Iap inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula: U1-M-U2, where U1 and U2 have general formula (I), where: G stands for: IVb IVd ive, and values M, X1, X2, R2, R3, R3', R4, R4', R5, R5', R6, R6', R7, Z7, Z2, Z3, Z4, Q2 are given in item 1 of the formula.

EFFECT: compounds can be applied for induction of apoptosis in cell.

37 cl, 13 dwg, 43 ex

 

A related application

This application claims the priority and benefit of provisional patent application U.S. No. 60/915010, filed April 30, 2007, which is incorporated into this description in full by reference.

The technical field to which the invention relates.

The invention relates to organic compounds used for the treatment and/or prevention in a mammal, and, in particular, inhibitors of IAP proteins used to treat various types of cancer.

The level of technology

Apoptosis or programmed cell death is a genetically and biochemically regulated mechanism, which plays an important role in the development and homeostasis of the organism invertebrates, and vertebrates. Abnormalities in apoptosis, which leads to premature cell death was associated with a number of defects. Deficiency of apoptosis, which leads to insufficient cell death was associated with cancer and chronic viral infections (Thompson et al., (1995) Science 267, 1456-1462).

One of the key effector molecules of apoptosis is caspase (cysteine-containing aspartate-specific proteases). Caspase are strong proteases that cleave peptide bonds after aspartic acid residues and, in the case of activation, they split the vital proteins within the cell. On the Kolka caspase are strong proteases, to prevent premature cell death required strict control of this family of proteins. In General, caspase synthesized mainly in the form of inactive imagenow that require proteolytic processing to become active. This proteolytic processing is only one way to control caspase. The second mechanism is through a family of proteins that condense to and inhibit caspase them.

A family of molecules that inhibit caspase, is an inhibitor of apoptosis (IAP) (Deveraux et al., J Clin. Immunol. (1999), 19:388-398). IAP were originally discovered in baculovirus due to their functional ability to substitute protein P35, anti-apoptotic gene (Crook et al. (1993) J Virology 67, 2168-2174). IAP have been described for organisms ranging from Drosophila to man. Regardless of their origin, structure, IAP contain from one to three domains of IAP repeat baculovirus (BIR), and most of them also have on-end RING finger (finger)” motif. Domain BIR, in itself, is a zinc-binding domain, consisting of 70 residues, including 4 alpha-helix and 3 beta-chain, with the remnants of cysteine and histidine that coordinate the zinc ion (Hinds et al., (1999) Nat. Struct. Biol. 6, 648-651). It BIR domain, it is believed, causes the anti-apoptotic effect by inhibiting caspases and those who thus inhibiting apoptosis. As an example, human, associated with the X chromosome, IAP (XIAP) inhibits caspase 3, caspase 7 and mediated by Apaf-1-cytochrome C, activation of caspase 9 (Deveraux et al., (1998) EMBO J. 17, 2215-2223). Caspase 3 and 7 inhibited BIR2 domain of XIAP, while the BIR3 domain of XIAP is responsible for the inhibition of the activity of caspase 9. XIAP is expressed ubiquitously in most Mature and embryonic tissues (Liston et al, Nature, 1996, 379(6563):349), and sverkhekspressiya in several tumor cell lines panel of cell lines NCI 60 (Fong et al, Genomics, 2000, 70:113; Tamm et al, Clin. Cancer Res. 2000, 6(5):1796). Overexpression of XIAP in tumor cells, as has been shown, provides protection to a number of Pro-apoptotic stimuli and promotes resistance to chemotherapy (LaCasse et al, Oncogene, 1998, 17(25):3247). In line with this, we demonstrated a strong correlation between XIAP protein levels and survival for patients with acute myeloid leukemia (Tamm et al, above). Regulation according to the type of feedback the expression of XIAP antimyeloma the oligonucleotides have been shown to increase the sensitivity of tumor cells to death induced by a wide range of Pro-apoptotic funds, both in vitro and in vivo (Sasaki et al, Cancer Res., 2000, 60(20):5659; Lin et al, Biochem J., 2001, 353:299; Hu et al, Clin. Cancer Res., 2003, 9(7):2826). Smac/DIABLO-derived peptides, as was also shown, sensibiliser a number of different tumor cell lines to apoptosis induced near Pro-apoptotic drugs (Arnt et al, J. Biol. Chem., 2002, 277(46):44236; Fulda et al, Nature Med., 2002, 8(8):808; Guo et al, Blood, 2002, 99(9):3419; Vucic et al, J. Biol. Chem., 2002, 277(14):12275; Yang et al, Cancer Res., 2003, 63(4):831).

IAP melanoma (ML-IAP) IAP is a not detectable in most normal Mature tissues, but also showing high activity in melanoma (Vucic et al., (2000) Current Bio 10:1359-1366). Determination of protein structure proved significant homology domain of ML-IAP BIR and RING “finger” motif with the appropriate domains present in human XIAP, C-IAP1 and C-IAP2. BIR domain of ML-IAP, apparently, has the greatest similarity with the BIR2 and BIR3 XIAP, C-IAP1 and C-IAP2, and, apparently, responsible for the inhibition of apoptosis, as determined deletion analysis. In addition, Vucic et al., showed that ML-IAP can inhibit apoptosis induced by chemotherapeutic agent. Tools such as adriamycin and 4-tert-butylphenol (4-TBP), were tested in the cell culture system of melanomas sverkhekspressiya ML-IAP, and chemotherapeutic agents was significantly less effective in killing cells compared with control normal melanocytes. The mechanism by which ML-IAP produces anti-apoptotic activity, is associated, in part, by inhibition of caspase 3 and 9. ML-IAP does not effectively inhibits caspase 1, 2, 6, or 8.

Because apoptosis is strictly controlled by many interacting factors, about Eugenie, that IAP govern themselves was not unusual. The fruit fly Drosophila, Reaper (rpr), Head Involution Defective (hid), and GRIM proteins physically interact with and inhibit anti-apoptotic activity of Drosophila IAP family. The mammalian proteins SMAC/DIABLO act by blocking IAP, and thereby give the possibility of leaking apoptosis. It was shown that during normal apoptosis, SMAC is converted to the active form and is released from the mitochondria into the cytoplasm, where it is physically associated with the IAP and prevents linking IAP with caspase. This inhibition of IAP allows the caspase to remain active and, therefore, makes possible the occurrence of apoptosis. Interestingly, homology of sequences between IAP inhibitors shows that there is a motif of four amino acids at the N-end protestirovannyx, active proteins. This tetrapeptide, apparently, associated with the hydrophobic “pocket” in the BIR domain and disrupts the binding of the BIR domain with caspase (Chai et al., (2000) Nature 406:855-862, Liu et al., (2000) Nature 408:1004-1008, Wu et al., (2000) Nature 408 1008-1012).

A brief statement of the substance of the invention

In one aspect of the present invention offers new inhibitors of IAP proteins having the General formula

U1-M-U2

where U1and U2have General formula (I)

where

X1and X2are each, independently researched the Simo O or S;

R2represents alkyl, carbocycle, carbocyclic, heterocycle or geterotsiklicheskikh, each of which is optionally substituted with halogen, hydroxyl, oxo, tion, mercapto, carboxyla, alkyl, halogenation, alkoxy, alkylthio, sulfonyl, amino and nitro;

R3represents H or alkyl, optionally substituted with halogen or hydroxyl; or R3and R4together form a 3-6-membered heterocycle;

R3' represents H, or R3and R3' together form a 3-6-membered carbocycle;

R4and R4' are independently H, hydroxyl, amino, alkyl, carbocycle, carbocyclic, carbocyclic, carbocyclization, heterocycle, heteroseksualci, heterocyclizations or geterotsiklicheskikh; where each alkyl, carbocyclic, carbocyclic, carbocyclization, heterocycle, heteroseksualci, heterocyclizations and geterotsiklicheskikh optionally substituted with halogen, hydroxyl, mercapto, carboxyla, alkyl, alkoxy, amino, imino, and nitro; or R4and R4' together form a heterocycle;

R5represents H or alkyl;

G is selected from the group consisting of IVa-IVe

where R1p is ecstasy a H, OH or alkyl; or R1and R2together form a (5-8)-membered heterocycle;

R5' represents H or alkyl;

R6and R6' are each independently H, alkyl, aryl or aralkyl;

R7represents in each case independently H, cyano, hydroxyl, mercapto, halogen, nitro, carboxyl, amidino, guanidino, alkyl, carbocycle, a heterocycle, or-U-V; where U represents-O-, -S-, -S(O)-, S(O)2, -N(R8)-, -C(O)-, -C(O)-NR8-, -NR8-C(O)-, -SO2-NR8-, -NR8-SO2, -NR8-C(O)-NR8-, -NR8-C(NH)-NR8-, -NR8-C(NH)-, -C(O)-O - or-O-C(O)- and V represents alkyl, carbocycle or heterocycle; and where one or more CH2or CH groups of an alkyl optionally replaced by-O-, -S-, -S(O)-, S(O)2, -N(R8)-, -C(O)-, -C(O)-NR8-, -NR8-C(O)-, -SO2-NR8-, -NR8-SO2-, -NR8-C(O)-NR8-, -C(O)-O - or-O-C(O)-; and alkyl, carbocycle and heterocycle optionally substituted by hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyla, acyl, halogen-substituted alkyl, amino, cyano, nitro, amidino, guanidino, optionally substituted carbocycle or optionally substituted heterocycle;

R9' is a Q1or Q2;

And1represents a 5-membered heterocycle containing 1 to 4 heteroatoms, optionally substituted by the first amino, by hydroxyl, mercapto, halogen, carboxyla, amidino, guanidino, alkyl, alkoxy, aryl, aryloxy, acyl, acyloxy, acylamino, alkoxycarbonyl, cycloalkyl, alkylthio, alkylsulfonyl, alkylsulfonyl, aminosulfonyl, alkylaminocarbonyl, alkylsulfonate or heterocycle; where each alkyl, alkoxy, aryl, aryloxy, acyl, acyloxy, acylamino, cycloalkyl and heterocyclic Deputy optionally substituted by hydroxyl, halogen, mercapto, carboxyla, alkyl, alkoxy, halogenation, amino, nitro, cyano, cycloalkyl, aryl or heterocycle;

And2represents a 5-membered aromatic heterocycle containing 1 to 4 heteroatoms N, O or S and optionally substituted by one or more R7and R8groups;

L is a bond, -C(X3)-, -C(X3)NR12or-C(X3)O-, where X3represents O or S and R12represents H or R1;

Q1and Q2are independently H, alkyl, carbocycle, heterocycle; where one or more CH2or CH groups of an alkyl optionally replaced by-O-, -S-, -S(O)-, S(O)2, -N(R8)-, -C(O)-, -C(O)-NR8-, -NR8-C(O)-, -SO2-NR8-, -NR8-SO2-, -NR8-C(O)-NR8-, -NR8-C(NH)-NR8-, -NR8-C(NH)-, -C(O)-O - or-O-C(O)-; and where any of the above is of Lila, carbocycle and heterocycle is optionally substituted by one or more hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyla, acyl, halogen-substituted alkyl, amino, cyano, nitro, amidino, guanidino, optionally substituted carbocycle or optionally substituted heterocycle.

X3represents O or S;

Y represents a bond, (CR7R7)n', O, or S; where n' is 1 or 2 and R7represents H, halogen, alkyl, aryl, aralkyl, amino, arylamino, alkylamino, aralkylamines, alkoxy, aryloxy or aralkylated;

Z1represents NR8, O, S, SO or SO2;

Z2, Z3and Z4represent independently CQ2or N; and

M represents a linking group covalently linking U1and U2; and

n, in each instance, is independently 0-4.

In another aspect of this invention provides compositions containing the compounds of formula (I) and a carrier, diluent or excipient.

In another aspect of the present invention, it is proposed a method of inducing apoptosis in a cell comprising introducing into the above cell, the compounds of formula I.

In another aspect of the present invention, it is proposed a method of increasing the sensitivity of cells to apoptotic signals, including the introduction of Visayas is nnow cell of the compounds of formula I.

In another aspect of this invention proposes a method of inhibiting IAP binding protein with protein caspase, comprising contacting the specified IAP protein with a compound of formula I.

In another aspect of the present invention, it is proposed a method of treatment of a disease or condition associated with overexpression of IAP protein in a mammal, comprising an introduction to the specified mammal an effective amount of the compounds of formula I.

A detailed description of the preferred embodiments

"Acyl" means containing carbonyl Deputy represented by the formula-C(O)-R in which R represents H, alkyl, carbocycle, heterocycle, substituted carbocycle alkyl or substituted heterocycle alkyl, where alkyl, alkoxy, carbocycle and a heterocycle such as defined in the present description. Acyl groups include alkanoyl (for example, acetyl), aroyl (e.g., benzoyl) and heteroaryl.

"Alkyl" means a straight or branched, saturated or unsaturated (i.e., alkenyl, quinil) aliphatic hydrocarbon group containing up to 12 carbon atoms, unless otherwise stated. When used as part of another term, such as "alkylamino", the alkyl part may be a saturated hydrocarbon chain, however, also includes unsaturated hydrocarbon chains, such as "alkenylamine and alkynylamino. Examples of specific alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, ISO-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, n-heptyl, 3-heptyl, 2-etylhexyl, etc. the Terms "lower alkyl", "C1-C4alkyl and the alkyl with 1 to 4 carbon atoms" are synonymous and use them interchangeably, denoting methyl, ethyl, 1-propyl, isopropyl, cyclopropyl, 1-butyl, sec-butyl or tert-butyl. Unless otherwise specified, substituted alkyl groups may contain one, two, three or four deputies, which may be the same or different from each other. Examples of substituents are, unless otherwise agreed, halogen, amino, hydroxyl, protected hydroxyl, mercapto, carboxy, alkoxy, nitro, cyano, amidino, guanidine, urea, sulfonyl, sulfinil, aminosulfonyl, alkylsulfonyl, arylsulfonyl, aminocarbonyl, acylamino, alkoxy, acyl, acyloxy, carbocycle, a heterocycle. Examples of the above substituted alkyl groups include, but are not limited to; cyanomethyl, nitro methyl, hydroxymethyl, trisiloxanes, propionylacetate, aminomethyl, carboxymethyl, carboxyethyl, carboxypropyl, allyloxycarbonyl, allyloxycarbonyl, carbamoyloxymethyl, methoxymethyl, ethoxymethyl, tert-b is taximeter, acetoxymethyl, chloromethyl, methyl bromide, iodomethyl, trifluoromethyl, 6-hydroxyhexyl, 2,4-dichloro(n-butyl), 2-amino(ISO-propyl), 2-carbamoyloximes etc. Alkyl group may be substituted carbocyclic group. Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl group, as well as relevant-ethyl, -sawn, -butylene, -Pintilie, -hexylene group, etc. Substituted alkali include substituted mately, for example, a methyl group substituted by the same substituents as the "substituted Cn-Cmalkyl" group. Examples of substituted methyl group include groups such as hydroxymethyl, protected hydroxymethyl (for example, tetrahydropyranyloxy), acetoxymethyl, carbamoyloxymethyl, trifluoromethyl, chloromethyl, carboxymethyl, methyl bromide and iodomethyl.

"Amidon" means the group-C(NH)-other, in which R represents H, alkyl, carbocycle, heterocycle, substituted carbocycle alkyl or substituted heterocycle alkyl, and the alkyl, alkoxy, carbocycle and a heterocycle such as defined in the present description. Specific amidin represents a group-NH-C(NH)-NH2.

"Amino" means a primary (i.e.- NH2), secondary (i.e.- NRH) and tertiary (i.e.- NRR) amines in which R represents H, alkyl, carbocycle, heterocycle, salmenkaita alkyl or substituted heterocycle alkyl, and these alkyl, alkoxy, carbocycle and a heterocycle such as defined in the present description. Specific secondary and tertiary amines are alkylamine, dialkylamino, arylamino, diarylamino, aralkylamines and dialkylamino, in which alkyl such as defined in this context, and is optionally substituted. Specific secondary and tertiary amines are methylamine, ethylamine, Propylamine, Isopropylamine, phenylamine, benzylamine, dimethylamine, diethylamine, dipropylamine and Diisopropylamine.

Used in this context, the term "amino protective group" refers to a derivative groups, usually used to block or protect the amino group at the time when the reaction is carried out on other functional groups (of the same) connection. Examples of such protective groups include carbamates, amides, alkyl and aryl groups, imine, as well as many compounds representing derivatives of N-heteroatoms, which can be removed with regenerierung the desired amino group. Specific aminosidine groups are Boc, Fmoc and Cbz. Further examples of these groups are presented in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 2nd ed., John Wiley & Sons, Inc., New York, NY, 1991, chapter 7; E. Haslam, "Protective Groups in Organic Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, NY, 1973, Chapter 5, and T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, NY, 181. The term "protected amino" refers to amino groups, substituted one of the above aminosidine groups.

"Aryl", when used separately or as part of another term, means a carbocyclic aromatic group, regardless of whether it is condensed or not, containing a number of carbon atoms, which can be marked or not marked, up to 14 carbon atoms. Particular aryl groups are phenyl, naphthyl, biphenyl, phenanthrene, naphthacene, and the like (see, for example, Lang''s Handbook of Chemistry (Dean, J. A., ed) 13th ed. Table 7-2 [1985]). Specific aryl represents phenyl. Substituted phenyl or substituted aryl means a phenyl group or aryl group, substituted by one, two, three, four, or five, for example, 1-2, 1-3 or 1-4 substituents, selected, unless otherwise noted, from halogen (F, Cl, Br, I), hydroxy, protected hydroxy, cyano, nitro, alkyl (for example, C1-C6alkyl), alkoxy (for example, C1-C6alkoxy), benzyloxy, carboxy, protected carboxy, carboxymethyl protected carboxymethyl, hydroxymethyl protected hydroxymethyl, aminomethyl protected aminomethyl, trifloromethyl, alkylsulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfonyl, heterozygosities, heterozygosities is valkila, heterocyclyl, aryl or certain other groups. One or more marinovich (CH) and/or methylene (CH2) groups in these substituents can be in turn substituted by a group similar to the groups identified above. Examples of the term "substituted phenyl" include, but are not limited to, mono - or di(halo)phenyl group such as 2-chlorophenyl, 2-bromophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-forfinal, 2-forfinal and the like; mono - or di(hydroxy)phenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives and the like; nitrophenyl group, such as 3 - or 4-nitrophenyl; cyanophenyl group, for example, 4-cyanophenyl; mono - or di(lower alkyl)phenyl group such as 4-were, 2,4-dimetilfenil, 2-were, 4-(ISO-propyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl and the like; mono - or di(alkoxy)phenyl group, for example, 3,4-acid, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4-(1-chloromethyl)benzyloxyphenyl, 3-ethoxyphenyl, 4-(isopropoxy)phenyl, 4-(tert-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 3 - or 4-triptoreline; mono - or dicarboxyphenoxy or (protected carboxy)phenyl group such as 4-carboxyphenyl; mono - or di(hydroxymethyl)phenyl or (protected hydroxym the Teal)phenyl group, such as 3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; a mono - or di(aminomethyl)phenyl or (protected aminomethyl)phenyl group such as 2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or mono - or di(N-(methylsulfonylamino))phenyl group, such as 3-(N-methylsulfonylamino))phenyl. In addition, the term "substituted phenyl" includes disubstituted phenyl groups where the substituents are different from each other, for example, 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl, and the like, as well as tizamidine phenyl groups where the substituents are different, for example, 3-methoxy-4-benzyloxy-6-methylsulfonylamino, 3-methoxy-4-benzyloxy-6-phenylcarbonylamino, and Tetra-substituted phenyl group where the substituents are different from each other, such as 3-methoxy-4-benzyloxy-5-methyl-6-phenylcarbonylamino. Specific substituted phenyl groups include 2-chloraniline, 2-aminoaniline, 2-bromfeild, 3-metoksifenilny, 3-ethoxyphenyl, 4-benzyloxyphenyl, 4-metoksifenilny, 3 ethoxy-4-benzyloxyphenyl, 3,4-diethoxyaniline, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4-(1-chloromethyl)benzyloxyphenyl, 3-methoxy-4-(1-chloromethyl)benzyloxy-6-methylsulfonylamino the performance communications group. Condensed cyclic aryl system can be any substituted, for example, 1, 2 or 3, of the substituents defined in this context in the same way as for substituted alkyl groups.

