,075-5,039 (d, J=10,8 is C, 1H), 5,028-4,982 (d, J=a 13.8 Hz, 1H), 4,572-4,524 (d, J=14.4 Hz, 1H), 4,462-4,294 (dt, J=6.0 Hz, J=15,0 Hz, 2H), 3,439-3,253 (m, 8H)

The disodium salt of mono-{4-[(6S,9aS)-2-allyl-benzylcarbamoyl-8-(3-chloro-1H-indazol-7-ylmethyl)-4,7-dioxo-octahydro-pyrazino[2,1-c][1,2,4]triazine-6-ylmethyl]-phenyl}ester of phosphoric acid (Compound No. 35 in Table 2)

1H NMR (D2O): δ 7,604-7,574 (t, J=9.0 Hz, 1H), 7,369-7,166 (m, 7H), 7,071-6,991 (kV, J =6.0 Hz, 4H), 5,640-5,447 (m, 2H), 5,262-5,223 (t, J=6.0 Hz, 1H), 4,965-4,931 (d, J=10,2 Hz, 1H), 4,894-4,683 (m, 3H), 4,392-4,183 (DD, J=15.6 Hz, J=to 47.4 Hz, 2H), 3,678-3,250 (m, 8H)

Benzolamide (6S,9aS)-2-allyl-8-(1-benzyl-3-phenyl-1H-indazol-7-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid (Compound No. 10 in Table 2)

1H NMR (CDCl3): δ 7,538-7,186 (m, 17H), 7,110-6,951 (m, 3H), 6,979-6,951 (d, J=8,4 Hz, 2H), 6,738-6,697 (t, J=6.0 Hz, 1H), 6,622-6,593 (d, J=8,4 Hz, 2H), 5,676-5,499 (m, 4H), 5,367-5,329 (t, J=5.7 Hz, 1H), 5,120-4,984 (kV, J=15,0 Hz, 2H), 5,059-5,034 (d, J=7.5 Hz, 1H), 4,984-4,884 (d, J=30 Hz, 1H), 4,478-4,303 (dt, J=6.0 Hz, J=to 15.0 Hz, J=26,3 Hz, 2H), 3,766-3,601 (m, 2H), 3,452-3,224 (m, 6H)

Benzolamide (6S,9aS)-2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(3-phenyl-1H-indazol-7-ylmethyl)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid (Compound No. 21 in Table 2)

1H NMR (CDCl3): δ 8,037-8,012 (d, J=7.5 Hz, 1H), 7,997-7,973 (d, J=7.2 Hz, 2H), 7,522-7,472 (t, J=7.2 Hz, 2H), 7,522-7,100 (m, 10H), 6,926-6,898 (d, J=8,4 Hz, 2H), 6,726-6,686 (t, J=6.0 Hz, 1H), 6,557-6,529 (d, J=8,4 Hz, 2H), 5,690-5,539 (dt, J=6.0 Hz, J=10,2 Hz, 1H), 5,374-5,292 (m, 2H), 5,175-5,141 (d, J=10.5 Hz, 1H), 5,110-5,062 (d, J=14.4 Hz, 1H), 5,027-of 4.90 (d, J=17,1 Hz, 1H), 4,614-4,566 (d, J=14.4 Hz, 1H), 4,458-4,284 (DDD, J=6.0 Hz, J=14,7 Hz, J=20.7 Hz, 2H), 3,491-3,228 (m, 8H)

Benzolamide (6S,9aS)-2-allyl-8-(1-benzyl-1H-indazol-3-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid (Compound No. 9 in Table 2)

1H NMR (CDCl3): δ 7,984-7,957 (d, J=8,1 Hz, 1H), 7,397-7,129 (m, 14H), 6,938-6,910 (d, J=8,4 Hz, 2H), 6,695-6,654 (t, J=6.0 Hz, 1H), 6,480-6,452 (d, J=8,4 Hz, 2H), 5,688-5,538 (dt, J=6,6 Hz, J=16,8 Hz, 1H), 5,405-5,356 (DD, J=5,1 Hz, J=9.6 Hz, 1H), 5,326-5,287 (t, J=6.0 Hz, 1H), 5,174~5,126 (d, J=14.4 Hz, 1H), 5,115-5,079 (d, J=10,8 Hz, 1H), 4,996-4,938 (d, J=17,4 Hz, 1H), 4,890-4,841 (d, J=14,7 Hz, 1H), 4,459-4,283 (DDD, J=6.3 Hz, J=to 15.0 Hz, J=31.8 Hz, 2H), 3,550-3,212 (m, 8H)

Benzolamide (6S,9aS)-2-allyl-8-(5-chloro-1H-indazol-7-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid (Compound No. 16 in Table 2)

1H NMR (CDCl3): δ 8,064 (s, 1H), 7,735-7,730 (d, J=1.5 Hz, 1H), 7,404-7,245 (m, 8H), 7,124-7,119 (d, J=1.5 Hz, 1H), 6,932-6,904 (d, J=8,4 Hz, 2H), 6,730-6,690 (t, J=6.0 Hz, 1H), 6,578-6,550 (d, J=8,4 Hz, 2H), 5,708-5,575 (dt, J=6.3 Hz, J=and 12.6 Hz, 1H), 5,393-5,300 (m, 2H), 5,230-5,197 (d, J=9.9 Hz, 1H), 5,064-5,005 (d, J=17.7 and Hz, 2H), 4,563-4,516 (d, J=14.1 Hz, 1H), 4,474-4,297 (DDD, J=6.0 Hz, J=14,7 Hz, J=20.7 Hz, 2H), 3,458-3,255 (m, 8H)

Benzolamide (6S,9aS)-2-allyl-8-(3-cyclopropanecarbonyl-1H-indazol-7-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid (Compound No. 12 in Table 2)