"Carbocyclic", "carbocyclic", "carbocycle" and "carbocycle", separately and when used as part of a complex (composite) group, such as carballeira group, refers to mono-, bi-, or tricyclic aliphatic structure containing from 3 to 14 carbon atoms, for example, from 3 to 7 carbon atoms which may be saturated or unsaturated, aromatic or non-aromatic. Specific saturated carbocyclic groups are cyclopropyl, cyclobutyl, cyclopentyl and tsiklogeksilnogo group. Specific saturated carbocycle is cyclopropyl. Other specific saturated carbocycle is cyclohexyl. Specific unsaturated carbocycle are, for example, the previously defined aryl group such as phenyl. The terms "substituted carbocycle", "(substituted) carbonyl and(substituted) carbocycle" means these (same) groups, substituted by the same substituents as (definitions) "substituted alkyl" group.

Used herein, the term "carboxy-protective group" refers to one of the ester derivatives of the carboxylic group is islote, usually used to block or protect the carboxylic acid group at the time when the reaction is carried out on other functional groups of the compounds. Examples of such protective groups for carboxylic acids include 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethylbenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzyl, 2,2',4,4'-tetramethoxybenzene, alkyl, such as tert-butyl or tert-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, tert-butyldimethylsilyl, phenacyl, 2,2,2-trichlorethyl, beta-(trimethylsilyl)ethyl, β-(di(n-butyl)methylsilyl)ethyl, p-toluensulfonate, 4-nitrobenzenesulfonate, allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-1-EN-3-yl, and similar parts. Choosing varieties used carboxy-protective groups is not critical provided that the carboxylic acid derivative is stable in the conditions of post(s) reaction(s) on other positions (groups) molecules and that this protective group can be removed at the appropriate time without destroying the remainder of the molecule. In particular, it is important to carboxy-protected molecule are not exposed to strong nucleophilic bases, such as lithium hydroxide or NaOH, or damage to the Oia reducing conditions using a highly active metal hydrides, such as LiAlH4. (You should also avoid harsh environment and when carrying out reactions removal aminosidine groups and hydroxy-protective group, discussed below). Specific protective group of carboxylic acid are alkyl (e.g. methyl, ethyl, tert-boutelou), allyl, benzyl and p-nitroaniline group. Similar carboxy-protective group used in the cephalosporin, penicillin and peptide, can also be used to protect deputies carboxy group. Further examples of these groups are present in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 2nd ed., John Wiley & Sons, Inc., New York, N.Y., 1991, chapter 5; E. Haslam, "Protective Groups in Organic Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, NY, 1981, Chapter 5. The term "protected carboxy" refers to a carboxy group is substituted by one of the above carboxy-protective group.

"Connections" include their salts and solvate (e.g. hydrate).

"Guanidine" refers to the group-NH-C(NH)-other, in which R represents H, alkyl, carbocycle, heterocycle, substituted carbocycle alkyl or substituted heterocycle alkyl, where alkyl, alkoxy, carbocycle and a heterocycle such as is defined in this context. Specific guanidine is a group-NH-C(NH)-NH2.

Used herein, the term "hydroxy-protective g is the unitary enterprise" applies to the derived hydroxy group, usually used to block or protect the hydroxy group at the time when the reaction is performed with the participation of other functional groups on the same connection. Examples of such protective groups include tetrahydropyranyloxy, benzoyl, acetoxy, carbamoylated, benzyl, silyloxy (e.g., TBS, TBDPS) group. Further examples of these groups are present in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 2nd ed., John Wiley & Sons, Inc., New York, NY, 1991, chapters 2-3; E. Haslam, "Protective Groups in Organic Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, NY, 1973, Chapter 5, and T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, NY, 1981. The term "protected hydroxy" refers to a hydroxy group is substituted by one of the above hydroxy-protective groups.

The terms "heterocyclic group", "heterocyclic", "heterocycle", "heterocyclyl", or "heterocycle", separately and when used as part of a complex group such as heterocytolysine group, are used interchangeably and refer to any mono-, bi - or tricyclic, saturated or unsaturated, aromatic (heteroaryl) or non-aromatic cyclic structure containing a certain number of marked atoms, usually from about 5 to about 14 cyclic atoms, and these cyclic atoms are carbon and at least one heteroatom (nitrogen, sulfur or oxygen), for example, from 1 to 4 heteroatoms. Typically, 5-h of the n cycle is from 0 to 2 double bonds and the 6 - or 7-membered cycle is from 0 to 3 double bonds and heteroatoms of nitrogen or sulfur may be optionally oxidized in the form (for example, SO, SO2), and any nitrogen heteroatom may be optionally quaternity. Specific non-aromatic heterocycles are morpholinyl (morpholino), pyrrolidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 2,3-dihydrofuran, 2H-pyranyl, tetrahydropyranyl, thiiranes, titanyl, tetrahydrofuranyl, aziridinyl, azetidine, 1-methyl-2-pyrrolyl, piperazinil and piperidinyl. "Heterocytolysine" group represents videopreteen heterocyclic group, covalently linked to an alkyl group, as defined above. Specific 5-membered heterocycles containing oxygen atom or sulfur and from one to three nitrogen atoms, are thiazolyl, in particular thiazol-2-yl and N-oxide thiazol-2-yl, thiadiazolyl, in particular 1,3,4-thiadiazole-5-yl and 1,2,4-thiadiazole-5-yl, oxazolyl, for example, oxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl and 1,2,4-oxadiazol-5-yl. Specific 5-membered heterocycles containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as 1,3,4-triazole-5-yl; 1,2,3-triazole-5-yl, 1,2,4-triazole-5-yl, and tetrazolyl, such as 1H-tetrazol-5-yl. Specific benzo-condensed 5-membered heterocyclic structure are benzoxazol-2-yl, benzothiazol-2-yl and benzimidazole-2-yl. The particular 6-membered heterocycles containing one to three nitrogen atoms and obazatelno a sulfur atom or oxygen, for example, pyridyl, such as pyrid-2-yl, pyrid-3-yl and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as 1,3,4-triazine-2-yl and 1,3,5-triazine-4-yl; pyridazinyl, in particular, pyridazin-3-yl, and pyrazinyl. Specific group are N-oxides of pyridine and N-oxides pyridazine and pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and 1,3,4-triazine-2-ilen group. The substituents for "optionally substituted heterocycle", and additional examples of 5 - and 6-membered cyclic systems, discussed above, can be found in W. Druckheimer et al., U.S. patent 4278793. In a specific embodiment, such optionally substituted heterocyclic groups are substituted with hydroxyl, alkyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyla, acyl, halogen-substituted alkyl, amino, cyano, nitro, amidino and guanidino.

"Heteroaryl" separately and when used as part of a complex group, such as heteroalkyl group, refers to any mono-, bi - or tricyclic aromatic structure containing the indicated number of atoms, where at least one cycle represents a 5-, 6 - or 7-membered cycle which may contain one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and in a particular embodiment, at least one heteroatom is a nitrogen (Lang''s Handbook of Chemistry, above). In question is the definition includes any bicyclic group, where any of the above heteroaryl cycles condensed with a benzene ring. Specific heteroaryl contain heteroatom nitrogen or oxygen. The following cyclic structures are examples of heteroaryl (regardless of whether they are substituted or unsubstituted) groups denoted by the term "heteroaryl": thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, tetrazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, oxazinyl, triazinyl, thiadiazolyl, oxadiazolyl, detainer, dioxazines, oxathiazine, tetrazines, tetrazines, oxathiazine, datadesigner, imidazolines, dihydropyrimidin, tetrahydropyrimidin, tetrazolo[1,5-b]pyridazinyl and purines, as well as benzo-condensed derivatives, for example, benzoxazolyl, benzofuran, benzothiazole, benzothiadiazole, benzotriazole, benzimidazolyl and indolyl. Specific "heteroaryl" is a 1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl, sodium salt 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl, 1,2,4-thiadiazole-5-yl, 3-methyl-1,2,4-thiadiazole-5-yl, 1,3,4-triazole-5-yl, 2-methyl-1,3,4-triazole-5-yl, 2-hydroxy-1,3,4-triazole-5-yl sodium salt of 2-carboxy-4-methyl-1,3,4-triazole-5-yl, 2-carboxy-4-methyl-1,3,4-triazole-5-yl, 1,3-oxazol-2-and is, 1,3,4-oxadiazol-5-yl, 2-methyl-1,3,4-oxadiazol-5-yl, 2-(hydroxymethyl)-1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazole-5-yl, 2-thiol-1,3,4-thiadiazole-5-yl, 2-(methylthio)-1,3,4-thiadiazole-5-yl, 2-amino-1,3,4-thiadiazole-5-yl, 1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, 1-(1-(dimethylamino)ETH-2-yl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl, sodium salt of 1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(methylsulfonyl acid)-1H-tetrazol-5-yl, sodium salt of 1-(methylsulfonyl acid)-1H-tetrazol-5-yl, 2-methyl-1H-tetrazol-5-yl, 1,2,3-triazole-5-yl, 1-methyl-1,2,3-triazole-5-yl, 2-methyl-1,2,3-triazole-5-yl, 4-methyl-1,2,3-triazole-5-yl, N-oxide of pyrid-2-yl, 6-methoxy-2-(n-oxide)peridas-3-yl, 6-hydroxypyridine-3-yl, 1-methylpiperid-2-yl, 1-methylpiperid-4-yl, 2-hydroxypyrene-4-yl, 1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-astrazen-3-yl, 1,4,5,6-tetrahydro-4-(formylmethyl)-5,6-dioxo-astrazen-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-astrazen-3-yl, sodium salt of 2,5-dihydro-5-oxo-6-hydroxy-astrazen-3-yl, sodium salt of 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-astrazen-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-astrazen-3-yl, 2,5-dihydro-5-oxo-6-methoxy-2-methyl-astrazen-3-yl, 2,5-dihydro-5-oxo-astrazen-3-yl, 2,5-dihydro-5-oxo-2-methyl-astrazen-3-yl, 2,5-dihydro-5-oxo-2,6-dimethyl-astrazen-3-yl, tetrazolo[1,5-b]pyridazin-6-yl and 8-aminotetrazole[1,5-b]pyridazin-6-yl. An alternative group of "heteroaryl includes: 4-(carboxymethyl)-5-methyl-1,3-thiazol-yl, sodium salt of 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl, 1,3,4-triazole-5-yl, 2-methyl-1,3,4-triazole-5-yl, 1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, 1-(1-(dimethylamino)ETH-2-yl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl, sodium salt 1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(methylsulfonyl acid)-1H-tetrazol-5-yl, sodium salt of 1-(methylsulfonyl acid)-1H-tetrazol-5-yl, 1,2,3-triazole-5-yl, 1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-astrazen-3-yl, 1,4,5,6-tetrahydro-4-(2-formylmethyl)-5,6-dioxo-astrazen-3-yl, sodium salt of 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-astrazen-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-astrazen-3-yl, tetrazolo[1,5-b]pyridazin-6-yl and 8-aminotetrazole[1,5-b]pyridazin-6-yl. Heteroaryl groups are optionally substituted as described for compounds.

"Inhibitor" means a compound that reduces or prevents the binding of IAP proteins to proteins caspase, or which reduces or prevents the inhibition of apoptosis protein IAP. Alternatively, the "inhibitor" means a compound that prevents the binding interaction of X-IAP with caspase or binding interaction of ML-IAP with SMAC.

"Optionally substituted", unless otherwise stated, means that the group can be unsubstituted or substituted by one or more (e.g., 0, 1, 2, 3, or 4) substituents listed for the group in question, the mum mentioned substituents may be the same or different from each other. In a separate embodiment, optionally substituted group has 1 Deputy. In another embodiment, the optionally substituted group has 2 Deputy. In another embodiment, the optionally substituted group has 3 Deputy.

"Pharmaceutically acceptable salts" include both additive salt of the acid and salt additive base. "Pharmaceutically acceptable additive acid salt" refers to salts that retain the biological effectiveness and properties of the free bases and which are neither biologically nor with any other terms are not junk, and these salts can be formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc. and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, alifaticheskih, heterocyclic, carboxylic and sulfonic classes of organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, as erbenova acid, glutamic acid, Anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, albanova acid, phenylacetic acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate acid, salicylic acid, etc.

"Pharmaceutically acceptable salt additive bases include salts derived from inorganic bases, such as salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Specific additive salts of the bases are ammonium salts of potassium, sodium, calcium and magnesium. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins, such as Isopropylamine, trimethylamine, diethylamine, triethylamine, Tripropylamine, ethanolamine, 2-Diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, geranamine, choline, betaine, Ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polianinova resin and the like, In particular, organic non-toxic bases are Isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline and FEIN.

"Sulfonyl" means-SO2-R group in which R represents H, alkyl, carbocycle, heterocycle, substituted carbocycle alkyl or substituted heterocycle alkyl, where alkyl, alkoxy, carbocycle and heterocycle are as defined in the present description. Specific sulfonylurea groups represent alkylsulfonyl (i.e.- SO2-alkyl), for example, methylsulphonyl; arylsulfonyl, for example, phenylsulfonyl; aralkylamines, for example, bansilalpet.

The present invention provides new compounds having the General formula

U1-M-U2

where M represents a linking group covalently linking U1and U2.

U1and U2have General formula (I)

M represents a linking group covalently linking U1and U2. In a specific embodiment, M is a linking group covalently linking R2, R3, R4, R5or G from U1with R2, R3, R4, R5or G from U2. In a specific embodiment, M covalently connects G from U1with G from U2. In a specific embodiment, M is a linking group covalently linking R2from U1with R2from U2.

In a specific embodiment, M is alkylene not necessarily replaced by the th-alkyl and hydroxyl, and in which one or more nonadjacent methylene groups are optionally replaced by-O - or-NH-. In a specific embodiment, the specified alkylen is unsaturated or partially unsaturated. In a specific embodiment, M represents-CH2-[C≡C]0-4-CH2-. In a specific embodiment, M represents-CH2-C≡C-CH2-.

In a specific embodiment, M is -(CR10R11)1-14-, where R10and R11are independently alkyl or hydroxyl. In a specific embodiment, R10and R11both represent methyl. In a specific embodiment, one of R10and R11represent hydroxyl. In a specific embodiment, M represents -(CH2)1-6-(CHOH)-(CH2)1-6-. In a specific embodiment, M represents -(CH2)1-6-(C(CH3)2)-(CH2)1-6-. In a specific embodiment, M represents -(CH2)1-14for example, -(CH2)2-12-, -(CH2)4-8-, -(CH2)4-6-, -(CH2)1-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)9-, -(CH2)10-, -(CH2)11- and -(CH2)12-.

In a specific embodiment, M represents -(CH2)q[(CH2)r-O-]s-(CH2) twhere q is 1 or 2, r is 1 to 4, s is 0-8 and t is 1-4. In a specific embodiment, M represents -(CH2)1-4-[O-(CH2)1-4]1-8-(CH2)0-4-. In a specific embodiment, M represents -(CH2)3-[O-(CH2)2]3-CH2-. In a specific embodiment, M represents -(CH2)2-[O-(CH2)2]2. In a specific embodiment, M represents -(CH2)1-4-[NH-(CH2)1-4]1-8-(CH2)0-4-. In a specific embodiment, M represents -(CH2)3-[NH-(CH2)2]-CH2-.

G is selected from the group consisting of IVa-IVe:

and A1, A2, L, Q1, Q2X3, Y, Z1, Z2, Z3, Z4, R1, R5', R6, R6', R7, R7', R9' and n such as the one described in this context. In a specific embodiment, G is an IVa. In a specific embodiment, G is an IVb. In a specific embodiment, G is an IVc. In a specific embodiment, G is an IVd. In a specific embodiment, G is a IVe.

A1represents a 5-membered heterocycle containing 1 to 4 heteroatoms, optionally substituted amino, hydroxyl is m, mercapto, halogen, carboxyla, amidino, guanidino, alkyl, alkoxy, aryl, aryloxy, acyl, acyloxy, acylamino, alkoxycarbonyl, cycloalkyl, alkylthio, alkylsulfonyl, alkylsulfonyl, aminosulfonyl, alkylaminocarbonyl, alkylsulfonate or heterocycle; where each alkyl, alkoxy, aryl, aryloxy, acyl, acyloxy, acylamino, cycloalkyl and heterocyclic Deputy is optionally substituted by hydroxyl, halogen, mercapto, carboxyla, alkyl, alkoxy, halogenation, amino, nitro, cyano, cycloalkyl, aryl or heterocycle. In one embodiment, the 5-membered heterocyclic group, A1are optionally substituted amino, hydroxyl, mercapto, halogen, carboxyla, amidino, guanidino, alkyl, alkoxy, aryl, aryloxy, acyl, acyloxy, acylamino, cycloalkyl or heterocycle; where each alkyl, alkoxy, aryl, aryloxy, acyl, acyloxy, acylamino, cycloalkyl and heterocyclic Deputy optionally substituted by hydroxyl, halogen, mercapto, carboxyla, alkyl, halogenation, amino, nitro, cycloalkyl, aryl or heterocycle. In a specific embodiment, A cycle1is aromatic. In a specific embodiment, A cycle1has the formula IIa or IIb:

where Q'1made the focus of an NR 8, O or S; Q'2, Q'3, Q'4, Q'5, Q'6, Q'7and Q'8are independently CR9or N; where R9represents H, amino, hydroxyl, mercapto, halogen, carboxyl, amidino, guanidino, alkyl, alkoxy, aryl, aryloxy, acyl, acyloxy, acylamino, cycloalkyl or heterocycle; and each alkyl, alkoxy, aryl, aryloxy, acyl, acyloxy, acylamino, cycloalkyl and heterocyclic Deputy, i.e. R9optionally substituted by hydroxyl, halogen, mercapto, carboxyla, alkyl, halogenation, amino, nitro, cycloalkyl, aryl or heterocycle; R8represents H, alkyl, acyl, aryl, cycloalkyl or heterocycle; wherein each alkyl, aryl, cycloalkyl and heterocycle optionally substituted with hydroxyl, halogen, mercapto, carboxyla, alkyl, halogenation, amino, nitro, cycloalkyl, aryl or heterocycle; and Q'9represents CH or N. In a specific embodiment, A cycle1represents a group of formula IIa. In a specific embodiment, the loop A1represents a group of formula IIa, where Q'4represents CR9in which R9represents aryl or heteroaryl, optionally substituted as described above. In a specific embodiment, the loop A1represents a group of formula IIa, where Q'4is Soboh the CR 9R9represents phenyl. In a specific embodiment, A cycle1represents a group of formula IIa, where Q'4represents CR9and R9represents phenyl and Q'3represents CH or CF. In another embodiment, A cycle1represents a group of formula IIa, where Q'4represents CR9and R9represents pyridin-2-yl. In another embodiment, A cycle1represents a group of formula IIa, where Q'4represents CR9, R9represents pyridin-2-yl and Q'3represents the C-Me.

In another embodiment, A cycle1according to the formula IIa or IIb is a pyrrole cycle, optionally substituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocycle or heterocycle-alkyl, optionally substituted with halogen, hydroxyl, mercapto, carboxyla, alkyl, halogenation, amino, nitro, aryl or heteroaryl. In one embodiment, the loop A1substituted aryl or heteroaryl group. In a specific embodiment, A cycle1selected from the group consisting of:

where R8' represents H, alkyl (e.g. methyl, ethyl or propyl) or aryl (e.g., acetyl). In a specific embodiment, R8' represents H.

In another embodiment, A cycle1before the hat is furan, optionally substituted by alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocycle or heterocycle-alkyl, optionally substituted with halogen, hydroxyl, mercapto, carboxyla, alkyl, halogenation, amino, nitro, aryl or heteroaryl. In one embodiment, A cycle1substituted aryl or heteroaryl group. In a specific embodiment, A cycle1selected from the group consisting of:

In another embodiment, A cycle1represents thiophene, optionally substituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocycle or heterocycle-alkyl, optionally substituted with halogen, hydroxyl, mercapto, carboxyla, alkyl, halogenation, amino, nitro, aryl or heteroaryl. In yet another variant, the cycle A1substituted aryl or heteroaryl group. In a specific embodiment, A cycle1selected from the group consisting of:

In another embodiment, A cycle1is a pyrazole, optionally substituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocycle or heterocycle-alkyl, optionally substituted with halogen, hydroxyl, mercapto, carboxyla, alkyl, halogenation, amino, nitro, aryl or heteroaryl. In yet another variant, the cycle A1the two which is substituted aryl or heteroaryl group. In a specific embodiment, A cycle1selected from the group consisting of:

where R8' represents H, alkyl (e.g. methyl, ethyl or propyl) or acyl (e.g. acetyl). In a specific embodiment, R8' represents H.

In another embodiment, A cycle1represents an imidazole, optionally substituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocycle or heterocycle-alkyl, optionally substituted with halogen, hydroxyl, mercapto, carboxyla, alkyl, halogenation, amino, nitro, aryl or heteroaryl. In one embodiment, the loop A1is a substituted aryl or heteroaryl group. In a specific embodiment, A cycle1selected from the group consisting of:

where R8' represents H, alkyl (e.g. methyl, ethyl or propyl) or acyl (e.g. acetyl). In a specific embodiment, R8' represents H.

In another embodiment, a cycle1is oxazole, optionally substituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocycle or heterocycle-alkyl, optionally substituted with halogen, hydroxyl, mercapto, carboxyla, alkyl, halogenation, amino, nitro, aryl or heteroaryl. In one embodiment, A cycle1substituted aryl and the and heteroaryl group. In a specific embodiment, A cycle1selected from the group consisting of:

In another embodiment, the cycle A' represents isoxazol optionally substituted by alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocycle or heterocycle-alkyl, optionally substituted with halogen, hydroxyl, mercapto, carboxyla, alkyl, halogenation, amino, nitro, aryl or heteroaryl. In one embodiment, A cycle1substituted aryl or heteroaryl group. In a specific embodiment, A cycle1selected from the group consisting of:

In another embodiment, A cycle1represents a thiazole, optionally substituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocycle or heterocycle-alkyl, optionally substituted with halogen, hydroxyl, mercapto, carboxyla, alkyl, halogenation, amino, nitro, aryl or heteroaryl. In yet another variant, the cycle A1substituted aryl or heteroaryl group. In a specific embodiment, A cycle1selected from the group consisting of:

In another embodiment, A cycle1represents isothiazol, optionally substituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocycle or heterocycle-alkyl, neobyazatel is substituted with halogen, by hydroxyl, mercapto, carboxyla, alkyl, halogenation, amino, nitro, aryl or heteroaryl. In yet another variant, the cycle A1substituted aryl or heteroaryl group. In a specific embodiment, A cycle1selected from the group consisting of:

In another embodiment, A cycle1represents a 1,2,3-triazole, optionally substituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocycle or heterocycle-alkyl, optionally substituted with halogen, hydroxyl, mercapto, carboxyla, alkyl, halogenation, amino, nitro, aryl or heteroaryl. In yet another variant, the cycle A1substituted aryl or heteroaryl group. In a specific embodiment, A cycle1selected from the group consisting of:

where R8' represents H, alkyl (e.g. methyl, ethyl or propyl) or acyl (e.g. acetyl). In a specific embodiment, R8' represents H.

In another embodiment, a cycle1represents a 1,2,4-triazole, optionally substituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocycle or heterocycle-alkyl, optionally substituted with halogen, hydroxyl, mercapto, carboxyla, alkyl, halogenation, amino, nitro, aryl or heteroaryl. In yet another variant, the cycle A1 substituted aryl or heteroaryl group. In a specific embodiment, A cycle1selected from the group consisting of:

In another embodiment, A cycle1is oxadiazol, optionally substituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocycle or heterocycle-alkyl, optionally substituted with halogen, hydroxyl, mercapto, carboxyla, alkyl, halogenation, amino, nitro, aryl or heteroaryl. In one embodiment, A cycle1substituted aryl or heteroaryl group. In a specific embodiment, A cycle1selected from the group consisting of:

In another embodiment, A cycle1is a thiadiazole, optionally substituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocycle or heterocycle-alkyl, optionally substituted with halogen, hydroxyl, mercapto, carboxyla, alkyl, halogenation, amino, nitro, aryl or heteroaryl. In yet another variant, the cycle A1substituted aryl or heteroaryl group. In a specific embodiment, A cycle1selected from the group consisting of:

In another embodiment, a cycle1is tetrazole, optionally substituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl the sludge, the heterocycle or heterocycle-alkyl, optionally substituted with halogen, hydroxyl, mercapto, carboxyla, alkyl, halogenation, amino, nitro, aryl or heteroaryl. In yet another variant, the cycle A1substituted aryl or heteroaryl group. In a specific embodiment, A cycle1selected from the group consisting of:

In a specific embodiment, A cycle1represents:

In a specific embodiment, the loop A1represents:

A2represents a 5-membered aromatic heterocycle containing 1 to 4 heteroatoms N, O or S that is substituted by a group Q1and optionally additionally substituted by one or more R7(for substitution at the carbon atom of the cycle) and one or more R8(for substitutions under cyclic nitrogen).

In a specific embodiment, the loop A2has a General formula II:

where Z1represents NR8, O or S; and Z2', Z3'and Z4'are each independently N or CR7. Group Q1attached to the loop A2formula II and II' when the member cycle between Z2'and Z3'.In a particular embodiment, Z1'represents S. In a particular embodiment, Z1'represents . In another specific embodiment, Z1'represents NR8'where R8'as defined in this context. In a particular embodiment, Z1'represents NR8where R8represents H. In another specific embodiment, Z1'represents NR8where R8represents Me. In another embodiment, Z1'represents O or S, then Z2'represents N and Z3'represents N or CR7. In a particular embodiment, Z1'represents S, whereas Z2'represents N and Z3'represents CR7. In a particular embodiment, Z1'represents S, whereas Z2'represents N and Z3'represents CH.

In a specific embodiment, A cycle2(shown with Q1) is an aromatic heterocycle selected from the group consisting of IIa1-ICC1:

X1and X2are each independently O or S. In a particular embodiment, X1and X2are both O. In another particular embodiment, X1and X2represent both S. In another specific embodiment, X1represents S, while X21represents O, then X2represents S.

Y represents a bond, (CR7R7)n', O or S. In one embodiment, Y is a bond, (CR7R7)n', O, or S; where n' is 1 or 2 and R7as defined in this context, or represents H, halogen, alkyl, aryl, aralkyl, amino, arylamino, alkylamino, aralkylamines, alkoxy, aryloxy or aralkylated. In a particular embodiment, Y is (CHR7)n', O or S; where n' is 1 or 2 and R7represents H, halogen, alkyl, aryl, aralkyl, amino, arylamino, alkylamino, aralkylamines, alkoxy, aryloxy or aralkylated. In a particular embodiment, Y is CH2. In a specific embodiment, n is 1. In a particular embodiment Y is a bond. In a specific embodiment, n is 1 and Y represents CHR7where R7represents aralkylated, for example, benzyloxy. In a specific embodiment, n is 1 and Y represents CHR7where R7represents F. In a particular embodiment, n is 1 and Y represents CHR7where R7represents aralkylamines, for example, benzylamino. In another specific embodiment, Y is O. In another particular embodiment, Y is S.

Z1represents NR , O, S, SO or SO2; where R8as defined in this context. In one embodiment, Z1represents NR8, O or S. In another embodiment, Z1represents NR8where R8represents H, alkyl, aryl or aralkyl. In a particular embodiment, Z1represents NR8where R8represents benzyl. In a particular embodiment, Z1represents NR8where R8represents Me. In a particular embodiment, Z1represents NR8where R8represents H. In a particular embodiment, Z1represents O. In a particular embodiment, Z1represents S.

Z2, Z3and Z4represent independently CQ2or N. In a particular embodiment, Z2represents N. In a particular embodiment, Z3represents N. In a particular embodiment, Z4represents N. In one embodiment, Z2, Z3and Z4represent CQ2. In yet another variant, Z2represents N, Z3represents CQ2and Z4represents CQ2. In one embodiment, Z2represents CQ2, Z3represents N and Z4represents CQ2. In one embodiment, Z2represents CQ2, Z3represents CQ2and Z 4represents N. In one embodiment, Z2represents N, Z3represents CQ2and Z4represents N.

Q1and Q2are independently H, alkyl, carbocycle, heterocycle; where one or more CH2or CH groups of an alkyl optionally replaced by-O-, -S-, -S(O)-, S(O)2, -N(R8)-, -C(O)-, -C(O)-NR8-, -NR8-C(O)-, -SO2-NR8-, -NR8-SO2-, -NR8-C(O)-NR8-, -NR8-C(NH)-NR8-, -NR8-C(NH)-, -C(O)-O - or-O-C(O)-; and where any of the above alkyl, carbocycle and heterocycle optionally substituted by one or more hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyla, acyl, halogen-substituted alkyl, amino, cyano, nitro, amidino, guanidino, optionally substituted carbocycle or optionally substituted heterocycle. The substituents of "optionally substituted carbocycle" and "optionally substituted heterocycle" such as is defined in this context. In a specific embodiment, such carbocyclic and heterocyclic groups substituted by hydroxyl, alkyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyla, acyl, halogen-substituted alkyl, amino, cyano, nitro, amidino and guanidino. In a particular embodiment, Q1and Q2represent independently carbocycle or heterocycle, optionally C is displaced by halogen, amino, oxo, alkyl, carbocycle or heterocycle; where one or more groups CH2or CH alkyl optionally replaced by-O-, -S-, -S(O)-, S(O)2, -N(R8)-, -C(O)-, -C(O)-NR8-, -NR8-C(O)-, -SO2-NR8-, -NR8-SO2-, -NR8-C(O)-NR8-, -NR8-C(NH)-NR8-, -NR8-C(NH)-, -C(O)-O - or-O-C(O)-; and where the specified alkyl, carbocycle or heterocycle optionally substituted with halogen, amino, hydroxyl, mercapto, carboxyla, alkoxy, alkoxyalkyl, hydroxyalkoxy, alkylthio, acyloxy, aryloxyalkanoic, alkylsulfonyl, alkylsulfonyl, alkylsulfanyl and alkylsulfonates.

In a particular embodiment, Q1and Q2represent independently carbocycle or a heterocycle selected from the group consisting of III-1 to III-16

where n is 1-4, for example, 1-3, for example 1-2, e.g. 1; T represents O, S, NR8or CR7R7; W represents O, NR8or CR7R7; and R7and R8such as defined in the present description.

In a particular embodiment, Q1and Q2represent independently carbocycle or a heterocycle selected from the group consisting of IIIa-IIIs:

where n is 1-4, for example, 1-3, for example 1-2, e.g. 1; T represents O, S, NR8or CR7R7; W represents O, NR8or CR7R7; and R7and R8such as is defined in this context. In a particular embodiment, Q1and Q2represent independently any one of the IIIa-IIIi, where R8represents H and R7selected from the group consisting of H, F, Cl, Me, methoxy, hydroxyethoxy, methoxyethoxy, acetoxidans, methylsulfonyl, methylsulfonylamino, phenyl and morpholine-4-yl. In another specific embodiment, Q1and Q2represent independently IIId. In a particular embodiment, Q1and Q2represent independently IIId, which is substituted in the 4-position R7. In another specific embodiment, Q1and Q2represent independently IIId, which is substituted in the 5-position, R7. In a particular embodiment, Q1and Q2are independently F, Me, iPr, phenyl, phenyl substituted as follows: 2-Cl, 3-Cl, 4-Cl, 2-F, 3-F or 4-F, substituted, benzyl(ω), pyrid-3-yl(ω) or pyrid-4-yl(ω).

R1represents H, OH or alkyl; or R1and R2together form a (5-8)-membered heterocycle. In a specific embodiment, R1represents H. In a particular variation, R1and R2together form a 6-membered cycle. In concr the coherent version R1and R2together form a 7-membered cycle. In another specific embodiment, R1and R2together form 8-membered cycle. In another specific embodiment, R1and R2together form a 7-membered cycle, whereas Y is S. In another specific embodiment, R1represents H, while Y represents CH2. In another specific embodiment, R1represents H, while Y is S. In another specific embodiment, R1represents H, while Y represents O.

R2represents alkyl, carbocycle, carbocyclic, heterocycle or geterotsiklicheskikh; each optionally substituted with halogen, hydroxyl, oxo, tion, mercapto, carboxyla, alkyl, halogenation, alkoxy, alkylthio, acyl, hydroxyacyl, alkoxyaryl, sulfonyl, amino and nitro. In a specific embodiment, R2represents alkyl, carbocycle, carbocyclic, heterocycle or geterotsiklicheskikh; each optionally substituted with halogen, hydroxyl, oxo, tion, mercapto, carboxyla, alkyl, halogenation, alkoxy, alkylthio, acyl, hydroxyacyl, meloxicalm, sulfonyl, amino and nitro. In one embodiment, R2represents alkyl, carbocycle, carbocyclic, heterocycle or geterotsiklicheskikh; each, not necessarily Sames the config halogen, by hydroxyl, mercapto, carboxyla, alkyl, alkoxy, amino and nitro. In a specific embodiment, R2represents alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocycle or geterotsiklicheskikh. In a specific embodiment, R2represents alkyl, cycloalkyl or heterocycle. In a specific embodiment, R2selected from the group consisting of tert-butyl, isopropyl, cyclohexyl, tetrahydropyran-4-yl, N-methylsulfonylmethane-4-yl, tetrahydrothiopyran-4-yl, tetrahydrothiopyran-4-yl (where S is the oxidised form of SO or SO2), cyclohexane-4-it 4-hydroxycyclohexane, 4-hydroxy-4-methylcyclohexane, 1-methyltetrahydrofuran-4-yl, 2-hydroxyprop-2-yl, buta-2-yl, thiophene-3-yl, piperidine-4-yl, N-acetylpiperidine-4-yl, N-hydroxyethylpiperazine-4-yl, N-(2-hydroxyacyl)piperidine-4-yl, N-(2-methoxyacetyl)piperidine-4-yl, pyridine-3-silt, phenyl and 1-hydroxic-1-yl. In one embodiment of this invention R2represents tert-butyl, isopropyl, cyclohexyl, cyclopentyl, phenyl or tetrahydropyran-4-yl. In a specific embodiment, R2represents phenyl. In a specific embodiment, R2represents cyclohexyl. In another embodiment, R2represents tetrahydropyran-4-yl. In another specific embodiment, R2represents isopropyl (i.e. side chain valinovoi and is inability). In another specific embodiment, R2represents tert-butyl. In a specific embodiment, R2is oriented so that the amino acid, or similar amino acids, which(th) it includes, is in the L-configuration.

R3represents H or alkyl, optionally substituted with halogen or hydroxyl; or R3and R4together form a 3-6-membered heterocycle. In one embodiment, R3represents H or alkyl; or R3and R4together form a 3-6-membered heterocycle. In one embodiment, R3represents H or methyl, ethyl, propyl or isopropyl. In a particular embodiment, R3represents H or methyl. In another specific embodiment, R3represents methyl. In another specific embodiment, R3is vermeil. In another specific embodiment, R3represents ethyl. In another specific embodiment, R3represents a hydroxyethyl. In a specific embodiment, R3is vermeil. In a specific embodiment, R3represents a hydroxyethyl. In another embodiment, R3is oriented so that the amino acid, or similar amino acids, which it involves, is in the L-configuration. In a specific embodiment, R3and R4together with atoms on which they depend form a 3-6-membered heterocycle. In concr the coherent version of R 3and R4together form azetidinone cycle. In a specific embodiment, R3and R4together form pyrrolidin.

R3' represents H, or R3and R3' together form a 3-6-membered carbocycle. In one embodiment, R3' represents H. In another embodiment, R3and R3' together form a 3-6-membered carbocycle, for example, cyclopropyl. In a specific embodiment, R3and R3' are both methyl.

R4and R4' are independently H, hydroxyl, amino, alkyl, carbocycle, carbocyclic, carbocyclic, carbocyclization, heterocycle, heteroseksualci, heterocyclizations or geterotsiklicheskikh; where each alkyl, carbocyclic, carbocyclic, carbocyclization, heterocycle, heteroseksualci, heterocyclizations and geterotsiklicheskikh optionally substituted with halogen, hydroxyl, mercapto, carboxyla, alkyl, alkoxy, amino, imino, and nitro; or R4and R4' together form a heterocycle. In one embodiment, R4and R4' are independently H, hydroxyl, amino, alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heteroaryl or heteroaromatic, where each alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heteroaryl and heteroaromatic optionally substituted what alogena, by hydroxyl, mercapto, carboxyla, alkyl, alkoxy, amino and nitro; or R4and R4' together form a heterocycle. In a specific embodiment, R4and R4' together form a heterocycle, for example, azetidinone cycle, or pyrolidine cycle. In a specific embodiment, R4and R4' are both H. In another specific embodiment, R4represents methyl and R4' represents H. In a particular embodiment, one of R4and R4' represents a hydroxyl (OH), while the other represents H. In another embodiment, one of R4and R4' represents amino, such as, for example, NH2, NHMe and NHEt, while the other represents H. In a particular variation, R4' represents H and R4represents H, alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heteroaryl or heteroaromatic. In a specific embodiment, R4represents a group selected from the group consisting of:

R5represents H or alkyl. In a specific embodiment, R5represents H or methyl. In a specific embodiment, R5represents H. In another specific embodiment, R5represents methyl.

R6and R6' are each independently H, alkyl, aryl, aryl or ar is lcil. In a specific embodiment, R6represents alkyl, for example methyl. In another specific embodiment, R6represents aryl, for example phenyl. In another specific embodiment, R6is aralkyl, for example, benzyl. In a specific embodiment, R6and R6' are the same, for example, both alkyl, for example, are both methyl. In another specific embodiment, R6represents methyl and R6' represents H.

R7in each case, represents independently H, cyano, hydroxyl, mercapto, halogen, nitro, carboxyl, amidino, guanidino, alkyl, carbocycle, a heterocycle, or-U-V; where U represents-O-, -S-, -S(O)-, S(O)2, -N(R8)-, -C(O)-, -C(O)-NR8-, -NR8-C(O)-, -SO2-NR8-, -NR8-SO2-, -NR8-C(O)-NR8-, -NR8-C(NH)-NR8-, -NR8-C(NH)-, -C(O)-O - or-O-C(O)- and V represents alkyl, carbocycle or heterocycle; and where one or more groups CH2or CH in the composition of the alkyl optionally replaced by-O-, -S-, -S(O)-, S(O)2, -N(R8)-, -C(O)-, -C(O)-NR8-, -NR8-C(O)-, -SO2-NR8-, -NR8-SO2-, -NR8-C(O)-NR8-, -NR8-C(NH)-NR8-, -NR8-C(NH)-, -C(O)-O - or-O-C(O)-; and each alkyl, carbocycle and heterocycle optionally substituted by hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyla, acyl, halogen-substituted alkyl, AMI is about, cyano, nitro, amidino, guanidino, optionally substituted carbocycle or optionally substituted heterocycle. The substituents of "optionally substituted carbocycle" and "optionally substituted heterocycle" such as is defined in this context. In a specific embodiment, such carbocyclic and heterocyclic groups substituted by hydroxyl, alkyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyla, acyl, halogen-substituted alkyl, amino, cyano, nitro, amidino and guanidino.

In one embodiment, R7represents H, halogen, alkyl, aryl, aralkyl, amino, arylamino, alkylamino, aralkylamines, alkoxy, aryloxy or aralkylated.

R8represents H, alkyl, carbocycle or heterocycle, where one or more groups CH2or CH specified alkyl optionally replaced by-O-, -S-, -S(O)-, S(O)2, -N(R8or-C(O)-; and the alkyl, carbocycle and heterocycle optionally substituted by hydroxyl, alkoxy, acyl, halogen, mercapto, oxo (=O), carboxyla, acyl, halogen-substituted alkyl, amino, cyano nitro, amidino, guanidino, optionally substituted carbocycle or optionally substituted heterocycle. The substituents of "optionally substituted carbocycle" and "optionally substituted heterocycle" such as is defined in this context. In a specific embodiment, such Carbo is ilycheskie and heterocyclic group substituted by hydroxyl, the alkyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyla, acyl, halogen-substituted alkyl, amino, cyano, nitro, amidino and guanidino. In a specific embodiment, R8represents H, alkyl, or acyl. In one embodiment, R8represents methyl. In another embodiment, R8represents acetyl. In a specific embodiment, R8represents H. In one embodiment, R7represents H, halogen, amino, hydroxyl, carboxyl, alkyl, halogenated or aralkyl. In a specific embodiment, R7represents a halogen, for example Cl or F. In a particular embodiment, R7represents H. it is Obvious that the replacement defined for R7and R8and all other variables of the groups in the present description, are in accordance with a valid value.