1Η NMR (300 MHz, CDCl3) δ 8,32~8,29 (DD, J=2.0 Hz, J=2.0 Hz, 1H), δ 7,34~7,14 (m, 8H), δ at 6.84 (d, J=8,3 Hz, 2H), δ 6,70 (t, J=59 Hz, 1H), δ of 6.49 (d, J=8,4 Hz, 2H), δ ceiling of 5.60-5,49 (m, 1H), δ 5,34~of 5.24 (m, 2H), δ 5,12 (d, J=10,3 Hz, 2H), δ is 4.93 (d, J=17,1 Hz, 1H), δ 4,42~of 4.25 (m, 2H), δ 3,35 (d, J=7.8 Hz, 2H), δ 3,31~of 3.27 (m, 2H), δ 3,25-3,17 (m, 2H), δ 1,28-of 1.15 (m, 3H), δ 1,04~0,97 (m, 2H)

Benzolamide (6S,9aS)-2-allyl-6-(4-hydroxy-benzyl)-8-(1H-indazol-3-ylmethyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid (Compound No. 1 in Table 2)

1H NMR (CDCl3, 300 MHz) δ 10,55 (s, 1H), 8,00 (d, J=8,1 Hz, 1H), 7,18 and 7.36 (m, 8H), to 6.80 (d, J=8,4 Hz, 2H), of 6.68 (t, J=6.0 Hz, 1H), 6.35mm (d, J=8,4 Hz, 2H), 5,58-of 5.68 (m, 1H), 5,02-5,31 (m, 5H), and 4.75 (d, J=14,7 Hz, 1H), 4,23-however, 4.40 (m, 2H), 3.27 to is 3.57 (m, 8H)

The disodium salt of mono-{4-[(6S,9aS)-2-allyl-1-benzylcarbamoyl-8-(1-benzyl-3-phenyl-1H-indazol-7-ylmethyl)-4,7-dioxo-octahydro-pyrazino[2,1-c][1,2,4]triazine-6-ylmethyl]-phenyl}ester of phosphoric acid (Compound No. 36 in Table 2)

1H-NMR (300 MHz, CDCl3): δ 3,02-to 3.36 (m, 1H), 3,28-to 3.36 (m, 4H), 3,48 (d, J=17,1 Hz, 1H), 3,62 (DD, J=11.3 Hz, J=21,7 Hz, 2H), 3,80 (DD, J=3,6 Hz, J=11.5 Hz, 1H), 4,25 (DD, J=4,7 Hz, J=15.2 Hz, 1H), 4,33-to 4.38 (m, 1H), and 4.40 (DD, J=6,7 Hz, J=15.1 Hz, 1H), a 4.83 (d, J=14,8 Hz, 1H), to 4.98 (d, J=14,8 Hz, 1H), 5,11 (t, J=10.5 Hz, 2H), by 5.18 (DD, J=2,6 Hz, J=6.3 Hz, 1H), 5,46-to 5.58 (m, 2H), 6,69 (t, J=6,4 Hz, NH), 6,79 (d, J=8,4 Hz, 2H), 6,92-6,95 (m, 4H), 7,12-7,29 (m, 10H), 7,42-of 7.55 (m, 6H).

Organized the screening of libraries of the present invention on the subject of biological activity using a variety of techniques and methods. Usually, a screening procedure can be done by (1) interaction mimetics library with interesting biological the second target, such as a receptor, in order to ensure the coupling between mimetics library and the target, and by (2) detection of the fact of binding using an appropriate analysis, such as calorimetric analysis revealed Lam et al. (Nature 354:82-84, 1991) or Griminski et al. (Biotechnology 12:1008-1011, 1994) (which are both included in the context of this document by reference). In a preferred embodiment, the library members are in solution, and the target is immobilized on a solid phase. Alternatively, the library can be mobilitat on the solid phase and can be explored through its interaction with the target in solution.

Inhibitory activity against the Wnt signaling was measured by gene-reporter TopFlash. A lower IC50 value indicates a higher inhibitory activity. The connection can be classified as active, if the IC50 represents 10 μm or below. If the IC50 is a 5~10 μm, the connection may be promising for use as a pharmaceutical product. The connection is strong, if the IC50 is a 1~5 μm, and the connection is very strong, if the IC50 represents 1 μm or below.

Most of the compounds of the present invention showed IC50 of 5 μm or below, which means that they have strong inhibitory activity on the to compared to signaling Wnt.

Table 3 below shows the compounds selected from the library of the present invention for studies concerning the biological activity and their IC50 values, which were measured through analysis of gene-reporter, as described in Example 2.

It was discovered in accordance with the present invention that compounds of General formula (I) have a lower CYP3A4 inhibitory activity (higher IC50 value). Details on a smaller parameter CYP3A4 inhibitory activity are disclosed in Example 1. Smaller CYP3A4 inhibitory activity means that the compounds of the present invention are more preferred pharmacologically regarding adverse reactions.

Table 4 below shows the compounds selected from the library of the present invention for studies concerning the biological activity and their IC50 values, which were measured by screening P450 CYP3A4 inhibitory activity, as described in Example 1.

The present invention also relates to methods of prevention and treatment of acute myeloid leukemia, cluchuis administration to a patient compounds, having the formula (I)above.

In one aspect the present invention provides compounds that inhibit the formation of the complex of β-catenin, p300 and TCF binding to c-Myc protein, and complex formation of β-catenin, p300 and TCF binding on the promoter of survivin.

In another aspect the present invention provides compounds, in particular compounds having the formula (II), which controls c-Myc protein. In accordance with the present invention it was found that compounds of General formula (I) have an impact on cell proliferation and inhibit the growth of cancer cells AML as described in Example 3.

GI50 for MV-4-11 shows the activity of inhibiting cell growth in relation to cancer cells and AML. Lower GI50 value means higher inhibitory activity. The connection can be classified as active if GI50 is 10 μm or less. If GI50 is 5~10 μm, the connection may be promising as a pharmaceutical drug. The connection is strong, if GI50 is 1~5 μm, and the connection is very strong, if GI50 is 1 μm or below.

Most of the compounds of the present invention showed GI50 5 μm or below, which means that they have strong inhibitory activity against cancers the m cells of AML.

Table 5 below shows the compounds selected from the library of the present invention for studies concerning the biological activity and their GI50 values, which were measured through analysis of inhibition of cell growth, as described in Example 3.

The following non-limiting examples illustrate the connections and the application of this invention.