R9' is a Q1or Q2defined in this context. In one embodiment, R9' represents alkyl, carbocycle, replaced by carbocycle alkyl, a heterocycle or substituted heterocycle alkyl, where each optionally substituted with halogen, hydroxyl, mercapto, carboxyla, alkyl, halogenation, alkoxy, alkylsulfonyl, amino, nitro, aryl or heteroaryl. In a specific embodiment, R9' represents alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heteroaryl or g is terbarukan, where each optionally substituted with halogen, hydroxyl, mercapto, carboxyla, alkyl, halogenation, amino, nitro, aryl and heteroaryl.

n is 1-4. In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3. In one embodiment, n is 4.

The compounds of this invention contain one or more asymmetric carbon atoms. Therefore, the compounds can exist as diastereomers, enantiomers or mixtures thereof. The syntheses of compounds can use the racemates, diastereomers or enantiomers as starting products or as intermediate products. Diastereomeric compounds can be separated by chromatographic methods or crystallization. Similarly, enantiomeric mixtures can be separated using the same or other methods known in this field. Each of the asymmetric carbon atoms may be in the R - or S-configuration, and both of these configurations are not beyond the scope of this invention. In a particular embodiment, the compounds of this invention have the following stereochemical configuration represented by the formula I', in which the monomer has the same stereochemical orientation:

where X1X2, Y, Z1, Z2, Z3, Q, R1, R2, R3 , R3', R4, R4', R5, R6and R6' such as the one described in the present description, and G1and G2represent independently IVa', IVb', IVc', IVd or IVe':

where A1, A2, L, Q1, Q2X3, Y, Z1, Z2, Z3, Z4, R1, R5', R6, R6', R7, R9' and n such as the one described in the present description. In a specific embodiment, G1and G2represent IVa'. In a specific embodiment, G1and G2are IVb'. In a specific embodiment, G1and G2represent IVc'. In a specific embodiment, G1and G2are IVd'. In a specific embodiment, G1and G2are IVe'.

In specific embodiments, G1and G2represent independently II a-II e

where X1X2, Y, Z1, Q, R1, R2, R3, R4, R4', R5, R6and R6' such as the one described in the present description.

In a particular embodiment, the compounds of this invention have the formula V or Va

In a particular embodiment, compounds according to this image the structure have the formula VI or VIa

In a particular embodiment, the compounds of this invention have the formula VII or VIIa

In a particular embodiment, the compounds of this invention have the formula VIII or VIIIa

In a particular embodiment, the compounds of this invention have the formula IX or IXa

In a particular embodiment, the compounds of this invention have the formula X, Xa or Xb

Additionally, this invention encompasses prodrugs of the compounds described above. Suitable prodrugs, in cases where they are applicable, contain a known amino-protective and carboxy-protective group, which hatshepsuts, for example, hydrolyzed, with the receipt of the parent compound under physiological conditions. A specific class of prodrugs is a compound in which the nitrogen atom in the amino, amidino, aminoethylamino, aminoalkylsilane or guanidino group replaced with hydroxy (OH) group, alkylcarboxylic (-CO-R) group, alkoxycarbonyl (-CO-OR), aryloxyalkyl-alkoxycarbonyl (-CO-O-R-O-CO-R group, where R represents a monovalent or divalent the group, defined above, or a group having the formula-C(O)-O-CP1P2-halogenated, where P1 and P2 are the same or different from each other and represent H, lower alkyl, lower alkoxy, cyano, halogen-lower alkyl or aryl. In a particular embodiment, the nitrogen atom is one of the nitrogen atoms amidino-group of compounds according to this invention. These proletarienne connection is produced by interaction of the above compounds according to this invention with an activated acyl compound, linking the nitrogen atom in the compound according to this invention with a carbonyl activated acyl compounds. Suitable activated carbonyl compounds contain an easily removable group associated with the carbon of the carbonyl, and include acylhomoserine, acylamine, arylpyrimidine salt, Allakaket, in particular, allproxy, such as p-nitrophenoxy, dinitrophenoxy, forfinancial and diferencial. Reactions are usually exothermic and is carried out in inert solvents at low temperatures, such as in the range from -78 to about 50°C. furthermore, the reaction is usually carried out in the presence of inorganic bases such as potassium carbonate or bicarbonate, or organic bases, such as amine, including pyridine, triethylamine, etc. One way to get policestation in USSN 08/843369, filed April 15, 1997 (the corresponding international PCT publication WO9846576), the contents of which are incorporated into this description in full by reference.

Specific compounds of formula I include the following:

The compounds of this invention may exist in different resonance forms, and all such resonance forms are included in the scope of this invention.

Syntheses

Compounds according to this invention will be received, using standard methods of organic synthesis from commercially available starting materials and reagents. It should be borne in mind that the synthetic methods used to produce compounds according to this invention, as a rule, depend on the specific type of substituents present in the connection, and that may require different stages of protection and unprotect, which are common in organic synthesis, but which may not be represented on the diagrams below. In the General scheme of synthesis for the preparation of compounds according to this invention will first get a monomer U1and U2 and then condense them using linking group M. Monomers can be obtained by using the typical methods of peptide chemistry by condensation analogues of amino acid residues typical ways amide condensation, which is described in US2005/0261203, US2006/0014700, US2006/0167066 and PCT/US2006/062335, the contents of each of which is included in the present description by reference.

In figure 1, analogues of amino-protected amino acid residues condense and then the resulting product is removed protection with the final products.

Scheme 1

Monomers in which R4or R4' are other than H, can be obtained in accordance with standard methods of organic chemistry, for example, by reductive amination, in which the original analogue amino acid residue, for example, NH2-CH(R3)-C(O)-OH are subjected to interaction with a suitable aldehyde or ketone to produce the desired substituents R4and R4'illustrated in the following diagram. Then the R4/R4' substituted amino acid intermediate product is subjected to conjugation with the following amino acid intermediate product or residue of the connection, using the standard methods of peptide condensation.

Scheme 2

In a specific embodiment, the Ala is put in engagement with the 1-methylindol-2-carboxaldehyde and restore using cyanoborohydride sodium, dissolved in a mixture of 1% HOAc/DMF, obtaining N-substituted alanine residue, which can be used to obtain the compounds according to this invention, as shown in the following diagram.

Scheme 3

Alternatively, the recovery procedure amination to introduce substituents R4/R4' represents the final stage in the connection.

In cases where compounds of this invention contain the substituents R4or R4', other than H, they can also be obtained by substitution of a suitable acid intermediate product, which contains the group that you want, the desired amine. For example, Br-CH(R3)-C(O)-OH replaced with the amine R4-NH2or R4-NH-R4' according to the following scheme.

Scheme 4

Alternatively, the substitution reaction with the introduction of the substituents R4or R4' may be implemented as the final stage in the connection, as shown in the following diagram.

Scheme 5

In a particular embodiment, to obtain the N-substituted residues alanine 2-bromopropionic acid is subjected to interaction with the following amines dissolved in DMF, and bubbled until then, until replacement:

Compounds according to this invention, in which either X1or X2represents sulfur, i.e. the compound contains thioamide, you can get recognized methods of organic chemistry. For example, compounds in which X2represents sulfur, can be derived from Fmoc-protected analogue amino acid residue-NH2-CH(R2)-COOH, which is subjected to interaction with tianyoude reagent, such as reagent Lawesson or P4S10.

The monomers (U1or U2), in which G has the formula IVa, in which L represents-C(X3)-receive the General scheme of synthesis, which may include a stage in which the N-protected 6-amino-azabicyclo-octane group condensed with an activated ester of the desired acid (for example, natalymartynova acid) with subsequent removal of the protection of the cyclic amine and the subsequent or amino acid residues, using a typical method amide condensation.

Scheme 6

N-protected 6-amino-azabicycloalkanes intermediate product can be obtained by the methods described in Caryet al,Tetrahedron Letters, 1989, 30:5547, which is illustrated on the following diagram. In General, activated ester cyclopentadecane acids condense with methylbenzylamino. Methylbenzidine group service is t as aminosidine group for cyclic product to condensation with amino acid residues. The obtained amide restore sociallyengaged obtaining a secondary amine, which is then subjected to interaction with N-bromosuccinimide. The N-bromelin is subjected to cyclization in the presence of catalytic amount of bromide monovalent copper to obtain 6-bromo-substituted azabicycloalkanes. Then the latter is subjected to interaction with ammonium hydroxide, converting 6-bromo group into the corresponding 6-amino cyclic intermediate product, which can then be used for the synthesis of compounds according to this invention.

Scheme 6A

The monomers (U1or U2), in which G has the formula IVb, obtained by linking the amine-substituted cycle with a similar Proline, using conventional methods of amide condensation. Amine-substituted cycle A is commercially available or it is produced using conventional methods of organic chemistry. For example, 1-aryl-5-aminotetrazole, such as phenyl-5-aminotetrazole, can be obtained according to the scheme below from commercially available phenyltoloxamine by interacting with sodium azide and mercury dichloride.

Scheme 7a

3-Aryl-5-amino-1,2,3-triazoles such as 3-phenyl-3H-[1,2,3]triazole-4-ylamine, can be obtained by methods described in J. Org. Chem, 1981, 46:856-9 and illustrated on either sleduyushei scheme, through the cooperation of phenylamine with aminoacetonitrile.

Diagram 7b

Similarly, 5-amino-1-phenyl-1H-[1,2,3]triazole-4-carbonitrile can be obtained by interaction of phenylamine with 2-aminomalononitrile, as illustrated in the following diagram.

Scheme 7C

4-Aryl-5-amino-1,2,5-oxadiazole, such as 4-phenyl-furazan-3-ylamine, can be obtained by the methods described in Lakhan et al, Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry (1987) 26B(7):690-2) and illustrated on the following diagram by the interaction of benzylcyanide with hydroxylamine.

Scheme 7d

4-Aryl-3-amino-1,2,4-triazoles, such as 4-phenyl-4H-[1,2,4]triazole-3-ylamine, can be obtained by interaction of phenylisothiocyanate with hydrazinecarboxamide obtaining 5-amino-4-phenyl-4H-[1,2,4]triazole-3-thiol in which the thiol group can be removed in the presence of a catalyst of Raney Nickel, as illustrated on the following diagram.

Scheme 7E

4-Aryl-5-amino-1,2,3-triazoles, such as 3,5-diphenyl-3H-[1,2,3]triazole-4-ylamine, can be obtained by methods described in J. Org. Chem., 1990, 55:3351-62 and illustrated in the following diagram, by the interaction of benzoylacetonitrile with azidobenzoyl (or alternative trimethylsilylacetamide, TMS-N3).

Scheme 7f

4-Aryl-3-aminopyrazole, such as 4-phenyl-2H-pyrazole-3-ylamine, can be obtained by methods described in the patent EP 269859 and illustrated on the following diagram, through the cooperation of benzoylacetonitrile with tritherapy ether orthomorphisms acid with 3-oxo-2-phenyl-propionitrile, which is subjected to interaction with hydrazine.

Scheme 7g

Various hydrazines and derivatives benzoylacetonitrile can be used to obtain substituted-4-aryl-3-aminopyrazoles, as illustrated by the following schema.

Scheme 7h

1-Aryl-5-aminopyrazole, such as 2-phenyl-2H-pyrazole-3-ylamine, can be obtained by reacting phenylhydrazine with 3-oxopropanenitrile. Various NITRILES can be used for the introduction of a substituent at the 3-position of the cycle of pyrazole, as illustrated on the following diagram.

Scheme 7i

3-Aryl-4-aminoimidazole, such as 3-phenyl-3H-imidazol-4-ylamine, can be obtained by interaction of phenylamine with aminoacetonitrile and triethylamin ether orthomorphisms acid, as illustrated in the following diagram. Deputy in the 2-position of the imidazole can be entered using the analogues teeterboro ether orthomorphisms acid, as follows.

Scheme 7j

5-Aryl-4-aminoimidazole, such as 5-phenyl-3H-imidazol-4-ylamine, can be obtained by interaction of formamidine with aminophenylacetylene, as illustrated on the following diagram. Deputy in the 2-position of the cycle of imidazole can be entered using the analogues of formamidine.

Scheme 7k

4-Aryl-[1,2,3]thiadiazole-5-ylamine, such as 4-phenyl-[1,2,3]thiadiazole-5-ylamine, can be obtained according to the following. 2-Bromo-1-phenylethanone subjected to interaction with phthalimido lithium and product substitution is subjected to interaction with ethyl ether of hydrazinecarboxamide. The obtained ethyl ester of hydrazinecarboxamide subjected to cyclization with the formation of the thiadiazole by reacting thionyl chloride with subsequent removal phthalimide group with hydrazine.

Scheme 7l

The monomers (U1or U2), in which G has the formula IVc, obtained from commercially available reagents using conventional methods of organic chemistry. For example, in cases when the cycle A is a thiazole, an intermediate product can be obtained according to the following scheme:

Scheme 8A

where Q, Y, R1, R6And R6' such, as defined in this context, and Pr represents an amino-protective group. The analog of Proline in to the m alpha nitrogen protected (Pr), for example, using Boc or Cbz, and amitirova, turn to the appropriate thioamide, for example, using a reagent of Lawesson, in accordance with the methods described in Williams et al (J. Org. Chem, 2001, 66:8463). Then thioamide subjected to cyclization with the appropriate bromide with getting thiazole, substituted by a group Q, for example, using the methods described in Ciufolini et al, (J. Org. Chem. 1997, 62:3804). Alternatively, the bromide in the present scheme may contain a functional group that can be used to associate the desired group Q with thiazole obtained in the cyclization stage.

Monomers in which G has the formula IVc in which a cycle is oxazol, the intermediate product can be obtained according to the following schema.

Scheme 8b

where Q, Y, R1, R6and R6' such, as defined in this context, and Pr represents an amino-protective group. The original analog of Proline is subjected to interaction with the appropriate amine using conventional methods of education amide. The obtained amide is subjected to cyclization, for example, using Burgess reagent by methods described in Pihko et al (J. Org. Chem., 1999, 64:652), obtaining dihydrooxazolo. Then dihydrooxazolo restore, getting the desired oxazole substituted by a group of Q. alternatively, the amine of the first stage of the scheme may contain, instead of the Q function with the national group, which can be used directly or indirectly for desirable binding group Q thiazole obtained from the cyclization stage.

The monomers (U1or U2), in which G has the formula IVd, can be obtained by condensation of analogues of amino acid residues using typical methods amide condensation. The following diagram, where Q, Y, Z1, Z2, Z3, Z4, R1, R6and R6' such, as defined in this context, and Pr represents a suitable protective group, amine-protected analogs of amino acid residues condense and then the resulting product is removed protection, receiving end of the connection.

Scheme 9

Alternatively, the monomers, in which G has the formula IVd, can be obtained by condensation of amino acid analogues in any order and can be obtained using solid-phase carrier, which is common in this area. For example, the diagram below illustrates an alternative way of condensation analogues of amino acid residues.

Scheme 9a

Analogs of thiazolidinedione formula IVd, in which Z1represents S, can be obtained according to scheme 3, where Q, Y, Z1, Z2, Z3, Z4, R1, R6and R6'such completeley in this context, and Pr is a suitable protective group.

Scheme 9b

Aminandcondense withbusing conventional methods of education amide, getting amidecthat in turn corresponds thioamidedby interacting with reagent Lawesson. Thioamidedcyclist, for example, in the presence of K3Fe(CN)6in EtOH with gettingefrom which to remove the protection with the desired amino acid analogue thiazolef.

Alternatively, analogs of thiazolidinedione, in which Z1represents S, can be obtained according to the following schema.

Scheme 9c

Chlorine-substituted amineacondensed with the acid chloride acidbobtaining amidewithwhich is subjected to interaction with the reagent Lawesson and heat, receiving cyklinowanie connectiond. Then connectdremove the protection with the desired intermediate product thiazoleeto be used for producing compounds according to this invention.

Analogs of oxazolidinedione formula IVd, in which Z1represents O, can be obtained by the methods described in Wang et al.(Bioorganic & Medicinal Chemistry (2004), 12(1):17-21), as illustrated in the following diagram.

Scheme 9d

Like the previous schemes, the acid chloride acidbcondense with aminesaobtaining amidec. However, amidecrefluxed in a solution of p-toluenesulfonic acid in toluene, gettingdand remove the protective group Pr, getting the desired oxazole.

Alternatively, analogs of oxazolidinedione formula IVd can be obtained by the methods described in Kauffman et al. (Journal of Heterocyclic Chemistry (2002), 39(5), 981-988), illustrated on the following diagram.

Scheme 9F

Acidawith dioxane, thionyl chloride and N-methylpyrrolidinone refluxed in an atmosphere of inert gas and the resulting acid chloride acid condense with hydroxy/aminebgetting amidec. Then it is heated with boric acid in dibutylbarbituric, gettingeand remove the protective group Pr, getting the desired intermediate product oxazolee.

Analogs of imidazolidinedione formula IVd, in which Z1represents NH, can be obtained by the methods described in Kumar et al. (Bioorganic & Medicinal Chemistry 2002, 10(12):3997-4004), as illustrated on the following diagram.

Scheme 9f

The acid chloride acidacondense with nitro/Aminbgetting amidec. The nitrogroup amidecrestore to the corresponding amined for example, iron, and then cyclist by heating with acetic acid to obtaine. The protective group of Preremove, receiving the desired amino acid analogue imidazolef.

Dimeric compounds according to this invention will be received, using conventional methods of organic chemistry. They can be obtained, based on the monomer U1and bind () with a second monomer U2. Dimeric compounds according to this invention having the General formula Va, in which R2represents tert-butyl-protected piperidine, can be obtained by dissolving Fmoc-protected monomerain HCl in dioxane, followed by interaction with diisocyanate linker.

Scheme 10

Dimeric compounds according to this invention having the General formula VIa, in which R2is hydroxyphenyl, can be obtained by reacting Boc-protected monomerawith propylbromide with getting propenyloxy monomerbwhich is subjected to dimerization by Association with Pd(OAc)2, CuI and DABCO in acetonitrile, followed by removal of the Boc by means of HCl in dioxane.

Scheme 11

Dimeric compounds according to this invention having the General formula VIIa, which are connected by Proline residues, you can get way of the interaction of the hydroxyproline residue with4-ethynylbenzaldehydebobtained from the corresponding alcohola. The resulting etinilestradioldwill dimerized by Association with Pd(OAc)2, DABCO and CuI in acetonitrile, followed by removal of Boc using HCl in dioxane.

Scheme 12

Dimeric compounds according to this invention having the General formula Xa can be obtained by reacting Fmoc-protected monomeracarboxylic acid with a suitable diamine, using HATU and DIPEA in DMF, followed by removal of Fmoc with 4-aminomethylpyridine.

Scheme 13

Indications

The compounds of this invention inhibit the binding of IAP proteins by caspase, in particular, linking the interaction of X-IAP with caspase 3 and 7. The compounds also inhibit the binding of ML-IAP protein Smac. Therefore, the compounds of this invention are useful for inducing apoptosis in cells or sensibilizirovannoy cells to apoptotic signals, in particular cancer cells. The compounds of this invention are used to induce apoptosis in cells that sverkhekspressiya IAP proteins. Alternatively, the compounds of this invention are used to induce apoptosis in cells in which the path of apoptosis via mitochondria is disrupted so that the release Sma protein (ML-IAP inhibited ,for example, through positive regulation of Bcl-2 orbyregulation according to the type of feedback Bax/Bak. Wider connections can be used to treat all types of cancer who do not undergo apoptosis. Examples of such cancers include neuroblastoma, carcinoma of the bowel, such as cancer, rectal cancer, colon cancer, familial adenomatous polyposis; carcinoma and hereditary non-polyposis; cancer of the colon and rectum, carcinoma of the esophagus, carcinoma of lip carcinoma of the larynx, carcinoma of hypopharynx, carcinoma of tongue carcinoma of the salivary glands, gastric carcinoma, adenocarcinoma, medullary carcinoma thyroid, papillary carcinoma thyroid cancer, kidney cancer, carcinoma of the renal parenchymal tissue, carcinoma of the ovary, carcinoma of the cervix, carcinoma of the body of the uterus, endometrial cancer, horiokartsinoma, carcinoma of the pancreas, carcinoma of the prostate, carcinoma of the testis, cancer of the breast, carcinoma of the urinary tract, melanoma, brain tumors, such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral tumor neuroectoderm, Hodgkins lymphoma, non-Hodgkins lymphoma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), Mature T-cell leukemia, liver-to mocny cancer, carcinoma of the gall bladder, carcinoma of the bronchus, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, sarcoma of Wenge and plasmacytoma.