EXAMPLE OBTAIN 1

Obtaining (N-Fmoc-N'-R4-hydrazino)-acetic acid

Two-liter, two-neck, round bottom flask provided with a glass stopper and calcium tube. Put the solution R4-hydrazine (20 g, 139 mmol, where R4represents methyl) in THF (300 ml) and was added to the solution DiBoc (33 g, 153 mmol) in THF. Saturated aqueous sodium bicarbonate solution (500 ml) was added dropwise via an additional funnel over 2 hours under vigorous stirring. After 6 hours was slowly added a solution of Fmoc-Cl (39 g, 153 mmol) in THF. The resulting suspension was stirred for 6 hours at 0°C. This mixture was extracted with ethyl acetate (EA, 500 ml) and left the organic layer. The resulting solution was dried with sodium sulfate and evaporated under vacuum. The next stage was carried out without the cleaning.

A two-neck, round bottom flask of 1 l provided with a glass stopper and calcium tube. Put in it a solution of the product from the previous step in MeOH (300 ml) and was slowly added conc. HCl (30 ml, 12 N.) via an additional funnel with magnetic stirring in a bath of ice water, and stirred over night. The resulting mixture was extracted with EA (1000 ml) and left the organic layer. The resulting solution was dried with sodium sulfate and evaporated under vacuum. The residue was purified by recrystallizationn-hexane and EA with obtaining N-Fmoc-N'-methylhydrazino (32,2 g, 83%).1H NMR (DMSO-D6) δ of 7.90-7,88 (d, J=6 Hz, 2H), δ 7,73-of 7.70 (d, J=9 Hz, 2H), 7,44-7,31 (m, 4H), to 4.52-4,50 (d, J=6 Hz, 2H), or 4.31-4.26 deaths (t, J=6 Hz, 1H), 2,69 (s, 1H).

(2) Receivingtert-butyl ether (N-Fmoc-N'-R4hydrazino)-acetic acid

A two-neck, round bottom flask of 1 l provided with a glass stopper and reflux condenser connected to a calcium tube. In it was placed a solution of N-Fmoc-N'-R4hydrazine (20 g, 75 mmol) in toluene (300 ml). Was slowly added a solution oftert-butylbromide (22 g, 111 mmol) in toluene (50 ml). Was slowly added Cs2CO3(49 g, 149 mmol). Was slowly added NaI (11 g, 74 mmol) under vigorous stirring. The reaction mixture was stirred at boiling point for 1 day. The product mixture was filtered and the extras who were garofali EA (500 ml). The resulting solution was dried over sodium sulfate and evaporated under vacuum. The obtained product was purified by chromatography with a solution of hexane:EA=2:1 to receivetert-butyl ether (N-Fmoc-N'-methyl-hydrazino)-acetic acid (19,8 g, 70%).1H-NMR (CDCl3-d) δ 7,78 to 7.75 (d, J=9 Hz, 2H), δ to 7.61-to 7.59 (d, J=6 Hz, 2H), 7,43-7,26 (m, 4H), 4,42-and 4.40 (d, J=6 Hz, 2H), 4,23 (user., 1H), only 3.57 (s, 2H), 2,78 (s, 3H), of 1.50 (s, 9H).

(3) Receiving (N-Fmoc-N'-methyl-hydrazino)-acetic acid

A two-neck, round bottom flask of 1 l provided with a glass stopper and reflux condenser connected to a calcium tube. Put in ittert-butyl ether (N-Fmoc-N'-R4-hydrazino)-acetic acid (20 g, 52 mmol). Was slowly added a solution of HCl (150 ml, 4M solution in dioxane) under vigorous stirring in a bath of ice water. The reaction mixture was stirred at room temperature for 1 day. The obtained solution was concentrated under reduced pressure at 40°C. was Added a saturated aqueous solution of NaHCO3(100 ml) and the aqueous layer washed with diethyl ether (100 ml). Slowly was added dropwise concentrated HCl at 0°C (pH 2-3). The resulting mixture was extracted and left the organic layer (500 ml, MC). The resulting solution was dried with sodium sulfate and evaporated under vacuum. The residue was purified by recrystallization fromthe -hexane and ethyl acetate to obtain (N-Fmoc-N'-methyl-hydrazino)-acetic acid (12 g, 72%).1H-NMR (DMSO-d6) δ 12,38 (s, 1H), 8,56 (user., 1H), 7,89-7,86 (d, J=9 Hz, 2H), 7,70-to 7.67 (d, J=9 Hz, 2H), 7,43-7,29 (m, 4H), 4,29-4,27 (d, J=6 Hz, 2H), 4,25-4,20 (t, J=6 Hz, 1H), 3,47 (s, 2H), has 2.56 (s, 3H).

EXAMPLE of GETTING 2

Benzolamide (6S,9aS)-2-allyl-6-(4-hydroxy-benzyl)-8-(1-methyl-1H-indazol-4-ylmethyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid

To obtain the target compounds was carried out by the General Scheme of the Library of Reverse-Turn Mimetics, which are described earlier in this description as below:

In the above scheme, 'Pol' is bromatology resin (Advanced ChemTech), and the detailed procedure is illustrated below.

Stage 1

Bromatology resin (37 mg, 0.98 mmol/g) and a solution of (1-methyl-1H-indazol-4-yl)methanamine in DMSO (1.4 ml) were placed in a block Robbins (FlexChem), includes 96-well plates. The resulting reaction mixture was shaken at 60°C, using a rotary kiln [Robbins Scientific] within 12 hours. The resin is washed with DMF, MeOH and then DHM.

Stage 2

To the resulting resin solution was added commercially available Fmoc-Tyr(OtBu)-OH (4 equiv.), PyBob (4 equiv.), HOAt (4 equiv.) and DIEA (12 equiv.) in DMF. After the resulting reaction mixture was shaken for 12 hours at room t is mperature, the resin is washed with DMF, MeOH, and then DHM.