Compounds according to this invention is used to increase the sensitivity of cells to apoptotic signals. Accordingly, the compounds may be introduced to, together with, or after application of radiation therapy or cytotoxic or anticancer chemotherapy. Suitable compounds for cytotoxic chemotherapy include, but are not limited to, (i) antimetabolites such as cytarabine, fludarabine, 5-fluoro-2'-deoxyuridine, gemcitabine, hydroxyurea or methotrexate; (ii) DNA-fragmenting agents such as bleomycin, (iii) DNA-crosslinking agents, such as chlorambucil, cisplatin, cyclophosphamide or nitrogen secret; (iv) intercalating agents such as adriamycin (doxorubicin or mitoxantrone; (v) inhibitors of protein synthesis, such as L-asparaginase, cycloheximide, puromycin or diphtheria toxin; (vi) the poisons of topoisomerase I, such as camptothecin or topotecan; (vii) poisons topoisomerase II, such as etoposide (VP-16) or teniposide; (viii) microcantilevers the military agents, such as colcemid, colchicine, paclitaxel, vinblastine or vincristine; (ix) kinase inhibitors such as flavopiridol, staurosporin, STI571 (CPG 57148B) or UCN-01 (7-hydroxystaurosporine); (x) a variety of drugs undergoing clinical testing, such as tiplady, PS-341, phenylbutyrate, ET-18-OCH3or inhibitors farnesyltransferase (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechingallate, theaflavin, flavanols, procyanidins, betulinaacid and its derivatives; (xi) hormones, such as glucocorticoids or phenetidine; (xii) hormone antagonists, such as tamoxifen, finasteride or antagonists of LHRH. In a particular embodiment, the compounds according to this invention is administered in conjunction with cytotoxic compound selected from the group consisting of cisplatin, doxorubicin, Taxol, Taxotere and mitomycin C. In a specific embodiment, the cytotoxic compound is doxorubicin.

Another class of active compounds that can be used in this invention, is a compound that is able to sensitize (K) or to induce apoptosis by binding to death receptors (agonists of the receptors of death"). Such agonists of death receptors include ligands of death receptors such as tumor necrosis factor α (TNF-α), factor necrosophic β (TNF-β, lymphotoxin-α), LT-β (lymphotoxin-β), TRAIL (Apo2L, DR4 ligand, CD95 ligand (Fas, APO-1)ligand TRAMP (DR3, Apo-3), DR6 ligand, as well as fragments and derivatives of any of these ligands. In one embodiment, the ligand receptor death is a TNF-α. In a specific embodiment, the ligand receptor death is a Apo2L/TRAIL. In addition, agonists of death receptors include agonistic antibodies to receptors of death, such as antibody against CD95-antibody against TRAIL-R1 (DR4), antibody against TRAIL-R2 (DR5), antibody against TRAIL-R3 antibody against TRAIL-R4, the DR6 antibody against the antibody against TNF-R1 and antibody against TRAMP (DR3), as well as fragments and derivatives of any of these antibodies.

To increase the sensitivity of cells to apoptosis, the compounds of this invention can also be used in combination with radiation therapy. The expression "radiation therapy" refers to the use of electromagnetic or corpuscular radiation for the treatment of neoplasia. Radiation therapy is based on the principle that the intense radiation to be delivered into the region of the target, will lead to loss of reproductive cells in tumor and normal tissues. Mode diagram dosage of ionizing radiation is typically defined in units of absorbed dose of ionizing radiation (rad), time and fractionation, and must be carefully selected oncologist is m The amount of radiation that a patient receives, usually depends on a number of factors under consideration, however, the two most important factors are the location of the tumor relative to other vital structures or organs of the body, and the degree of tumor spread. Examples radiotherapy funds include, but are not limited to, radiation therapy and this method is known in this area (Hellman, Principles of Radiation Therapy, Cancer, in Principles I and Practice of Oncology, 24875 (Devita et al., 4th ed., vol.1, 1993). Recent advances in radiation therapy include three-dimensional conformal radiation therapy external beam modulated in intensity-modulated radiation therapy (IMRT), stereotactic radiosurgery and brachytherapy (interstitial radiation therapy), while in the latter case the radiation source is placed directly into the tumor as implanted "capsules". These modern methods of therapeutic treatment deliver higher doses of radiation to the tumor, which explains their higher efficiency compared to conventional radiation therapy external beam.

Ionizing radiation from beta-emitting radionuclides considered as the most suitable for radiotherapy applications due to moderate linear energy transfer(LET) ionizing particle (electron) and its intermediate path (usually is several millimeters of tissue). Gamma rays delivered dose at lower levels significantly 'greater distances. Alpha particles are the other extreme, they deliver a very high dose of the LET, but have extremely limited way and must, therefore, be in close contact with the cells of the tissue to be processed. In addition, alpha-emitters are usually heavy metals, which limits the ability of chemistry and is a high threat due to leakage of the radionuclide from the area to be processed.Depending on the type of tumor, which can be processed, all types of existing emitters are within the scope of this invention.

In addition, the present invention covers the types of non-ionizing radiation such as, for example, ultraviolet (UV)radiation, hard visible radiation, microwave radiation (hyperthermic therapy), infrared (IR) radiation and lasers. In a specific embodiment, the present invention is applied UV radiation.

In addition, this invention includes pharmaceutical compositions or drugs containing the compounds according to this invention and a therapeutically inert carrier, diluent or excipient, and methods of using compounds according to this invention for obtaining such compositions and, in addition to the state funds. Typically, finished dosage form obtained by mixing compounds of the formula I used in the methods according to this invention, when the ambient temperature at the appropriate pH, and at the desired degree of purity with physiologically acceptable carriers, i.e. carriers, which are nontoxic to recipients at the dosages and concentrations used in the galenical form of introduction. the pH of the drug depends mainly on the particular use and the concentration of the compound, however, the pH may range from about 3 to about 8. The drug in acetate buffer at pH 5 is a suitable option. In one embodiment, an inhibitory compound for use is in sterile form. The connection is usually stored in the form of solid compositions, although acceptable and liofilizovannye drugs or aqueous solutions.

The composition of this invention receive, dispense, and introduce a way, not protivorechivymi standard medical practice. Factors considered when considered in this context include the specific violation is subject to treatment; specific mammal to be treated, the clinical condition of the individual patient, the cause of the violation, place of delivery, route of administration, schemes, and other factors known to medical practitioners. "Effective amount" soy is inane, be inserted, will be determined by the above factors, and represents the minimum number required for inhibition of IAP interaction with caspase, induction of apoptosis or increase the sensitivity of cancer cells to the apoptotic signal. This number must be lower than the quantity which is toxic to normal cells, or mammal, in General.

Typically, the initial pharmaceutically effective amount of the compounds according to this invention, administered parenterally, per dose is in the range from about 0.01-100 mg/kg, for example, from about 0.1 to 20 mg/kg of body weight of the patient per day, with the typical initial dose used of the compound is from 0.3 to 15 mg/kg/day. Single dosage forms for oral administration such as tablets and capsules, may contain from about 25 to about 1000 mg of the compounds according to this invention.

The connection according to this invention can be administered by any suitable means, including oral, local, transdermal, parenteral, subcutaneous, intraperitoneal, intra-lungs and intranasal introduction, and, if required, in the case of local treatment, introduction directly into the area of pathology. Parenteral infusions include intramuscular, intravenous, intraarterial, and traperitoneal or subcutaneous administration. An example of a suitable dosage form for oral administration is a tablet containing about 25 mg, 50 mg, 100 mg, 250 mg or 500 mg of the compounds according to this invention, compounded with about 90-30 mg anhydrous lactose, about 5-40 mg croscarmellose sodium, about 5-30 mg polyvinylpyrrolidone (PVP) K30 and about 1-10 mg of magnesium stearate. First, the powdered ingredients are mixed together and then mixed with a solution of PVP. The resulting composition may be dried, granulated, mixed with magnesium stearate and compressed to form tablets using conventional equipment. The aerosol product can be obtained by dissolving the compounds in this invention, for example, 5-400 mg, in a suitable buffer solution, for example, phosphate buffer, add tonic, for example, salts such as sodium chloride, if desired. To remove impurities and pollutants solution is typically filtered, for example using a filter of 0.2 micron.

Examples

The invention is better understood when considering the following examples. However, these examples should not be construed as limiting the scope of this invention. Reagents and solvents receive from commercial sources and used in the form in which they are received.

Used in the present description, the abbreviations represent the th following:

AcOH: acetic acid;

ACN: acetonitrile;

Chg: cyclohexylglycine;

DHM: dichloromethane

DIPEA: diisopropylethylamine;

DMAP: 4-dimethylaminopyridine;

DME: 1,2-dimethoxyethane;

DMF: dimethylformamide;

DMSO: dimethyl sulfoxide;

EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;

EEDQ: 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline;

EtOAc: ethyl acetate;

EtOH: ethanol;

LC-MS: the combination of liquid chromatography and mass spectrometry;

HATU: hexaphosphate O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium;

HOBt, N-Hydroxybenzotriazole

HBTU: hexaphosphate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium;

HPLC: high performance liquid chromatography;

MeOH: methanol;

NBS: N-bromosuccinimide;

TASF: divertioculitis Tris(dimethylamino)sulfone;

TEA: triethylamine;

TFA: triperoxonane acid;

THF: tetrahydrofuran;

Example 1

2-[tert-Butoxycarbonyl-(1H-pyrrol-2-ylmethyl)amino]propionic acid

Ethyl ester of alanineb(5 g, 32.5 mmol), pyrrole-2-carboxaldehydea(3.1 g, 32.5 mmol), cyanoborohydride sodium (2,04 g, 32.5 mmol) and AcOH (1%) are mixed in DMF and stirred over night. The reaction is quenched with H2O and evaporated DMF. The mixture is diluted with EtOAc, washed with 0.1 n NaOH, dried and concentrated, obtaining productcto 2.5 g of the Obtained esterc(25 g, 12.8 mmol), di-tert-BUTYLCARBAMATE (a 3.06 g, 14 mmol) are mixed in THF, H2O with NaHCO3and stirred over night. THF is evaporated and the mixture is diluted with EtOAc, washed with 1N NaOH, saturated NH4Cl and saturated salt solution. After drying, the mixture is concentrated and receiving Boc-protected esterd3,3, Boc-protected esterd(1,67 g, 5.6 mol), monohydrate of lithium hydroxide (284 mg, 6,77 mmol) are mixed in THF and H2O at 0°C. the THF is distilled off in vacuum and the solution acidified with dilute H2SO4, extracted with EtOAc twice. The organic layers are combined, dried and evaporated, getting the product 2-[tert-butoxycarbonyl-(1H-pyrrol-2-ylmethyl)amino]propionic acide.

Example 2

Tetrahydropyranyloxy

Tetrahydropyranyloxy purchased from NovaBiochem or synthesized according to literature: Ghosh, A. K.; Thompson, W. J.; holloway, M. K.; McKee, S. P.; Duong, T. T.; Lee, H. Y.; Munson, P. M; Smith, A. M.; Wai, J. M; Darke, P. L.; Zugay, J. A.; Emini, E. A.; Schleife, W. A.; Huff, J. R.; Anderson, P. S.J.Med. Chem.,1993, 36,2300-2310.

Example 3

Piperidinylmethyl

Piperidinylmethyl synthesized according to the methods described by Shieh et al. (Tetrahedron: Asymmetry,2001,12,2421-2425).

Example 4

4,4-Diverticulopexia

4,4-Diverticulopexia receive according to the methods described in p. the patent application U.S. 20030216325.

Example 5

Boc (S)-2-amino-2-(4-hydroxycyclohexyl)acetic acid

Following the method described Sheih et al. (Tetrahedron:Asymmetry,2001,12,2421-2425), a solution of ketonea(8,4 g) and EtOAc (30 ml) was added to a solution of methyl ester of N-Cbz-phosphonoglycineb, TMG (4,5 ml) and EtOAc (30 ml). The solution is incubated at room temperature for 48 h, then washed with 1N HCl (3×50 ml), saturated salt solution (1×50 ml), dried (Na2SO4), filtered and concentrated. The remainder adsorb on celite and purified by chromatography, then further purified by recrystallization from a mixture of EtOAc/hexane, receiving of 5.2 g of the productc.

Following the procedure described Sheih, (Tetrahedron: Asymmetry,2001, 12,2421-2425), a solution of enaminewith(5.0 g), (S,S)-Me-BPE-Rh(I) (1.5 g, Strem Chemicals, Newburyport, MA) and MeOH (100 ml) was vigorously shaken under a pressure of H270 psi for 48 hours the Solvent is removed under reduced pressure. The residue is treated with EtOAc and filtered through SiO2using additional amount of EtOAc. The solvent is removed under reduced pressure, obtaining 4.0 g of productdin the form of a colorless solid.

A mixture of Cbz-carbamated(4.0 g), Boc2O (2.9 g), 20% Pd(OH)2•C (1.0 g) and MeOH (30 ml) incubated in an atmosphere of H2within 6 hours the Mixture is filtered is through celite with MeOH. The solvent is removed under reduced pressure, obtaining 4.5 g of residueethat directly use (next stage).

The balance ofewith the above stage dissolved in H2O (10 ml), AcOH (30 ml), THF (5 ml) and dichloracetic acid (3 ml) and incubated at room temperature over night. Add water (5 ml) and the solution was kept in the same conditions until the completion of the hydrolysis, controlled by analysis by HPLC-MS. Gently add firm Na2CO3until then, until there is no further gas evolution, the mixture is diluted with aqueous NaHCO3and extracted with a mixture of 10% EtOAc/DHM. The combined organic phases are washed once with saturated salt solution, dried (Na2SO4), filtered and concentrated. The residue is purified by chromatography, gaining 2.9 g of productf.

A mixture of ketonef(1.5 g), MeOH (50 ml) was treated with NaBH4(290 mg) at 0°C for 20 minutes the Mixture is acidified to ~pH1 10% aqueous citric acid and MeOH is removed under reduced pressure. The residue is diluted with water and extracted with a mixture of 20% EtOAc/DHM. The combined organic phases are washed once with saturated salt solution, dried (Na2SO4), filtered and concentrated. The residue is purified by chromatography, receiving of 1.17 g of productgand 0,23gr producth.

A mixture of esterg(1,17 g), LiOH•H2O (160 mg), THF (3 ml) and water (4.5 ml) is vigorously stirred at room temperature over night. The mixture is diluted with saturated salt solution and exhaustively extracted with EtOAc. The combined organic phases are washed once with saturated salt solution, dried (Na2SO4), filtered and concentrated, receiving acidi(525 mg).

Example 6

N-Boc-N-cyclopropylmethyl-L-alanine

The hydrochloride of the methyl ester of L-alaninea(5 g, 35.8 mmol) and cyclopropanecarboxaldehydebor 2.67 ml, 35.8 mmol) are suspended in 50 ml of THF mass./1% AcOH. Add 5 ml of CH3OH leads to the transformation of the turbid solution in the clear. Add NaCNBH4(2.25 g, 35.8 mmol) and the reaction mixture was stirred over night. The reaction mixture was quenched by addition of 1N aqueous NaOH, extracted with EtOAc twice, the organic layers dried over Na2SO4and concentrate to dryness. The crude product is purified by chromatography using 30% mixture of EtOAc/hexane (stained with ninhydrin), receiving the connectionwith(1 g, 18%). Connectionwith(1 g, 6,37 mmol) and di-tert-boc-dicarbonate (2.1 g, of 9.55 mmol) was diluted in THF (20 ml) and H2O (20 ml), add NaHCO3(1.3 g, 15.9 mmol). The reaction mixture was stirred overnight to complete the reaction. THF is removed under reduced pressure, the aqueous layer was extracted 3 times with EtOAc. The combined organic layers are washed with 1N NaOH, saturated NH4Cl, and then a saturated solution of salt, concentrated to dryness. Boc-protected compoundd(1.39 g, 5.40 mmol) is stirred with LiOH.H2O (1,14 g, 27 mmol) in THF (20 ml) and H2O (20 ml) over night at room temperature. THF is evaporated and the aqueous layer was adjusted to pH=4 by adding 10% citric acid, then extracted 3 times with EtOAc. The combined organic layers washed with saturated salt solution and concentrated. The crude product is purified on a column of reversed phase C-18, elwira a mixture of 0%-50% acetonitrile/H2O, to obtain the pure compoundsein the form of a white solid (794 mg).

Example 7

N-Boc-N-methyl-L-alanyl-L-cyclohexylglycine

A solution of Fmoc-L-cyclohexylglycine (3.6 g, 9.6 mmol), dissolved in DHM (50 ml) and DIPEA (5.6 ml, 32 mmol), added to 2-chlorotriethylsilane resin (5 g, 8 mmol) and gently stirred for 3 hours at room temperature. The resin was washed 4 times DHM, 3 times with a mixture DHM/MeOH/DIPEA (17:2:1), 3 times DHM and 2 times dimethylacetamide (DMA). The Fmoc group is removed, treating the resin with a mixture of 20% piperidine/DMA (50 ml) for 15 minutes. The resin is washed 6 times with DMA. A solution of Boc-N-methylalanine (3.3 g, 16 mmol), HBTU (6,1 g, 16 mmol) and DIPEA (5.6 ml, 32 mmol) and DMA/GHM (1:1, 50 ml) is added to the resin and gently stirred for 2 hours is in at room temperature. The resin is washed 5 times with DMA, 2 times DHM and dried under reduced pressure. Dipeptide otscheplaut from the resin by gentle agitation with a mixture of HOAc/TFE/GHM (1:1:3, 100 ml) for 2 hours at room temperature. The resin is removed by filtration and the solution concentrated. Residual AcOH is removed by azeotropic distillation with hexane (15-fold volume). The solid residue purified HPLC with reversed phase (C18, MeCN-H2O with 0.1%TFA) and solvent removed by lyophilization, receiving 1.2 g (43%) of the dipeptide, N-Boc-N-methyl-L-alanyl-L-cyclohexylglycine, in the form of a white powder.

Example 8

N-Boc-N-methyl-L-alanyl-L-dihydroporphyrin

A mixture of methyl ester of N-Cbz-dehydrophenylalaninea(Burk, M. J.; Gross, M. F.; Martinez, J. P. J. Am Chem. Soc.1995,117,9375, and references in this document) (5,2 g, 17 mmol), 5% Pd-C (500 mg), MeOH (75 ml) and THF (25 ml) incubated in an atmosphere of H2within 24 hours the Mixture is filtered through celite and the celite washed with MeOH, and concentrated under reduced pressure, obtaining quantitative output Aminbin the form of a colorless oil, which was directly used (to next stage).

Aminbobtained above is mixed with CH2Cl2(40 ml), saturated aqueous NaHCO3(40 ml) and cooled to 0°C. and Then added dropwise to benzyloxycarbonylamino (3.0 ml) and the mixture vigorously stirred for whom and through the night. The phases are separated and the aqueous phase extracted with CH2Cl2(3×20 ml). The combined organic phases are washed with saturated salt solution (1×50 ml), dried (Na2SO4), filtered, adsorb on celite and chromatographic (ISCO column with 120 g of silica, elution with gradient of 5-55% EtOAc-hexane)to give 4.15 g (80%) of racemic methyl ester Cbz-Pernilla. The enantiomers separated on a column (Chiracel OD, elwira a mixture of 10% EtOH-hexane. Under these conditions, first eluted the desired S-enantiomerwith.

A mixture of methyl ester (S)-N-Cbz-Pernilla (2.4 g, 7.82 mmol), 10% Pd·C (700 mg), MeOH (80 ml) is maintained at 1 atmosphere of H2within 24 hours the Mixture is filtered through celite with MeOH and concentrated under reduced pressure, obtaining 1.35 g (100%) Amindin the form of a colorless oil. Alternatively, perangin can be synthesized in enantio(isomorphous) pure form, following the method described by Ghosh (Ghosh, A. K.; Thompson, W. J.; Holloway, M. K.; McKee, S. P.; Duong, T. T.; Lee, H. Y.; Munson, P. M.; Smith, A. M; Wai, J. M.; Darke, P. L.; Zugay, J. A.; Imini, E. A.; Schleif, W. A.; Huff, J. R.; Anderson, P. S. J. Med. Chem.,1993,36,2300).