Stage 3

To the resulting resin swollen in DMF before the reaction, was added 25% piperidine in DMF and the reaction mixture was shaken for 30 min at room temperature. This phase of removing the protective groups repeated again, and the obtained resin was washed with DMF, methanol, and then DHM. To the resulting resin solution was added hydrazine powered acid (4 equiv.), HOBt (4 equiv.) and DIC (4 equiv.) in DMF and the reaction mixture was shaken for 12 hours at room temperature. The obtained resin was washed with DMF, MeOH, and then DHM.

Stage 4

The resin obtained in stage 3, was treated with formic acid (1.2 ml per well) for 18 hours at room temperature. After the resin was separated by filtration, the obtained filtrate are condensed under reduced pressure using a vacuum system SpeedVac [SAVANT] to obtain the product as oil. The obtained product was diluted 50% mixture of water/acetonitrile, and then after freezing was liofilizovane.1H NMR (CDCl3, 300 MHz) δ 8,08 (s, 1H), 7,21-7,38 (m, 8H), of 6.99 (d, J=8,4 Hz), 6.89 in-6,94 (m, 1H), 6,62-6,69 (m, 3H), 5.40 to-5,59 (m, 2H), of 5.34 (t, J=5.4 Hz, 1H), 5,17-5,23 (m, 1H), 5,07 (d, J=10.5 Hz, 1H), 4,67-4,96 (m, 2H), 4.26 deaths is 4.45 (m, 1H), 4,08 (s, 3H), 3,23-3,44 (m, 9H)

EXAMPLE of GETTING 3

Getting benzylamine (6S,9aS)-2-allyl-8-(3-cyclopropanecarbonyl-1H-indazol-7-ylmethyl)-6-(4-hydroxy-benzyl)-4,dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid

To obtain the target compounds was carried out by the General Scheme of the Library of Reverse-Turn Mimetics, which are described earlier in this description as below:

In the above scheme, 'Pol' is bromatology resin (Advanced ChemTech), and the detailed procedure is illustrated below.

Stage 1

Bromatology resin (37 mg, 0.98 mmol/g) and a solution oftert-butyl-7-(aminomethyl)-3-(cyclopropanecarbonyl)-1H-indazol-1-carboxylate in DMSO (1.4 ml) were placed in a block Robbins (FlexChem), includes 96-well plates. The resulting reaction mixture was shaken at 60°C, using a rotary kiln [Robbins Scientific] within 12 hours. The resin is washed with DMF, MeOH and then DHM.

Stage 2

To the resulting resin solution was added commercially available Fmoc-Tyr(OtBu)-OH (4 equiv.), PyBob (4 equiv.), HOAt (4 equiv.) and DIEA (12 equiv.) in DMF. After the resulting reaction mixture was shaken for 12 hours at room temperature, the resin washed with DMF, MeOH, and then DHM.

Stage 3

To the resulting resin swollen in DMF before the reaction, was added 25% piperidine in DMF and the reaction mixture was shaken for 30 min at room temperature. This phase of removing the protective groups repeated again, and the obtained resin was washed with DMF, methanol, and then DHM. To the resulting see the Les solution was added hydrazine powered acid (4 equiv.), HOBt (4 equiv.) and DIC (4 equiv.) in DMF and the reaction mixture was shaken for 12 hours at room temperature. The obtained resin was washed with DMF, MeOH, and then DHM.

Stage 4

The resin obtained in stage 3, was treated with formic acid (1.2 ml per well) for 18 hours at room temperature. After the resin was separated by filtration, the obtained filtrate are condensed under reduced pressure using a vacuum system SpeedVac [SAVANT] to obtain the product as oil. The obtained product was diluted 50% mixture of water/acetonitrile, and then after freezing was liofilizovane.1H-NMR (300 MHz, CDCl3) δ 8,32~8,29 (DD, J=2.0 Hz, J=2.0 Hz, 1H), δ 7,34~7,14 (m, 8H), δ at 6.84 (d, J=8,3 Hz, 2H), δ 6,70 (t, J=5,9 Hz, 1H), δ of 6.49 (d, J=8,4 Hz, 2H), δ ceiling of 5.60~5,49 (m, 1H), δ 5,34~of 5.24 (m, 2H), δ 5,12 (d, J=10.3 Hz, 2H), δ is 4.93 (d, J=17,1 Hz, 1H), δ 4,42~of 4.25 (m, 2H), δ 3,35 (d, J=7.8 Hz, 2H), δ 3,31~of 3.27 (m, 2H), δ 3.25 to us 3.17 (m, 2H), δ 1,28-of 1.15 (m, 3H), δ 1,04~0,97 (m, 2H)

EXAMPLE 4

Getting benzylamine (6S,9aS)-2-allyl-6-(4-hydroxy-benzyl)-8-[1-(2-hydroxy-ethyl)-1H-indazol-7-ylmethyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid

To obtain the target compounds was carried out by the General Scheme of the Library of Reverse-Turn Mimetics, which are described earlier in this description as below:

In the above scheme is e 'Pol' is bromatology resin (Advanced ChemTech), and the detailed procedure is illustrated below.

Stage 1

Bromatology resin (37 mg, 0.98 mmol/g) and a solution of 2-(7-(aminomethyl)-1H-indazol-1-yl)ethyl-tert-BUTYLCARBAMATE in DMSO (1.4 ml) were placed in a block Robbins (FlexChem), includes 96-well plates. The resulting reaction mixture was shaken at 60°C, using a rotary kiln [Robbins Scientific] within 12 hours. The resin is washed with DMF, MeOH and then DHM.

Stage 2

To the resulting resin solution was added commercially available Fmoc-Tyr(OtBu)-OH (4 equiv.), PyBob (4 equiv.), HOAt (4 equiv.) and DIEA (12 equiv.) in DMF. After the resulting reaction mixture was shaken for 12 hours at room temperature, the resin washed with DMF, MeOH, and then DHM.

Stage 3

To the resulting resin swollen in DMF before the reaction, was added 25% piperidine in DMF and the reaction mixture was shaken for 30 min at room temperature. This phase of removing the protective groups repeated again, and the obtained resin was washed with DMF, methanol, and then DHM. To the resulting resin solution was added hydrazine powered acid (4 equiv.), HOBt (4 equiv.) and DIC (4 equiv.) in DMF and the reaction mixture was shaken for 12 hours at room temperature. The obtained resin was washed with DMF, MeOH, and then DHM.