A mixture of amined(1.35 g, 7.8 mmol),N-Boc-N-methylalaninee(1,74 g, 8.6 mmol), EDC (1.65 g, 8,8 mmol) and MeCN (50 ml) maintained at room temperature throughout the night. MeCN is removed under reduced pressure and the residue once ablaut EtOAc, washed 0,5N HCl (3×10 ml), 0,5N NaOH (3×10 ml), dried (MgSO4), filtered and concentrated, obtaining 2.1 g (75%) of the protected dipeptidefin the form of a clear oil.

To a 0°C solution of esterf(2.10 g, 5,86 mmol) and THF (50 ml) is added LiOH•H2O (1,23 g of 29.3 mmol) and water (2 ml). The mixture was kept at 0°C for 2 h, then the cooling bath removed and the mixture is stirred over night. Then a large part of the THF is removed under reduced pressure and the residue was diluted with CH2Cl2washed 0,5N HCl, dried (MgSO4), filtered and concentrated, obtaining of 1.53 g (78%) of the dipeptide N-Boc-N-methyl-L-alanyl-L-dihydrophenylglycinegin the form of a colorless solid.

Example 9

(S)-tert-butyl 2-(4-phenylbenzo[d]thiazol-2-yl)pyrrolidin-1-carboxylate

To a stirred solution of Boc-L-Proline (1.0 g, 4.6 mmol) in 50 ml dry DMF added DIPEA (2.4 ml, of 13.8 mmol)and then HATU (1.75 g, 4.6 mmol). The resulting solution was stirred for 5 minutes at room temperature. Then add one portion to 2-aminobiphenyla(0,89 g, 5.3 mmol) and continue stirring at room temperature for 2 hours Then the solution is heated to 45°C for 5 h and cooled to room temperature for 16 hours Then the reaction mixture is poured into 250 ml of water, and to this mixture is added 50 ml us the seal of the salt solution. The aqueous phase is extracted with 3 times 50 ml of EtOAc and organicheskoi the extracts pooled. Then the organic phase was washed with 100 ml 1M HCl and 100 ml of saturated salt solution before drying over MgSO4, filtered and concentrated to obtain oil. This oil adsorb on silica gel and purified flash chromatography (40 g of SiO2, 0% to 40% EtOAc in hexano)to give the desired amidebin the form of a clear oil (1.2 g, 3.3 mmol, 71%).

To a stirred solutionb(1.06 g, 2.9 mmol) in 30 ml of toluene, add one portion of the reagent Lawesson (0,69 g, 1.7 mmol). The reaction mixture is heated to 80°C in an oil bath for 3 h, then cooled to room temperature for 16 hours the Solution adsorb on silica gel and purified flash chromatography (40 g of SiO2, 0% to 40% EtOAc in hexano), obtaining the required thioamidewithin the form of a clear oil (to 0.63 g, 1.6 mmol, 57%).

To a stirred solution of K3Fe(CN)6(1.51 g, 4.6 mmol) in 4 ml of water at 85°C, slowly add suspensionwithobtained first by wettingwith(of 0.42 g, 1.1 mmol) and few drops of EtOH, then adding 30% NaOH solution (1.2 ml, 9.0 mmol) and vigorous pipetting in a few minutes. After complete addition, the reaction mixture is stirred for 2½ hours at 85°C, after which the reaction is ionic mixture is diluted with 25 ml of water and filtered. The filtrate was dissolved in dichloromethane and adsorb on silica gel and purified flash chromatography (12 g SO2, 0% to 25% EtOAc in hexano), obtaining (S)-tert-butyl 2-(4-phenylbenzo[d]thiazol-2-yl)pyrrolidin-1-carboxylated(0,22 g, of 0.58 mmol, 52%).

Example 10

(S)-tert-butyl 2-(4-methylbenzo[d]thiazol-2-yl)pyrrolidin-1-carboxylate

Connectionwithreceive according to the methods in the above example 9. Ortho-toluidine (to 0.72 ml, 6.7 mmol) is converted into a compounda(1,49 g, 4.9 mmol, 87%). Then the connectiona(1,14 g, 3.7 mmol) is converted into a compoundb(0.27 g, 0.84 mmol, 23%). Connectionb(0.27 g, 0.84 mmol) is converted into a compoundc.

Example 11

(S)-tert-butyl 2-(4-isopropylbenzo[d]thiazol-2-yl)pyrrolidin-1-carboxylate

Connectionwithreceive according to the methods in example 9. 2-Isopropylaniline (0.9 ml, 5.2 mmol) is converted into a compounda(1,53 g, 4.9 mmol, 87%). Then the connectiona(1,53 g, 4.9 mmol) is converted into a compoundb(1,14 g, 3.3 mmol, 67%). Connectionb(1,14 g, 3.3 mmol) is transformed into (S)-tert-butyl 2-(4-isopropylbenzo[d]thiazol-2-yl)pyrrolidin-1-carboxylatewith(0.35 g, 1.0 mmol, 31%).

Example 12

(S)-tert-butyl 2-(4-bencivengo[d]thiazol-2-yl)pyrrolidin-1-carboxylate

Connectionwithreceive according to the methods described in the example . 2-Benzylaniline (1.18 g, 6.4 mmol) is converted into a compounda(1,43 g, 3.8 mmol, 59%). Then the connectiona(1.18 g, 3.1 mmol) is converted into a compoundbof 0.85 g, 2.1 mmol, 69%). Connectionbof 0.85 g, 2.1 mmol) is transformed into (S)-tert-butyl 2-(4-bencivengo[d]thiazol-2-yl)pyrrolidin-1-carboxylatewith(0.18 g, 0.46 mmol, 22%).

Example 13

7-phenyl-2-(pyrrolidin-2-yl)thiazolo[5,4-b]pyridine

tert-Butyl ether (2-chloro-4-iodopyridine-3-yl)carbamino acida(4,20 g of 11.8 mmol), phenylboronic acid (1.90 g, 15.6 mmol), potassium carbonate (2,42 g, 17.5 mmol) and tetranitroaniline palladium(0) (0.68 g, 0.59 mmol) is weighed into a 20 ml vial for processing in a microwave oven. Bubble vaccum, then rinsed 3 times with gas-nitrogen. Type of 16.7 ml of dry DMF, followed by 3.3 ml of water, the mixture Tegaserod, barbotine nitrogen through it for the night. Then, the vial sealed and subjected to microwave treatment at 130°C for 40 minutes. The resulting solution was poured into 250 ml of water and extracted with EtOAc (3×50 ml). The combined organic extracts dried over MgSO4filter and concentrate. The oil obtained adsorb on silica gel and purified flash chromatography (150 g of SiO2, 0% to 40% EtOAc in hexano)to give 2-chloro-3-amino-4-phenylpyridineb(0.84 g, 4.1 mmol, 35%) and Boc-protected 2-chloro-3-amino-4-phenylpyridinewith(1,74 g, 5.7 mmol, 48% in the form of yellow and white solids, respectively.

Connectionc(1,74 g, 5.7 mmol) dissolved in 50 ml of a mixture of 4:1 methylene chloride/TFA and add 1 ml of toluene. The resulting solution was heated to 40°C for 2 h, after which the reaction mixture is concentrated to obtain yellow solid. This solid is dissolved in 50 ml of methylene chloride and washed with 100 ml of aqueous 1N NaOH. After separating layers, the aqueous phase is extracted with twice 50 ml of methylene chloride. The organic extracts are combined, dried over MgSO4, filtered and concentrated to obtain a yellow solid, which is transferred to the next stage without additional purification.

To a stirred solution of 2-chloro-3-amino-4-phenylpyridine in dry methylene chloride added pyridine (2.5 ml, of 30.9 mmol) and then dropwise (S)-benzyl 2-(chlorocarbonyl)pyrrolidine-1-carboxylate (1,83 g, 6.8 mmol)obtained in example 14. The reaction mixture is stirred for 16 h under nitrogen atmosphere, then poured into 200 ml of 1N HCl. The layers are separated and the aqueous phase is extracted with methylene chloride (3×50 ml). The combined organic extracts dried over MgSO4filter and concentrate. The oil obtained adsorb on silica gel and purified flash chromatography (40 g of SiO2, 0% to 60% EtOAc in hexano)to give the desired amidedin the form of foam (of 2.51 g, 5.8 mmol, 100%).

<> Connectiond(of 2.51 g, USD 5.76 mmol) and reagent Lawesson (1,37 g, 3.4 mmol) dissolved in 50 ml dry toluene and heated to 100°C for 16 hours. The solution is cooled, then adsorb on silica gel and purified flash chromatography (120 g of SiO2, 0% to 40% EtOAc in hexano)to give the desired 7-asiansuiteein the form of a white foam (1,30 g, 3.1 mmol, 54%).

Connectione(of 1.30 g, 3.1 mmol) dissolved in 30 ml of TFA. Add thioanisole (2,9 ml of 24.7 mmol) and the solution heated to 40°C for 16 hours. Then volatile components are removed under vacuum and the oil obtained is dissolved in diethyl ether (50 ml). The solution was poured into 1N NaOH (200 ml) and the layers separated. The aqueous phase is extracted with diethyl ether (2×50 ml) and the organic extracts combined. The organic phase is dried over MgSO4and filtered. Added 4n HCl in dioxane (0.8 ml, 3.2 mmol) and precipitated white solid. The product is cooled to 4°C for 4 hours, then filtered, washing with cold diethyl ether (3×50 ml), receiving cleaners containing hydrochloride salt of 7-phenyl-2-(pyrrolidin-2-yl)thiazolo[5,4-b]pyridinef(0,g, 2.7 mmol, 86%) as fine white crystals.

Example 14

(S)-benzyl 2-(chlorocarbonyl)pyrrolidine-1-carboxylate

Cbz-Pro-OHa(2.0 g, 8.0 mmol) dissolved in DHM (10 ml) and add oxalicacid (6 ml of a 2M solution of 12.0 mmol). EXT the keys DMF (2 drops) and the mixture is stirred at room temperature for 30 minutes The solution is concentrated, obtaining 2.1 g (100%) carboxylic acid, (S)-benzyl 2-(chlorocarbonyl)pyrrolidine-1-carboxylatebin the form of a pale yellow oil.

Example 15

7-Phenyl-2-((S)-pyrrolidin-2-yl)thiazolo[5,4-c]pyridine

4-amino-3,5-dichloropyridinea(2.0 g, 12.3 mmol), tetrakis(triphenylphosphine)palladium (696 mg, 0.6 mmol), phenylboronic acid (1.9 g, 15.9 mmol) and potassium carbonate (2.2 g, 15.9 mmol) are mixed in a 10 ml vial for microwave treatment in an atmosphere of N2. Add DMF (6 ml) and deoksigenirovanii H2O (1.2 ml). N2bubbled through the mixture for 5 min and the mixture is heated for 20 min at 140°C in a microwave oven. The mixture was diluted with water (30 ml) and extracted with EtOAc (3×20 ml). The combined organic phases are washed with water (50 ml) and saturated salt solution (50 ml), dried over MgSO4filter and concentrate. The obtained brown oil adsorb on silica gel and purified flash chromatography (SiO2, 0% to 70% ethyl acetate/hexane)to give 970 mg (37%)bin the form of a colorless oil. MS: m/z=205 (M+H).

4-Amino-3-chloro-5-vinylpyridinb(650 mg, and 3.16 mmol) dissolved in DHM (10 ml). Add Cbz-Pro-Cl (1.6 g, 6.3 mmol), dissolved in DHM (5 ml), followed by the addition of pyridine (467 mg, 6.3 mmol) and the mixture is stirred over night at room tempera is ur. The reaction mixture was quenched 0,5N HCl, the phases are separated and the aqueous phase extracted with DHM (2×20 ml). The combined organic phases are dried over MgSO4filter and concentrate. The oil obtained adsorb on silica gel and purified flash chromatography (SiO2, 0% to 100% EtOAc/hexane)to give 1.12 g (80%)within the form of a colorless oil. MS: m/z=436 (M+H).

Following the General methodology described Charette (Charette, A.B. et al, J. Org. Chem.,2003,68, 5792-5794), the connectiond(1.7 g, 3.9 mmol) and pyridine (0,89 ml, 4.7 mmol) are mixed together in DHM (20 ml) at 0°C and the solution stirred for 5 minutes, Slowly add the anhydride of triftoratsetata (1.3 g, 4.7 mmol). The solution is stirred for 3 hours and give him the opportunity to come to room temperature. The reaction is quenched by the rapid addition of 20% aqueous ammonium sulfide (2.0 ml, 5.8 mmol) and stirred over night at room temperature. The mixture is filtered through a bed of silica gel and washed DHM (50 ml). The filtrate is concentrated and the oil obtained adsorb on silica gel and purified flash chromatography (SiO2, 0% to 70% ethyl acetate/hexane), receiving 500 mg (28%)ein the form of a yellow solid. MS: m/z=452 (M+H).

Connectionfdissolved in DMF (5 ml) and the solution stirred at 120°C for 3 days. The mixture is cooled to room Tempe is atory, dilute 20 ml of H2O and extracted with EtOAc (3×25 ml). The combined organic phases are washed with water (50 ml) and saturated salt solution (50 ml), dried over MgSO4filter and concentrate. The oil obtained adsorb on silica gel and purified flash chromatography (SiO2from hexanol to ethyl acetate)to give 423 mg (98%)gin the form of a yellow oil. MS: m/z=415 (M+H).

Connectiong(423 mg, 1.0 mmol) and thioanisole (993 mg, 8.0 mmol) was dissolved in TFA (40 ml). The mixture is stirred at 40°C during the night. The mixture is cooled to room temperature and concentrate. The residual oil is dissolved in a simple ether (20 ml) and washed with 1N NaOH (30 ml). The aqueous phase is extracted with simple ether (2×20 ml). The combined organic phases are dried over MgSO4and filtered. 4n HCl in dioxane add up until not precipitated solid. The solid is collected by filtration, washed with simple ether and dried in the air, receiving 240 mg (76%) of 7-phenyl-2-((S)-pyrrolidin-2-yl)thiazolo[5,4-c]pyridinehin the form of a pale yellow solid. MS: m/z=282 (M+H).

Example 16

7-phenyl-2-((S)-pyrrolidin-2-yl)thiazolo[5,4-d]pyrimidine

Iron powder (12.5 g, 112 mmol) are added to a suspension of 4,6-dichloro-5-nitropyrimidinea(7.0 g, 36,1 mmol) in acetic acid (70 ml). The mixture is stirred at 40°C for 45 mi is. The mixture was poured on ice and neutralized by adding solid sodium bicarbonate. The aqueous phase is extracted with EtOAc (3×200 ml). The combined organic phases are dried over MgSO4, filtered and concentrated, obtaining a pale yellow solid. Recrystallization in hot ethyl acetate to give 3.6 g (61%) of compoundbas off-white needles. MS: m/z=165 (M+H).

Connectionwithproduced from compoundb(1.0 g, 6.1 mmol)using General method for obtaining compounds ofbin example 15. The method leads to the production of 410 mg (28%)within the form of a yellow solid. MS: m/z=206 (M+H). Connectiondproduced from compoundwith(270 mg, 1.3 mmol)using General method for obtaining compounds ofwithin example 15. The technique results in 565 mg (99%)din the form of a colorless oil. MS: m/z=437 (M+H).

The mixture of compoundsd(550 mg, of 1.26 mmol) and reagent Lawesson (341 mg, 0.84 mmol) in toluene (10 ml) is heated at 80°C over night. The solution is concentrated and adsorb on silica gel and purified flash chromatography (SiO2, 0% to 60% ethyl acetate/hexane), getting 514 mg (98%)ein the form of a pale yellow solid. MS: m/z=417 (M+H).

Connectionfproduced from compounde(510 mg, 1.2 mmol)using the method for obtaining the connection is in hin example 15. The technique results in 378 mg (98%) 7-phenyl-2-((S)-pyrrolidin-2-yl)thiazolo[5,4-d]pyrimidinefas not quite white solid. MS: m/z=283 (M+H).

Example 17

2,3-diaminobiphenyl

2-Aminobiphenyla(21,9289 g, 130 mmol) is dissolved in Ac2O (30 ml, 318 mmol) and stirred for 10 minutes. Add an additional portion of Ac2O (10 ml, 106 mmol), then stirred for another 10 minutes. The sample was poured on ice. The obtained solid is filtered under vacuum and washed with H2O, receiving N-acetyl-2-aminobiphenylb(26,955 g, 128 mmol, 98%).

Following the General methodology described Stepan (Stepan, A. H., et al., J. Am. Chem. Soc.,1949,71,2438), N-acetyl-2-aminobiphenylb(7,198 g, to 34.1 mmol), HOAc (6 ml) and Ac2O (5 ml) are mixed and heated at 120°C for several minutes until, while N-acetyl-2-aminobiphenylbwill not dissolve. The sample is cooled to room temperature. HOAc (1.5 ml) is added slowly to a 2.3 ml fuming HNO3(2,3 ml of 54.5 mmol) in a bath with ice. Keeping the temperature less than about 26.5°C, N-acetyl-2-aminobiphenylbquickly add 1.5 ml HNO3the mixture is then added dropwise remaining HNO3the blend. The sample was stirred at room temperature for 4 hours, then stored at 4°C over night. The reaction mixture by pouring the Ute into ice and extracted once with benzene. The benzene layer stored at 4°C for 1 hour. The obtained solid is filtered under vacuum and washed with cold benzene, receiving N-acetyl-2-amino-3-nitrobiphenylwith(2,346 g, to 9.15 mmol, 27%).

N-Acetyl-2-amino-3-nitrobiphenylwith(1,008 g, 3.93 mmol), EtOH (19 ml, 325 mmol) and concentrated HCl (5 ml, 50 mmol) are mixed and refluxed at 120°C during the night. The sample adsorb on silica gel and purified flash chromatography (12 g of SiO2, 0-33% EtOAc in hexano)to give 2-amino-3-nitrobiphenyld(determined as 0.720 g, to 3.36 mmol, 85%).

2-Amino-3-nitrobiphenyld(0,613 g of 2.86 mmol) and purge with nitrogen for 30 minutes, then add HOAc (5 ml), and then iron powder (0,4895 g, 8,76 mmol). The sample is heated at 60°C for 30 minutes, then add HOAc (5 ml). The sample was stirred at 60°C for 1 hour, then poured into ice. The sample is extracted with EtOAc (3×100 ml). The EtOAc extracts are washed with saturated NaHCO3(3×100 ml). The EtOAc layer is dried over MgSO4filter and concentrate, receiving 2,3-diaminobiphenyle(0,439 g of 2.38 mmol, 83%).

Example 18

2(S)-[[(2-Itfeel)amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-pyrrolidinecarbonyl acid

Boc-Pro-OHa(5,0030 g, 23.2 mmol) was dissolved in dry CH2Cl2(50 ml), then cooled to 0°C. Add the keys dry pyridine (3.8 ml, of 46.4 mmol). Added dropwise floramite cyanuric acid (2.2 ml, 25.5 mmol). The sample warmed to room temperature and stirred for 30 minutes. Type H2O (5 ml) for quenching the reaction. The reaction mixture was diluted with H2O and Astrovirus three times CH2Cl2. CH2Cl2the extracts are washed with saturated NaCl. CH2Cl2the layer is dried over MgSO4filter and concentrate, getting floramite acidb, which is used without further purification. Floramite acidbdissolved in dry CH2Cl2(50 ml). Add 2-iodoaniline (4,9932 g of 22.8 mmol) and the sample is stirred over night. The reaction mixture adsorb on silica gel and purified flash chromatography (80 g of SiO2, 0-50% EtOAc in hexano)to give 2(S)-[[(2-itfeel)amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-pyrrolidinecarbonyl acidwith(3,845 g, 9,24 mmol, 40%).

Example 19

2(S)-[[(2-(4-pyridyl)phenyl)amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-pyrrolidinecarbonyl acid

2(S)-[[(2-Itfeel)amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-pyrrolidinecarbonyl acida(0,4810 g of 1.16 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0,3240 g, was 1.58 mmol), K2CO3(0,2190 g, was 1.58 mmol) and Pd(PPh3)4(0,0702 g, 0,0607 mmol) are mixed in a 5 ml vial for microwave is processing. Sample vacuum and rinsed three times with nitrogen. Add dry DMF (2 ml) and deoksigenirovanii H2O (0.4 ml). The sample is subjected to microwave treatment at 130°C for 10 minutes. The reaction mixture was diluted with H2O and extracted three times with EtOAc. The EtOAc extracts are dried over MgSO4and filtered. The crude product adsorb on silica gel and purified flash chromatography (4 g SiO2, 0-100% EtOAc in hexano)to give 2(S)-[[(2-(4-pyridyl)phenyl)amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-pyrrolidinecarbonyl acidb(0,404 g, 1.10 mmol, 95%).