Stage 4

The resin obtained in stage 3, was treated with formic acid (1.2 ml per well) for 18 cha is s at room temperature. After the resin was separated by filtration, the obtained filtrate are condensed under reduced pressure using a vacuum system SpeedVac [SAVANT] to obtain the product as oil. The obtained product was diluted 50% mixture of water/acetonitrile, and then after freezing was liofilizovane.1H NMR (CDCl3, 300 MHz) δ of 8.04 (s, 1H), of 7.70 (d, J=7.8 Hz, 1H), 7,21-7,38 (m, 5H), 6,99 for 7.12 (m, 5H), 6,66-6,69 (m, 3H), 5,44-of 5.55 (m, 3H), 5,35 (t, J=5,1 Hz, 1H), 4,90-free 5.01 (m, 2H), 4,56-of 4.77 (m, 3H), 4,24-of 4.44 (m, 2H), 4,03-4,11 (m, 2H), 3,17-of 3.48 (m, 8H), to 3.02 (t, J=5.7 Hz, 1H)

EXAMPLE of GETTING 5

Getting disodium 4-((2-allyl-1-(benzylcarbamoyl)-8-((2-methyl-2H-indazol-7-yl)methyl)-4,7-dioxo-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl)phenylphosphate (2)

To a solution of 2-allyl-N-benzyl-6-(4-hydroxybenzyl)-8-((2-methyl-2H-indazol-7-yl)methyl)-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide (1) (1.0 equiv.) in THF (10 ml/mmol) was added POCl3(4.0 equiv.) and tea (3.0 equiv.) at 0°C. After stirring at room temperature for 1 hour was slowly added saturated aqueous solution of NaHCO3and was stirred for 1 hour. The resulting mixture was washed with EtOAc, and then the aqueous layer was acidified using 1 N. aqueous solution of HCl at 0°C, and then was extracted with EtOAc. The organic layer was dried using Na2SO4and concentrated under vacuum. The obtained residue was led the ri using EtOAc and n-hexane to obtain the intermediate compound (2) in a solid white color. This solid is made using 0.1 G. of an aqueous solution of NaOH to pH 11.0 and was liofilizovane with obtaining the target compound(3) (87%).

EXAMPLE 1

Screening of P450 CYP3A4 inhibitory activity

The compounds:

The analysis was performed in a volume of 200 μl in 96-well titration microplate, using cDNA-expressed human CYP3A4 liver (supersome, BD Gentest™ #456202). As a substrate for CYP3A4 used 7-benzyloxy-4-trifluoromethyl-coumarin (BFC). The analyte and the substrate BFC was dissolved in 100% acetonitrile. The final volume of acetonitrile in the incubation mixture was less than 1% (by volume). In each cell was added in a buffer solution of potassium phosphate (pH of 7.4, final concentration 0.1 M), MgCl2(the final concentration of 8.3 mm), EDTA (final concentration 1,67 mm)stock solution of the compounds, CYP3A4 supersome and NADP (final concentration 0.25 mm). The reaction was initiated by addition of substrate (BFC, final concentration 30 M) after inactivated for 10 minutes at 37°C. After incubation for 10 minutes at 37°C the reaction was stopped by adding 75 μl of a mixture of acetonitrile:0.5 M Tris-base=4:1 (by volume). After this, the measured fluorescent signal using fluorimetry. BFC metabolite, 7-hydroxy-4-trifluoromethyl-coumarin, and the measure, when the wavelength of excitation of 409 nm and the wavelength of fluorescence at 530 nm. Figure 2 shows the IC50 of tested compound A in the analysis of inhibition of CYP3A4. Compounds A, B and C showed weak inhibition of CYP3A4 enzyme.

EXAMPLE 2

The bioanalysis gene-reporter TopFlash for measuring IC50compared to SW480 cells

The analyzed compound (Compound (D)used in this sample received in the sample receiving 3.

The SW480 cells were transfusional using transfairusa agent Superfect™ (Qiagen, 301307). The cells were trypsinization within a short period of time, 1 day prior to transfection and were sown in 6-well plate (5×105cells/cell), so that the day of transfection they were 50-80% confluent.

Four micrograms (TopFlash) and one microgram (pRL-null) DNA was diluted in 150 μl of serum-free medium and added 30 μl transfairusa agent Superfect™. The resulting mixture of DNA-Superfect were incubated at room temperature for 15 min, and then to it was added 1 ml of 10% FBS DMEM for another 3 hours of incubation. While the formed complexes, cells were washed FBI twice without antibiotics.

Complexes of DNA-transfiziologii agent Superfect™ was added to the cells before incubation at 37°C in 5% CO2within 3 hours. After incubation were added to restoring the environment with 10% FBS, to bring the end about what to eat to 1.18 ml After incubation for 3 hours the cells were collected and perceivable in 96-well plates (3×104cells/cell). After incubation over night at 37°C in 5% CO2these cells were treated with Compound D within 24 hours. Finally, check the activity by luciferase assay (Promega, E 1960). Figure 3 illustrates the results of measuring IC50Connection D with respect to the SW480 cells. The IC50 value was 0,083±0,007 mm.

EXAMPLE 3

Inhibitory activity of cell growth in cancer cells AML (Analysis of inhibition of cell growth)

The compounds:

Analysis of inhibition of cell growth was performed to investigate the rate of inhibition of cell proliferation of the investigated compounds. Cell MV-4-11 (human cell line acute myeloid leukemia) were cultured in the medium of Dulbecco modified by the method of Claims (IMDM)with 10% fetal bovine serum (FBS), 1×penicillin/streptomycin (10,000 units/ml penicillin, 10000 g/ml streptomycin in a 0.85% NaCl). Cell MV-4-11 collected with the medium IMDM and moved 5×104cells/cell in each cell 96-well culture plates (Nunc, #167008). The compounds were subjected to serial dilution and did two of each solution concentration. In the process of mass rasba the population of tested compound was repeatedly diluted with the same volume of medium in 96-well block for analysis (costar, #3956). After dilution of each compound was added to each cell. During processing of the investigated compounds was also measured background absorption when added to the negative control tablet IMDM medium instead of the investigated compounds. The plates were incubated for 3 days (72 hours) at 37°C in a humid chamber with 5% CO2. On the last day of the culture in each cell was added 20 μl of a solution of CellTiter 96 Aqueous (Promega #G3581) and the plates were incubated for several hours at 37°C in a humid chamber with 5% CO2. After incubation was measured by the absorption of each cell at 490 nm using a device EnVision (Perkinelmer, USA). GI50 values were calculated using the program Prism 3.0. The results showed that the compounds affect cell proliferation and inhibit the growth of cancer cells in AML. Figure 4 shows the result of inhibition of Compound A. the GI50 Values for Compound A and Compound C was 0,220 μm and 0,037 μm, respectively.