Example 20

2(S)-[[(2-(3'-Chloro(1,1'-biphenyl))amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-pyrrolidinecarbonyl acid

Following the procedure of example 19, 2(S)-[[(2-itfeel)amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-pyrrolidinecarbonyl acida(0,4576 g, 1.10 mmol), 3-chlorophenylurea acid (0,2520 g of 1.61 mmol), K2CO3(0,2431 g of 1.76 mmol) and Pd(PPh3)4(0,0725 g, 0,0627 mmol) to give 2(S)-[[(2-(3'-chloro(1,1'-biphenyl))amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-pyrrolidinecarbonyl acidb(0,399 g 0,995 mmol, 90%).

Example 21

2(S)-[[(2-(2'-Chloro(1,1'-biphenyl))amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-pyrrolidinecarbonyl acid

Following the procedure of example 19, 2(S)-[[(2-itfeel)amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-PIR is holdingarea acid a(0,4554 g of 1.09 mmol), 2-chlorophenylurea acid (0,2518 g of 1.59 mmol), K2CO3(0,2592 g, 1.88 mmol) and Pd(PPh3)4(0,0752 g, 0,0651 mmol) to give 2(S)-[[(2-(2'-chloro(1,1'-biphenyl))amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-pyrrolidinecarbonyl acidb(0,414 g of 1.03 mmol, 94%).

Example 22

2(S)-[[(2-(4'-Chloro(1,1'-biphenyl))amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-pyrrolidinecarbonyl acid

Following the procedure of example 19, 2(S)-[[(2-itfeel)amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-pyrrolidinecarbonyl acida(0,4494 g at 1.08 mmol), 4-chlorophenylurea acid (0,2561 g of 1.62 mmol), K2CO3(0,2639 g, at 1.91 mmol) and Pd(PPh3)4(0,0732 g, 0,0633 mmol) to give 2(S)-[[(2-(4'-chloro(1,1'-biphenyl))amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-pyrrolidinecarbonyl acidb(0,411 g at 1.08 mmol, 100%).

Example 23

2(S)-[[(2-(3'-Fluoro(1,1'-biphenyl))amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-pyrrolidinecarbonyl acid

Following the procedure of example 19, 2(S)-[[(2-itfeel)amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-pyrrolidinecarbonyl acida(0,4507 g at 1.08 mmol), 3-ftorhinolonovy acid (0,2158 g, 1.54 mmol), K2CO3(0,2343 g, was 1.69 mmol) and Pd(PPh3)4(0,0756 g, 0,0654 mmol) to give 2(S)-[[(2-(3'-Fluoro(1,1'-biphenyl))amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-pyrrolidinecarbonyl acidb (0,387 g, 1.01 mmol, 89%).

Example 24

2(S)-[[(2-(2'-Fluoro(1,1'-biphenyl))amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-pyrrolidinecarbonyl acid

Following the procedure of example 19, 2(S)-[[(2-itfeel)amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-pyrrolidinecarbonyl acida(0,4487 g at 1.08 mmol), 2-ftorhinolonovy acid (0,2154 g, 1.54 mmol), K2CO3(0,2305 g, 1,67 mmol) and Pd(PPh3)4(0,0663 g, 0,0574 mmol) to give 2(S)-[[(2-(2'-Fluoro(1,1'-biphenyl))amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-pyrrolidinecarbonyl acidb(0,410 g, 1.07 mmol, 99%).

Example 25

2(S)-[[(2-(4'-Fluoro(1,1'-biphenyl))amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-pyrrolidinecarbonyl acid

Following the procedure of example 19, 2(S)-[[(2-itfeel)amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-pyrrolidinecarbonyl acida(0,4467 g, 1.07 mmol), 4-ftorhinolonovy acid (0,2230 g of 1.59 mmol), K2CO3(0,2434 g of 1.76 mmol) and Pd(PPh3)4(0,0686 g, 0,0594 mmol) to give 2(S)-[[(2-(4'-fluoro(1,1'-biphenyl))amino]carbonyl]-1-(1,1-dimethylethylamine ether)-1-pyrrolidinecarbonyl acida(0,382 g, 0,994 mmol, 92%).

Example 26

3-Amino-4-chloro-2-phenylpyridine

Following the General methodology described by Norman (Norman, M. H., et al, J. Med. Chem.,2000,43,4288), 2,4-dihydroxypyridine (4,931 g, 44.4 mmol) and H2SO4(20 ml) Pach is try and cooled to 0°C. Added dropwise HNO3(20 ml, 44.4 mmol). The sample is stirred for 30 minutes, then poured on ice. The obtained solid substance stored at 4°C for 1 hour, then filtered under vacuum, obtaining 2,4-dihydroxy-3-nitropyridine (5,143 g of 32.9 mmol, 74%).

Following the General methodology described by Norman (Norman, M. H., et al, J. Med. Chem.,2000,43,4288), 2,4-dihydroxy-3-nitropyridineb(2,0013 g, 12.9 mmol) and POCl3(25 ml, 268 mmol) are mixed in a nitrogen atmosphere. The mixture is heated to 106°C and stirred over night. The sample is concentrated and poured on ice. The reaction mixture was extracted with EtOAc (3×100 ml). The EtOAc extracts are washed with saturated NaCl (1×100 ml). The EtOAc layer is dried over MgSO4and filtered. The crude substance adsorb on silica gel, filtered through a layer of silica gel (50% EtOAc in hexano) and concentrate, receiving 2,4-dichloro-3-nitropyridinewith(2,058 g of 10.7 mmol, 83%).

2,4-Dichloro-3-nitropyridinewith(2,058 g of 10.7 mmol) was dissolved in HOAc (10 ml) under nitrogen atmosphere. Add iron powder (1,9191 g, to 34.4 mmol). The sample is heated at 40°C for two hours. The reaction mixture is poured on ice and then added NaHCO3getting neutral solution. The sample is extracted with EtOAc (3×100 ml). The EtOAc extracts are washed with saturated NaHCO3(1×100 ml). The combined aqueous layers again extracted with about the in once with 100 ml of EtOAc. The combined EtOAc extracts are dried over MgSO4, filtered and concentrated, obtaining 3-amino-2-4-dichloropyridined(1,510 g, 9,26 mmol, 87%).

Mix 3-amino-2-4-dichloropyridined(0,7047 g, 4,32 mmol), phenylboronic acid (0,5177 g, 4,24 mmol), K2CO3(0,8023 g, 5,80 mmol) and Pd(PPh3)4(0,0702 g, 0,0607 mmol). Sample vacuum and rinsed with nitrogen three times. Add dry DMF (2 ml) and deoxygenation H2O (0.4 ml). The sample is subjected to microwave treatment at 130°C for 40 minutes. The reaction mixture was diluted with H2O (50 ml) and extracted with EtOAc (3×50 ml). The EtOAc extracts are dried over MgSO4and filtered. The crude product adsorb on silica gel and purified flash chromatography (40 g of SiO2, 0-30% EtOAc in hexano)to give 3-amino-4-chloro-2-phenylpyridinee(0,435 g, 2,12 mmol, 49%).

Example 27

2(S)-[[4-Phenyl-2-thiazolo[4,5-c]pyridinyl]-1-(9H-fluoren-9-ylmethyl)ester-1-pyrrolidinecarbonyl acid

3-Amino-4-chloro-2-phenylpyridinea(0,435 g, 2,12 mmol) dissolved in dry CH2Cl2(10 ml). Add dry pyridine (0,86 ml, 10.6 mmol). Added dropwise Cbz-Pro-Cl (1,0804 g, 4.04 mmol), obtained according to example 14, CH2Cl2(5 ml). The sample is stirred for one hour. The reaction mixture adsorb on silica gel and purified flash chromatogra the Oia (40 g SiO 2, 0-100% EtOAc in hexano)to give 2(S)-[[4-chloro-2-phenyl-3-pyridinyl)amino]carbonyl]-1-(9H-fluoren-9-ylmethyl)ester-1-pyrrolidinecarbonyl acidb(0,986 g, 2,12 mmol, 100%).

2(S)-[[4-Chloro-2-phenyl-3-pyridinyl)amino]carbonyl]-1-(9H-fluoren-9-ylmethyl)ester-1-pyrrolidinecarbonyl acidb(0,986 g, 2,12 mmol) dissolved in dry toluene (20 ml). Add the reagent Lawesson (0,6315 g, 1.56 mmol). The sample is heated up to 80°C and stirred over night. The reaction mixture adsorb on silica gel and purified flash chromatography (40 g of SiO2, 0-100% EtOAc in hexano)to give 2(S)-[[4-phenyl-2-thiazolo[4,5-c]pyridinyl]-1-(9H-fluoren-9-ylmethyl)ester-1-pyrrolidin-carboxylic acidwith(0,294, 0.71 mmol, 33%).

Example 28

N-Boc-protected cyclomethycaine

Sulfidea(810 mg, 2.5 mmol), synthesized according to the General method Shieh [Shieh, W-C; Xue, S.; Reel, N.; Wu, R.; Fitt, J.; Repic, O. Tetrahedron: Asymmetry,2001, 12,2421-2425], dissolved in methanol (25 ml). Oxon (4,5g) was dissolved in deionized water (25 ml). Methanol substrate solution is cooled to -10°C, and an aqueous solution Oksana added slowly to the reaction mixture. The reaction mixture was kept on ice and give her the opportunity to gradually warm to room temperature with stirring over night. Deionized the ode is used for diluting the reaction mixture to a volume of approximately 150 ml then for the extraction poured into a mixture of 90% ethyl acetate-hexane. The organic phase is dried (Na2SO4), adsorb on celite and purified by chromatography (ISCO, column 40 g CombiFlash phase,5-90% ethyl acetate-hexane for 30 min), receiving 804 mg of 2.27 mmol, 91%) of product, sulfoneb.

Following the General methodology described Burk [Burk, M. J.; Gross, M. F.; Martinez, J. P. J. Am. Chem.Soc.1995, 117, 9375-9376], alkeneb(774 mg, 2,19 mmol), dry methanol (40 ml) and [(S,S)-Me-BPE-Rh(COD)]+OTf-(500 mg, 0.8 mmol) are mixed in a flask for shaking the device Parra, nitrogen purged. The flaskParra vacuum and then filled with hydrogen to a pressure of 60 psi and vigorously shaken over night. The methanol is removed under reduced pressure and the crude product is filtered through a small layer of silica gel, using ethyl acetate. Evaporation of the solvent give 730 mg (2.0 mmol, 94%) of productwithwith the release of >98%.

The Z-protected amino esterwith(804 mg, of 2.27 mmol) was dissolved in methanol (16 ml). To this solution was added BOC-anhydride (1.5 g, 6.8 mmol), and then 20% Pd(OH)2·C (250 mg). All the air is removed from the reaction flask by vacuum and the mixture is vigorously stirred for 5 minutes and Then the flask is filled with gas-hydrogen mixtures provide the possibility of saving is a rule mixed at room temperature for 6 hours After pumping of hydrogen, the mixture is filtered through celite using methanol, and by evaporation of the solvent receive the crude productd(508 mg, 1.56 mmol, yield 70%).

Esterd(508 mg, 1.56 mmol) was dissolved in 8 ml of THF. Add deionized water (4 ml), then LiOH•H2O (120 mg, 2.8 mmol). The mixture is stirred at room temperature overnight, acidified using aqueous 1N HCl, and extracted into ethyl acetate (3×25 ml). The organic extracts are dried Na2SO4filter and concentrate, getting 372 mg (1,21 mmol, yield 78%) of N-Boc-protected cyclic sulfonylamino acidethat is transferred to the next stage without additional purification.

Example 29

Following the General methodology described Grigg [Blaney, P.; Grigg, R.; Rankovic, Z.; Thornton-Pett, M.; Xu, J.Tetrahedron,2002,58,1719-1737], round-bottom flask is charged with sodium hydride (480 mg, 60% suspension in oil, to 12.0 mmol, 4.0 EQ.) and purge with nitrogen for 15 minutes In the flask was added THF (6.0 ml), and the suspension is cooled to 0°C using bath with a mixture of ice-water. A separate flask is charged with BOC-glycinea(525 mg, 3.0 mmol), dry THF (6.0 ml) and ethyliodide (1.0 ml, 12 mmol, 4 EQ.). This mixture is added dropwise to a suspension of NaH in THF under vigorous stirring, at 0°C. After stirring for 1 h, the reaction mixture is remaut to room temperature and give her the opportunity to mix throughout the night. The reaction mixture was again cooled to 0°C, and to absorb excess hydride is slowly added methanol (4 ml). For diluting the mixture with deionized water and methanol is removed under reduced pressure. Impurities are extracted in a mixture of 90% ethyl acetate-hexane, then the aqueous layer was acidified by adding solid citric acid to achieve a pH of 2-3. The product is extracted in a mixture of 90% ethyl acetate-hexane. This organic layer is dried (Na2SO4) and filtered. Removal of the solvents under reduced pressure gives a quantitative yield of the productb.

Example 30

A mixture of unprotected amino acidsa(775 mg, from 7.24 mmol) and sodium carbonate (1,69 g, 16.0 mmol) is dissolved in a 1:1 solution of deionized water and THF (15 ml each). To this mixture is added BOC-anhydrideb(1.73 g, of 7.96 mmol). The mixture is stirred at room temperature over night and the THF removed under reduced pressure. The mixture is then acidified to pH 2-3 saturated aqueous citric acid and the product extracted in a mixture of 10% ethyl acetate-dichloromethane. The organic layer is dried (Na2SO4), filtered and concentrated under reduced pressure, obtaining the pure BOC-protected amino acidwith(1.40 g, 6.7 mmol, 93%), which is subject to use without additional purification.

Example 31

Dimeric compound 1/p>

A 25 ml round bottom flask, dipeptidea(1.2 g, 2.1 mmol) and compoundb(500 mg, 1.2 mmol) dissolved in dichloromethane (5.0 ml). Add N,N-diisopropylcarbodiimide (0.35 ml, 2.2 mmol) and 1-hydroxy-7-asobancaria (300 mg, 2.2 mmol) and the mixture is stirred at room temperature over night. The mixture is then concentrated on silica gel and purified flash chromatography (100% Gex to 100% EtOAc, column 40 g)to give 1.1 g (87%) of compoundwithin the form of a white solid. MS: m/z=907.

In a 50 ml round bottom flask, compoundwith(1.1 g, 1.2 mmol) is dissolved in a solution of 4n HCl in dioxane (20 ml, 60 mmol) and the solution stirred at room temperature for 30 minutes. Then the solution is concentrated and receiving 1.0 g (99%) of compounddin the form of a pale yellow solid. MS: m/z=807.

A 10 ml round bottom flask, 1,4-diisocyanatobutane (9,0 μl, 0,071 mmol)dissolved in dichloromethane (0.5 ml), is added slowly to a solution of compoundd(120 mg, 0.14 mmol) and N,N-diisopropylethylamine (37 μl, 0.21 mmol) in dichloromethane (0.5 ml) and the mixture is stirred at room temperature for 6 hours the mixture is Then concentrated on silica gel and purified flash chromatography (100% DHM to 5% MeOH/DHM, column 12 g)to give 81 mg (65%) of compoundein the form of a white solid washes the VA. MS: m/z=1753.

A 25 ml round bottom flask, compounde(81 mg, 0.046 mmol) was dissolved in dichloromethane (5.0 ml) and added morpholine (and 0.40 ml, 4.6 mmol). The solution was stirred at room temperature over night. Then the solution is concentrated and purified HPLC with reversed phase, getting to 22.6 mg (37%) of compound 1 as a white solid. MS: m/z=1308.

Example 32

Dimeric compound 2

Connection 2 receive, using the method of (for) compound 1, (12.6 mg of a white solid substance). MS: m/z=1336.

Example 33

Dimeric compound 3

Boc anhydride (1.6 g, 7.2 mmol) in 10 ml of THF is added dropwise to a cooled ice stir a solution of 4-hydroxy-L-phenylglycine (1.0 g, 6 mmol) and NaHCO3(1.0 g, 12 mmol) in 10 ml of water. After the addition, the solution is heated to room temperature and stirred over night. THF is evaporated and add 10 ml of water. The aqueous layer was extracted twice with 20 ml ethyl acetate and the aqueous layer was acidified to pH 3 aqueous citric acid. The aqueous layer was extracted with twice 25 ml of ethyl acetate and the organic layers combined. The organic layer is washed twice with saturated salt solution and once with water, dried over MgSO4and concentrated, obtaining 1.5 g of Boc-4-hydroxy-L-phenylglycine (Boc-Phg(-OH)). According to LC-MS-protected amino acid has a single peak, which corresponds to the proper (desired) weight, and it is used without additional purification. The calculated mass 267,3 found 268,5.

Boc-L-Proline (9.7 g, 45,2 mmol), 4-phenyl-1,2,3-thiadiazole-5-amine (4.0 g, and 22.6 mmol), EDC (8,2 g, 42,9 mmol), HOBt (5.8 g, 42,9 mmol), DIPEA (19.7 ml, 113 mmol) are mixed and stirred for 3 days in 40 ml of DMF at 60°C. Add ethyl acetate and saturated aqueous NaHCO3. The aqueous layer was separated and extracted with ethyl acetate. The organic layers are combined and washed with aqueous NaHCO3and a saturated solution of salt. The organic layer is dried over MgSO4and concentrated to a brown residue. Pure Boc-prolyl-4-phenyl-5-amino-1,2,3-thiadiazolewithreceive by crystallization from 100 ml of hot acetonitrile, 5,9, Calculated mass 374,5 found 375,3.

Connectionwith(1.5 g, of 4.25 mmol) is treated with 20 ml of a mixture of 4n HCl/dioxane for 30 minutes and the solvent is removed. Boc-L-Phg(4-OH) (1,25 g, and 4.68 mmol), BOP (2.1 g, to 4.68 mmol), DIPEA (1,63 ml, 9,36 mmol) are mixed in 30 ml DMF and stirred for 3 hours at room temperature, receiving the connectiond. Normal processing: Add ethyl acetate and the organic layer washed twice aqueous sodium bicarbonate, washed twice with saturated salt solution, dried over MgSO4and concentrate. According to LC-MS is the STATCOM has a single peak, responsible proper (desired) weight, and the resulting productduse in the next stage without additional purification. The calculated mass 523,6 found 524,3.

Connectiondwith the previous stage treated with 20 ml of a mixture of 4n HCl/dioxane for 30 minutes and the solvent is removed. Boc-N-methylalanine (0.95 g, and 4.68 mmol), BOP (2.1 g, to 4.68 mmol) and DIPEA (1,63 ml, 9,36 mmol) are mixed in 30 ml DMF and stirred for 3 hours at room temperature. Normal processing: add ethyl acetate and the organic layer washed twice aqueous sodium bicarbonate, washed twice with saturated salt solution, dried over MgSO4and concentrate. The residue is purified by HPLC, obtaining 1.2 g of the compounde. The calculated mass 608,7 found 609,3.

Connectione(1.2 g, 1.97 mmol), 80% of the mass. propylbromide in toluene (879 mg, 5,91 mmol), K2CO3(817 mg, 5,91 mmol) are mixed in 40 ml of DMF and stirred for 16 hours at 60°C. To the solution was added water and extracted 3 times with ethyl acetate. The organic layers are combined, washed twice aqueous NaHCO3, washed twice with saturated salt solution, dried over MgSO4and concentrate. The crude residue purified HPLC, receiving 200 mg connectionf. The calculated mass 646,8 found 647,3.

Soy is inania f(200 mg, 0.31 mmol), Pd(OAc)2(1.2 mg, 0,0062 mmol), CuI (1.4 mg, 0,0062 mmol) and DABCO (104 mg, of 0.93 mmol) are mixed in 20 ml of acetonitrile and stirred over night at room temperature. Add ethyl acetate and the organic layer washed twice aqueous NaHCO3, washed twice with saturated salt solution, dried over MgSO4and concentrate. The residue is treated with 20 ml of a mixture of 4n HCl/dioxane for 30 minutes and concentrated. The crude residue purified HPLC, receiving 81 mg connection3. The calculated mass 1091,3 found 1091,7.