As described above, the present invention provides new compounds mimetics reverse turns, which can be used as pharmaceuticals, particularly in relation to cancer cells and AML. This invention has been described in detail with reference to its preferred options for implementation. However, experts in the art Dol who have to understand in these cases the implementation can make changes without deviating from the principles and essence of the present invention, the scope of which is defined in the attached claims and their equivalents.

1. The compound having the structure of Formula (I):

in the form of a single stereoisomer or mixture of stereoisomers, or its pharmaceutically acceptable salt,
where R1represents indazole or indazoles substituted by one or more substituents, independently selected from C1-7of alkyl, C6aryl, C6arils1-6of alkyl, C7-15arylalkyl substituted by one or more substituents independently selected from amino and nitro, With3-6cycloalkyl1-6of alkyl, hydroxys1-6of alkyl, C1-10acyl, amino, halogen, nitro, C2-10allexis1-6of alkyl, aminocarbonyl, aminocarbonyl1-6of alkyl, dis1-6alkylaminocarbonyl1-6of alkyl, C1-6alkoxycarbonyl1-6of alkyl, hydroxys1-6of alkyl, tsianos1-3of alkyl, morpholinyl1-3of alkyl, C1-6alkoxyl1-6alkylamide and C3-6cycloalkylcarbonyl; and
R6represents a C6aryl or6-12aryl, substituted by one or more substituents independently selected from the group consisting of halogen, hydroxyl, cyano, and C1- alkoxy; or (C6heterocyclyl containing 1-2 heteroatoms selected from nitrogen or oxygen;
each of X2and X3independently represents hydrogen, hydroxyl or a phosphate.

2. The compound according to claim 1, in which:
R1represents indazole or indazoles substituted by one or more substituents independently selected from methyl; isopropyl; cyclopropylmethyl; hydroxyethyl; cyclopropanecarbonyl; aminocarbonyl; cyanomethyl; morpholinylmethyl; aminocarbonylmethyl; dimethylaminocarbonylmethyl; methoxyethylamine; ethoxycarbonylmethyl; acetoxyethyl; phenyl; benzyl; and substituted C7-15arylalkyl having one or more substituents independently selected from amino and nitro.

3. The compound according to claim 1, in which R1selected from the group consisting of 2-methyl-2H-indazole, 1-methyl-1H-indazole, 3-cyclopropanecarbonyl-3-N-indazole, 1-hydroxyethyl-1H-indazole, 1H-indazole, 2-cyclopropylmethyl-2H-indazole, 3-amino-1H-indazole, 1-benzyl-1H-indazole, 3-chloro-1H-indazole, 6-chloro-1H-indazole, 3-phenyl-1H-indazole, 1-benzyl-3-phenyl-1H-indazole, 1-nitrobenzyl-1H-indazole, 1-aminobenzyl-1H-indazole, 2-methyl-3-cyclopropanecarbonyl-2H-indazole, 1-methyl-3-aminocarbonyl-1H-indazole, carbonyl-indazole, 2-isopropyl-2H-indazole, 2-aminocarbonylmethyl-2H-indazole, 1-Sanomat the l-3-cyclopropanecarbonyl-1H-indazole, 2-cyanomethyl-3-cyclopropanecarbonyl-2H-indazole, 1-morpholinyl-N-ethyl-1H-indazole, 2-morpholinyl-N-ethyl-2H-indazole, 2-dimethylaminocarbonylmethyl-2H-indazole, 2-methoxyethylamine-2H-indazole, 1-ethoxycarbonylmethyl-1H-indazole, 2-ethoxycarbonylmethyl-2H-indazole and 1-acetoxyethyl-1H-indazole.

4. The compound according to claim 1, in which:
X2represents hydrogen; and X3represents hydrogen or phosphate.

5. The compound according to claim 1, in which:
R6represents phenyl.

6. The compound according to claim 1, in which:
X2represents hydrogen;
X3represents a hydroxyl or a phosphate; and
R6represents phenyl.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , and pharmaceutically acceptable salts thereof, where L denotes O, S, or CH2; Y denotes N or CH; Z denotes CR3; G denotes CH; R1 denotes a heteroaryl ring of formula , where D1 denotes S, O; D2 denotes N or CR12; D3 denotes CR12; R2 denotes (C6-C10)-aryl; 5-9-member mono- or bicyclic heteroaryl with 1 or 2 heteroatoms independently selected from N or S; a saturated or partially saturated (C3-C7)-cycloalkyl; or a saturated 5-6-member heteocyclyl with 1 heteroatom selected from N, where said aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with one or two groups independently selected from (C1-C6)-alkyl, F, Cl, Br, CF3, CN, NO2, OR6, C(-O)R6, C(=O)OR6, C(=O)NR6R7, saturated 6-member heterocyclyl with 2 heteroatoms independently selected from N or O, and S(O)2R6, and where said alkyl is optionally substituted with one -OR8 group; R3 denotes H; (C1-C6)-alkyl; (C2-C6)-alkenyl; Cl; Br; OR6; SR6; phenyl; or a 6-member heteroaryl with 1 heteroatom selected from N, where said alkyl and alkenyl are optionally substituted with one group selected from C(=O)OR8, -OR8, -NR8R9; or a saturated 6-member heterocyclyl with 1 heteroatom selected from N or O.

EFFECT: disclosed compounds are used in treating and preventing diseases mediated by insufficient level of glucokinase activity, such as sugar diabetes.

16 cl, 479 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present patent claim discloses sulphonyl-substituted compounds of formula QUIN which are used for the purpose of a method for producing a macrocyclic compound of formula (I)

EFFECT: compounds of formula (I) are effective active agents for treating Hepatitis C viral (HCV) infection.

8 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 4-amino-3-arylamino-6-arylpyrazolol[3.4-d]-pyrimidine derivatives showing antiviral activity. In formula I: the groups A and B independently represent phenyl, naphthyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, pyrazolyl, triazinyl, imidazolyl, furanyl, thienyl, and in each of these groups one to three hydrogen atoms can be independently substituted by the radical R1; R1 can be NO2, CN, CONR22, COOR2, CHO, CONH2, halogen, saturated or unsaturated, linear or branched alkyl with a number of atoms in the chain 1 to 7, saturated or unsaturated, linear or branched alkanole with a number of atoms in the chain 1 to 8, OR2, SR2, NR22, SO2NR32, di- or trifluoromethyl, phenyl; R2 represents hydrogen, CF3, and linear or branched alkyl with a number of atoms in the chain 1 to 7; the radical R3 represents H, benzyl, or linear or branched alkyl with a number of atoms in the chain 1 to 7; the radicals R4 and R5 represent hydrogen.

EFFECT: developing the method for preparing the compound of formula (I) and applying the compounds of the present invention as a biological agent exhibiting antiviral activity, eg for treating picornavirus infections.

9 cl, 6 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: described are novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side with considerable absorption in the region up to 410-420 nm, having general formulae (a)-(k) (structural formula and values of radicals are given in the description), composition which is stabilised with respect to UV radiation and containing novel UV-absorbers, and use of the novel compounds as UV light stabilisers for organic materials.

EFFECT: obtaining novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side.

13 cl, 23 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: described is a novel compound - 6-(2'-amino-2'-carboxyethylthio)-2-methylthio-4-pivaloyloxy-methyl-1,2,4-triazolo[5,1-c] 1,2,4-triazin-7(4H)-one of formula having antiviral action and low toxicity.

EFFECT: compound can be used in medicine.

1 cl, 1 ex, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and synthesis of heterocyclic compounds - 5,6-dihydro-7H-pyrrolo[1,2-d][1,4]benzodiazepin-6-one derivatives of formula 1a-e by boiling 2-amino-N-(2-furan-2-yl-phenyl)-acetamides in a mixture of glacial acetic acid and concentrated hydrochloric acid with subsequent treatment with sodium bicarbonate while boiling.

EFFECT: method is characterised by simple execution.

2 tbl, 5 ex

Polycyclic compound // 2451685

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a new polycyclic compound with general formula (I-1) and (1-3) or a pharmaceutically acceptable salt thereof where X1- -CR1 =CR2 - where R1 and R2 independently stand for hydrogen or C1-6 alkyl while Het stands for a radical of the following formulae: that may be substituted 1-3 times additionally described is a pharmaceutical composition containing such compound and intended for prevention or treatment of diseases caused by β-amyloid.

EFFECT: production of a pharmaceutical composition prevention or treatment of diseases caused by β-amyloid.

7 cl, 392 ex, 12 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to compounds that may be applied for HIV infection treatment or prevention or for AIDS or AIDS-associated complex treatment. According to the invention, the compounds represent compounds with formula I, where A stands for A1 , A2 , A3 or A4 and R1, R2, R3, R4a, R4b, R5, R6, Ar, X1, X2, X4, X4 and X5 having values specified in the patent claim. Additionally, this invention relates to a pharmaceutical composition containing the said compounds.

EFFECT: production of compounds possessing inhibition activity with regard to HIV reverse transcriptase.

22 cl, 3 tbl, 29 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an amorphous form of N-{2- fluorine-5-[3-(thiophen-2-carbonyl)-pyrazolo[1,5-a]-pyrimidin-7-yl]-phenyl}-N-methyl-acetamide, methods for preparing it.

EFFECT: preparing the pharmaceutical compositions for GABA-receptor inhibition containing said form, and also to using them as a drug for treating and/or preventing anxiety, epilepsy, sleeping disorder and sleeplessness, for induction of sedative-hypnotic effect, for anaesthesia and muscular relaxation and for time modulation required for sleep induction and duration.

12 cl, 4 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted pyrazolopyrimidines derivatives of formula , wherein Y1, Y2, Y3, Y4 represent N or C-, wherein at least, two groups of Y1-Y4 represent carbon atom, R1 represents chlorine or bromine, R2-R7 represent, e.g. hydrogen, methyl or ethyl; and R10 and R11 independently represent, e.g. hydrogen or C1-C6alkyl, their optical isomers and pharmaceutically acceptable salts. Also, the invention refers to using said compounds for treating and preventing a number of acute and chronic mGluR5 related neurological disorders, such as, e.g. pains of various character, dyskinesia, Parkinson's disease, anxiety disorder, Alzheimer's disease and others, a pharmaceutical composition containing specified compounds and methods for preparing them.

EFFECT: compounds are strong mGluR5 modulators.

21 cl, 2 tbl, 274 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely a method for preparing a concentrate of Tambukan therapeutic mud. The method for preparing the concentrate of Tambukan therapeutic mud consisting in the fact that mud is pressed, filled with mixed ethanol and oil in the presence of Tween 80; the extract is poured out; mud is pressed and secondary filled with mixed ethanol and oil with added emulsifier T-2; the combined extracts are sterilised under certain conditions.

EFFECT: method enables increasing yield of hydrophobic substances, intensity of extraction process and reducing extraction time.

1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention relates to veterinary science. A method involves feeding of a hydrolytic preparation. A hydrolytic preparation represents gelatin autoclaved and imbedded in an aqueous solution of an electrically activated anolyte of pH 3.5-4.2 and redox potential +900…+1000 mV.

EFFECT: method enables preserving to 100% calves aged 21 days and younger and increasing their body weight.

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely gynaecology, physiotherapy. A method involves magnetic laser exposure. Said exposure is performed by a vaginal technique. That is ensured by using infrared light emitted diodes of power 60 mWt. The exposure is performed at frequency 1500 Hz, magnetic field intensity 30 mT. On the first day, duration of the procedure makes 5 minutes, on the following days - 10 minutes. Each procedure of the magnetic laser exposure is followed by vaginal introductions of silt sulphide mud tampons of temperature 22-24°C for 60 minutes. After the procedure, residual silt sulphide mud is removed by vaginal douching with mineral water. The procedures are once a day. The therapeutic course is 10 procedures.

EFFECT: higher clinical effectiveness ensured by activation of cell enzyme systems, provided biostimulating effect on immune cell membranes, enabled creation of thermal, biochemical and mechanical gradients.

1 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: invention refers to veterinary science. A method involves enterosorbents introduced in a diet. What is used as a sorbent is vermiculite fed daily in dose 100 g per an animal for 60 days, It is added with introducing Sedimin 10 ml per an animal and Vitadaptin 20 ml per an animal in the beginning of the therapeutic course and again in 30 days of treatment. Expanded vermiculite of particle size 0.1-2.0 mm produced by the Kovdorskoye deposit is used. Vermiculite is mixed with fodder, while Sedimin and Vitadaptin are injected intramuscularly.

EFFECT: higher clinical effectiveness.

2 cl, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmacology. A method involves using mineral-enriched water produced of deep-sea water with the mineral contents per one kg of enriched water makes 40 - 5900 mg. One or more magnesium, calcium, sodium and potassium are used as minerals.

EFFECT: method allows inhibiting effectively Helicobacter pylori proliferation and migration.

2 cl, 15 tbl, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns veterinary science. A polyfunctional enterosorbent contains schungite-containing minerals comprising silicon dioxide 15.0-70.0 wt %, with an average median particle size 15.0*10-6 m.

EFFECT: invention provides higher efficacy on a wide spectrum of toxic substances, including mycotoxines, nitrates, nitrites, heavy metal salts, and also as an antibacterial and antioxidant agent.

14 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to veterinary pharmaceutics, and can be used for preparing a hygienic ointment for prevention of skin diseases and hygienic application in naked skin treatment in animals, particularly for dubbing udder skin in cows for the purpose of nipple crack prevention, and also hand skin in milkers, for treating dermatitis. The method for making sapropel ointment involves heating of a mixture of natural sapropel and Vaseline in a microwave electromagnetic field (400-800 Wt - 40-60 minutes) which is accompanied by separation of tarry pyrolysis fractions in a non-oxygen medium under a layer of fused boiling Vaseline; then solid fractions are separated by hot filtration through a metal filter in the certain proportions.

EFFECT: invention provides method simplification, decrease in sapropel aeration, making an end-product with no characteristic odour.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to agriculture, particularly to veterinary science, and can be used in animal industries for mastitis prevention. An agent for treating dugs containing polyvinyl alcohol, differing by the fact that polyvinyl alcohol grade 11/2 is used, in addition contains 10 % liquid alkaline sapropel hydrolyzate and disinfectant liquid soap "Cleandesin-soft" in the following proportions, wt %: Polyvinyl alcohol grade PVA 11/2 2.0-6.0; 10 % liquid alkaline sapropel hydrolyzate 1-3; "Cleandesin-soft" 0.7-1.0; distilled water - the rest. After application, the agent dries up and forms a thin, strong enough film which is removed after washing the dugs with warm water prior to milking. The agent promotes a soothing effect on dug skin, stimulates wound repair and cracked dug healing and provides an effective mastitis prevention in cows.

EFFECT: agent is easy-to-use and effective, does not require heavy money costs and time expenditures.

1 ex

FIELD: medicine.

SUBSTANCE: invention relates to veterinary science. The method involves rectal introduction of cooled sapropelic mud.

EFFECT: method is simple and high-effective.

1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to experimental toxicology and can be used for prevention of toxic action of molybdenum in experimental animals in case of chronic poisoning. For this purpose natural sorbent zeolite irlit-1 is introduced via probe into stomach of animals in form of 6% suspension in amount 2.5% of body weight. Sorbent is introduced simultaneously with daily introduction of ammonium molybdate solution via probe into stomach in dose 5 mg/100 g of body weight in terms of metal.

EFFECT: method ensures considerable reduction of toxic effect of molybdenum in case of chronic poisoning due to reduction of accumulation and increase of heavy metal excretion from organism.

1 tbl, 1 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: present invention relates to novel 6-substituted isoquinolone derivatives of formula

or , or stereoisomeric forms and/or pharmaceutically acceptable salts thereof, where R2 denotes H or (C1-C6)alkyl; R3, R4 and R5 denote H; R6 and R6' independently denote H, (C1-C8)alkyl, (C1-C6)alkylene-R', (C1-C6)alkylene-C(O)O-(C1-C6)alkyl, C(O)-(C1-C6)alkylene-R', or R6 and R6', together with a N atom with which they are bonded form a (C5-C6)heterocyclyl group in which one or more carbon atoms can be substituted with 1, 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms or a combination of different heteroatoms; R7 denotes H, halogen, (C1-C6)alkyl; R8 denotes H; n equals 1; m equals 1, 2, 3, 4 or 5, and L denotes O or O-(C1-C6)alkylene; where, R' denotes (C3-C8)cycloalkyl, (C5-C10)heterocyclyl, (C6-C10)aryl; where in residues R6 and R6' alkyl or alkylene can optionally be substituted one or more times with COOH groups; and where in residues R6 and R6' (C6-C10)aryl and (C5-C10)heterocyclyl are unsubstituted or substituted one or more times with suitable groups independently selected from a group comprising CONH2 and (C1-C6)alkyl; where if m equals 3, R6 cannot denote H; where if m equals 3 and R6 denotes (C1-C8)alkyl, then the alkyl is substituted once or more times, preferably one to three times, with a COOH group. The invention also relates to use of the compound of formula (I) and a medicinal agent based on the disclosed compounds.

EFFECT: novel isoquinolone derivatives which inhibit Rho-kinase and/or Rho-kinase mediated phosphorylation of the myosin light-chain phosphate.

31 cl, 6 tbl

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