Example 34

Dimeric compound 4

4-Ethynylbenzoate alcohola(1 g, EUR 7.57 mmol) diluted in 20 ml DHM, and cooled to 0°C in a bath with ice. Added dropwise tribromide phosphorus (4.1 g, 15 mmol). The reaction mixture is allowed gradually to warm to room temperature and stirred under nitrogen atmosphere over night. The reaction is quenched by addition of H2O in a bath with ice, extracted with DHM. The combined organic layers washed with saturated salt solution, dried over Na2SO4and concentrate to dryness. The crude product is purified by chromatography (ISCO)using 100% hexane as eluent to obtain pure 4-ethynylbenzaldehydeb(220 mg). M+H+195,1.

NaH (135 mg, 3.4 mmol, 60% dispersion in mineral oil) with spenderat cooled in ice anhydrous THF solution (5 ml) under nitrogen atmosphere. Add methyl ester of N-boc-CIS-4-hydroxy-L-Prolinewith(417 mg, 1.7 mmol)and then 4-ethynylbenzoateb(220 mg, 1.13 mmol). The reaction mixture is allowed gradually to warm to room temperature and stirred under nitrogen atmosphere over night. The reaction is quenched by addition of H2O in a bath with ice, and concentrated to dryness. The crude product is purified by chromatography (ISCO)using a mixture of 10% MeOH/DHM as eluent, receiving 200 mg connectiond. M+H+346,2.

Connectiond(200 mg, 0,578 mmol) diluted in DHM (10 ml), cooled in a bath with ice, treated with pyridine (137 mg, at 1.73 mmol) and foramerica cyanuric acid (109 mg, 0.81 mmol) dropwise. After complete addition, the solution is heated to room temperature and stirred for 4 hours. Add 1 ml of H2O, the solution is stirred for 15 minutes. Add a further quantity of H2O (20 ml) and the aqueous layer was extracted twice DHM. The combined organic layers washed with saturated salt solution, dried over Na2SO4and concentrate to dryness. The rest is used in the next stage without additional purification. Crude oil (205 mg, 0,578 mmol), 4-phenyl-1,2,3-thiadiazole-5-aminee(207 mg, of 1.16 mmol) and pyridine (136 mg, of 1.76 mmol) are mixed in 10 ml DHM and stirred over night. dobavlaut additional amount DHM and washed with aqueous NaHCO 3. The aqueous layer was extracted twice DHM, washed with saturated salt solution, dried over Na2SO4and concentrate to dryness. The crude product is purified by chromatography (ISCO)using as eluent a mixture of 40%-80% EtOAc/hexane, to obtain 101 mg of the compoundf. M+H+505,4.

Connectionf(40 mg, 0.079 in mmol) is treated with 10 ml of a mixture of 4n HCl/dioxane for 30 minutes and the solvent is removed. The residue, Boc-N-Meala-Chg-OHg, DIC and HOAt mixed in 5 ml of dry DHM and stirred for 4 hours at room temperature. To the solution add H2O and extracted twice DHM. The organic layers are combined, dried over Na2SO4and concentrate. The crude product is purified by chromatography (ISCO)using as eluent a mixture of 40%-80% EtOAc/hexane, to obtain 48 mg of pure compoundh. M+H+729,5

Connectionh(20 mg, or 0.027 mmol), Pd(OAc)2(0,121 mg, 0,00054 mmol), DABCO (9 mg, 0,082 mmol) and CuI (0,105 mg, 0,00054 mmol) are mixed in 5 ml of acetonitrile and stirred over night at room temperature. Add ethyl acetate and the organic layer washed twice aqueous NaHCO3combined organic layers washed with saturated salt solution, dried over Na2SO4and concentrate. The residue is treated with 1:1 DHM and TFA (20 ml) for 30 minutes and the concentration of irout. The crude product is purified HPLC, receiving 7 mg of compound 4. M+H+1255,6.

Example 35

Dimeric compound 5

To a solution ofa(0.1 g, 0.12 mmol) in dichloromethane (2 ml) add Diisopropylamine (0,0456 ml, 0.26 mmol). To the mixture add adipocere (0,00862 ml, 0.06 mmol). The resulting solution was stirred at room temperature for 4 hours. To the mixture again, add Diisopropylamine (0,0456 ml, 0.26 mmol). The solution is stirred over night. The crude product adsorb on silica gel and purified flash chromatography (4 g SiO2, 0-5% methanol in dichloromethane)to give Fmoc-protected dimerb(0,073 g, 0.046 mmol, 78%).

To a solution of Fmoc-protected dimerb(0,073 g, 0.046 mmol) in dichloromethane (5 ml) is added morpholine (of 0.21 ml, 2.4 mmol). The mixture is stirred for 3 hours. The solution is again added morpholine (of 0.21 ml, 2.4 mmol). The solution is stirred over night. Sample concentrate and purify SFC (ethylpyridine, 20-60% methanol in CO2for 6,5 minutes at 50 ml/min), receiving dimer 5 (0,019 g of 0.017 mmol, 36%).

Example 36

Dimeric compound 6

To a solution ofa(0.1 g, 0.12 mmol) in dichloromethane (2 ml) add Diisopropylamine (0,0228 ml, 0.13 mmol). To the mixture of 1,6-diisocyanatohexane (0,00954 ml, 0,0593 mmol). The resulting solution was stirred PR is room temperature for 4 hours. Add a small crystal of N,N-dimethylaminopyridine. The mixture is stirred for 30 minutes. To the mixture again, add Diisopropylamine (0,0338 ml, 0.13 mmol). The mixture is stirred for 30 minutes. Add 1,6-diisocyanatohexane (0,00478 ml, 0,0297 mmol). The solution is stirred over night. The crude product adsorb on silica gel and purified flash chromatography (4 g SiO2, 0-5% methanol in dichloromethane)to give Fmoc-protected dimerbwith quantitative yield.

To a solution of Fmoc-protected dimerb(0.12 mmol) in dichloromethane (5 ml) is added morpholine (0,38 ml, 4.3 mmol). The mixture is stirred for 3 hours. The solution is again added morpholine (0,38 ml, 4.3 mmol). The solution is stirred over night. Sample concentrate and purify SFC (ethylpyridine, 20-60% methanol in CO2for 6,5 minutes at 50 ml/min), receiving dimer 6 (0,0392 g 0,033 mmol, 28%).

Example 37

Dimeric compound 7

4-Hydroxyphenylglycinea(1.0 g, 5,98 mmol) and concentrated HCl (6 ml) of 2,2-dimethoxypropane (33 ml, 813 mmol) is stirred over night at room temperature. The brown solution is evaporated and the net connectionbprecipitated from a solution of methanol and diethyl ether. Receive 1,3, Calculated mass 181,2, found mass 181,9. Connectionb(1.3 g, 5,98 mmol) and NaHCO3(1.0 g, 12,0 shall mol) is dissolved in 15 ml water and 15 ml of acetonitrile and Boc-anhydride (1.6 g, 7.2 mmol) in 10 ml of THF is added dropwise, and the solution is stirred over night at room temperature. The solution is evaporated and add ethyl acetate. Conduct regular processing: the organic solution was washed with aqueous NaHCO3saturated salt solution, water, dried over MgSO4and concentrate, receiving the connectionc. The calculated mass 281,2, found mass 282,1.

Connectionwith(1.63 g, 5.8 mmol), 80% of the mass. propylbromide in toluene (1,93 ml of 17.4 mmol), K2CO3(2.4 g, to 17.4 mmol) was dissolved in 30 ml of DMF and heated at 50°C over night. The solution is evaporated and conduct regular processing as described above. The compound obtaineddclean HPLC. The calculated mass 319,4 found mass 320,1. Connectiond(1.85 g, 5.8 mmol) dissolved in 50 ml of a mixture of THF/water (1:1) with LiOH (487 mg, 11.6 mmol) and stirred for 4 hours. The solution is evaporated and acidified with aqueous citric acid. The solution is extracted in EtOAc, washed with saturated salt solution, dried over MgSO4and concentrate, receiving connectionein the form of a yellow oil. Output 770 mg. Calculated mass 305,3 found mass 305,8.

To a cooled with ice to a solution of Boc-Proline (598 mg, 2,78 mmol) and pyridine (411 μl, 5,09 mmol) in 10 ml DHM added dropwise floramite cyanuric acid (406 mg, a 3.01 mmol). is Astaro allow to warm to room temperature and stirred for 90 minutes The solution is evaporated and add EtOAc and the organic layer was washed with saturated salt solution, dried over MgSO4and concentrate. To the residue add 4-phenyl-2,2'-betasol-5-amine (600 mg, 2,31 mmol) with pyridine and stirred over night at room temperature. The solution is evaporated, add EtOAc and conduct regular processing. Connectionfclean HPLC. Exit 270 mg. Calculated mass 456,6 found mass 457,3.

Connectionf(200 mg, 0.44 mmol) is treated with 20 ml of 4n HCl in dioxane for 30 min and the solvent is removed. Boc-Phg(4-O-propargyl)OHe(147 mg, 0.48 mmol), hexaflurophosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (BOP) (213 mg, 0.48 mmol) and DIPEA (168 μl, 0.96 mmol) are mixed in 20 ml DMF and stirred for 3 hours at room temperature. Conduct regular processing and carry out cleaning by HPLC, receiving the connectiong. The calculated mass 643,8 found mass 644,3.

Connectiong(282 mg, 0.44 mmol) is treated with 20 ml of 4n HCl in dioxane for 30 min and the solvent is removed. Boc-MeAla (98 mg, 0.48 mmol), BOP (213 mg, 0.48 mmol) and DIPEA (168 μl, 0.66 mmol) are mixed in 20 ml DMF and stirred for 3 hours at room temperature. Conduct regular processing and carry out purification by HPLC, receiving the connectionh. Yield 47 mg of the Calculated mass of 28.9, found lots 729,3.

Connectionh(94 mg, 0,128 mmol), compoundi(84 mg, 0,128 mmol), Pd(OAc)2(1.1 mg, 0,0051 mmol), CuI (0,98 mg, 0,0051 mmol) and DABCO (86 mg, 0.77 mmol) are mixed in 20 ml of acetonitrile and stirred over night at room temperature. Add ethyl acetate and the organic layer washed twice aqueous NaHCO3, washed twice with saturated salt solution, dried over MgSO4and concentrate. The residue is treated with 20 ml of a mixture of 4n HCl/dioxane for 30 minutes and concentrated. The crude residue purified HPLC, receiving 12 mg of compound 7. The calculated mass 1173,4 found 1173,8.

Example 38

Dimeric compound 8

Connectiona(160 mg, 0.2 mmol) dissolved in 1 ml DMF and added HATU (91 mg, 0.24 mmol), followed by the addition of 1,6-diaminohexane (12 mg, 0.1 mmol) and diisopropylethylamine (52 ál,0.3 mmol). The reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with EtOAc, washed 2x with saturated NaHCO3and washed with a saturated solution of salt. Dried over MgSO4and concentrate. The residue is dissolved in 2 ml of DMF, followed by addition of 4-aminomethylpyridine (120 μl, 1.0 mmol) and stirred at room temperature for 3 hours. Preparative HPLC gives compound 8. MS=1205,2 (M+1).

When the EP 39

Dimeric compound 9

Connectiona(135 mg, 0,17 mmol) dissolved in 1 ml DMF, added HATU (91 mg, 0.24 mmol), and then 1,6-diaminopropan (8 ál,0.09 mmol) and diisopropylethylamine (44 μl, 0.26 mmol). The reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with EtOAc, washed 2x with saturated NaHCO3and washed with a saturated solution of salt. Dried over MgSO4and concentrate. The residue is dissolved in 2 ml of DMF, followed by addition of 4-aminomethylpyridine (104 μl, 0.85 mmol) and stirred at room temperature for 3 hours. Preparative HPLC gives compound 8. MS=1164,5 (M+1).

Example 40

Dimeric compound 9

Connection 9 receive according to the procedures described for compound 8. MS=1310,7 (M+1).

Example 41

Dimeric compound 22

Connectiona(665,0 mg, 1,036 mmol) in N,N-dimethylformamide (10.0 ml, 129 mmol) was added 1-hydroxybenzotriazole (0,154 g to 1.14 mmol), 1,3-diaminopropan-2-ol (0,0467 g, 0,518 mmol) and N,N-diisopropylethylamine (0,451 ml, at 2.59 mmol). After the dissolution of solids (with the formation of a solution), add the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (0,218 g to 1.14 mmol) and the solution stirred at room temperature over night.

Rast is the PR heated to 50°C and continue stirring over night. The solution was diluted with EtOAc (150 ml) and washed with 1N HCl (2× 150 ml). The combined aqueous acidic phase is extracted with EtOAc 1× (100 ml) and the combined organic extracts are washed with 1N NaOH 2× (150 ml). The combined basic layers extracted with EtOAc 1× (100 ml). The combined organic phases are washed with saturated salt solution 1× (150 ml), dried (Na2SO4), filtered and concentrated using a Genevac evaporator and then subjected to flash chromatography (ISCO, solid phase 80G (0-80%) 10% MeOH/DHM, DHM)to give Boc-protected dimer.

Boc-protected dimer is treated with a solution DHM and TFA 1:1 (5 ml) for 10 minutes and concentrated. The crude product is purified HPLC, getting 77,3 mg end dimeric compounds 22.

Example 42

Dimeric compound 23

In the ampoule connectiona(700,0 mg, 1,091 mmol) is added, in order, 1-hydroxybenzotriazole (rate £ 0.162 g, 1.20 mmol), N,N-dimethylformamide (3,500 ml, 45,20 mmol), 2,2-DIMETHYLPROPANE-1,3-diamine (0,0655 ml, 0,545 mmol), N,N-diisopropylethylamine (value (0.475) ml, 2,73 mmol), hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (0,230 g, 1.20 mmol) and stirred at 50°C over night. The solution was diluted with EtOAc (150 ml) and washed with 1N HCl (2× 150 ml). The combined acidic aqueous phase is extracted with EtOAc 1× (100 ml) and the combined organic layers washed with saturated bicarbonate and 2× (150 ml). Joint basic phase extragere the t EtOAc 1× (100 ml) and the combined organic phases are washed with saturated salt solution 1× (150 ml), dried (Na2SO4), filtered, concentrated and then subjected to flash chromatography (ISCO, column solid phase 80G, 0-5% MeOH/DHM, 45 min)to give Boc-protected dimer.

To the residue add TFA/DHM 1:1 solution triperoxonane acid:methylene chloride (5,00 ml), stirred for 10 min at room temperature and then evaporated on a rotary evaporator and then adding DHM and again by evaporation on a rotary evaporator. The remainder of the concentrate using a Genevac (evaporator), receiving of 163.7 mg crude dimer, which is purified HPLC with getting 86,3 mg of pure dimeric compounds 23.

Example 43

Study of the inhibition of IAP

In the following experiments we used chimeric BIR domain, referred to as MLXBIR3SG, in which 11 out of 110 residues correspond to residues found in XIAP-BIR3, while the rest correspond to ML-IAP-BIR. Chimeric protein MLXBIR3SG it was established that binds to and inhibits caspase-9 is much better than any of the native BIR domains, except the associated on the basis of the Smac peptide and the Mature protein Smac, with an affinity that is similar to the affinity of native ML-IAP-BIR.Increased inhibition of caspase-9 chimeric domain BIR, MLXBIR3SG, correlated with increased inhibition of doxorubicin-induced apoptosis by transfection of MCF7 cells.

The sequence MLXBIR3SG:

MGSSHHHHHHSSGLVPRGSHMLETEEEEEEGAATLSRGPAFPGMGSEELRLASFYDWP LTAEVPPELLAAAGFFHTGHQDKVRCFFCYGGLQSWKRGDDPWTEHAKWFPGCQFLLR SKGQEYINNIHLTHSL (SEQ ID NO:1)

Analysis of the binding of peptides by method TR-FRET

Experiments on competition transfer of resonance energy fluorescence with time resolution was performed on a Wallac Victor2 apparatus for simultaneous reading of the tablets on many labels (Perkin Elmer Life and Analytical Sciences, Inc.) according to the methods described by Kolb et al (Journal of Biomolecular Screening, 1996, 1(4):203). Reagent cocktail containing 300 nm his-tagged MLXBIR3SG; 200 nm biotinylated SMAC peptide (AVPI); 5 mg/mlanti-hisallophycocyanin (XL665) (CISBio International); and 200 ng/ml streptavidin-europium (Perkin Elmer), received in the reagent-buffer(50 mm Tris [pH 7,2], 120 mm NaCl, 0.1% bovine globulin, 5 mm DTT and 0.05% octylglucoside). (Alternatively, this cocktail can be made using labeled with europium anti-His (Perkin Elmer) and streptavidin-allophycocyanin (Perkin Elmer) at concentrations of 6.5 nm and 25 nm, respectively). Reactive cocktail incubated at room temperature for 30 minutes. After incubation, the cocktail was added to a 1:3 serial dilutions of the compounds antagonist (initial concentration 50 μm) in 384-well black FIA plates (Greiner Bio-One, Inc.). After incubation for 90 minutes at room temperature, fluorescence was read filters for wavelength excitation of europium (340 nm) and wavelengths of emission of the europium (615 nm) and allophycocyanin (665 nm). Data antagonist was calculated as the ratio of the signal emitted the Oia of allophycocyanin at 665 nm to the signal emission of europium at 615 nm (these relations were multiplied by a factor of 10000 for easier manipulation of data). The obtained values are presented graphically as a function of the concentration of antagonist and led in accordance with equation 4 parameters using Kaleidograph software(Synergy Software, Reading, PA). Readings antagonistic activity was determined on the basis of the values IC50. Compounds according to this invention that were tested in this assay, demonstrated the value of the IC50lessthan 200 μm, which indicates that the manifestation of their inhibitory activity against IAP.

Analysis of the binding of peptides by the method of polarization fluorescence

The polarization was carried out on the instrument Analyst HT 96-384 (Molecular Devices Corp.) according to Keating, S.M., Marsters, J, Beresini, M., Ladner, C, Zioncheck, K., Clark, K., Arellano, F., and Bodary., S.(2000) in Proceedings of SPIE: In Vitro Diagnostic Instrumentation (Cohn, G.E., Ed.) pp.128-137, Bellingham, WA. Samples for measuring the inclination to fluorescence polarization was obtained by adding 1:2 serial dilutions MLXBIR3SG, based on the final concentration of 5 μm in the polarization buffer (50 mm Tris [pH 7,2], 120 mm NaCl, 1% bovine globulins, 5 mm DTT and 0.05% octylglucoside) to 5-carboxyfluorescein-anywherefrom AVP-Phe-NH2(AVP-Phe-FAM) at a final concentration of 5 nm.

The reaction mixture was read after incubation for 10 minutes at room temperature using a standard cut-off filters for flu is rescenter probe (λ wosb.=485 nm; λthe emitted.=530 nm) in 96-well black HE96 tablets (Molecular Devices Corp.). The values of fluorescence were presented graphically as a function of protein concentration, and received IC50by bringing data obtained in accordance with equation 4 parameters,using Kaleidograph software (Synergy software, Reading, PA). Experiments on competition was performed by adding MLXBIR3SG at 30 nm to wells containing 5 nm of probe AVP-Phe-FAM, 1:3 serial dilution of compounds antagonists, starting with a concentration of 300 μm in the polarization buffer. The samples were read after 10-minute incubation. The values of fluorescence polarization represented graphically as a function of the concentration of antagonist, and values IC50was obtained by aligning the received data in accordance with equation 4 parameters,using Kaleidograph software (Synergy software, Reading, PA). The inhibition constants (Kifor antagonists were determined from the values of IC50. Compounds according to this invention that were tested in this assay, demonstrated the IC50less than 10 microns. Compound 2 had the IC500,2787 μm, compound 10 had IC501,324 μm, compound 1 had the IC500,2309 μm, compound 4 had the IC502,4054 μm, compound 11 had IC501,0261 μm, compound 12 had IC501,0965 μm,compound 13 had IC 503,8188 μm, compound 14 had IC502,3450 μm, compound 15 had IC503,8334 μm, compound 16 had IC500,2341 μm, compound 24 was IC501,3802 μm, compound 17 had IC500,1677 μm, compound 23 had IC500,6793 μm and the connection 22 had IC500,3780 microns.

1. The compound having the formula
U1-M-U2
where U1and U2have General formula (I)

where X1and X2each represent O;
R2represents a C1-4alkyl, phenyl, 3-6-membered saturated carbocycle, or 4-7-membered saturated or unsaturated heterocycle containing 1 or 2 heteroatoms independently selected from O, N and S, where each alkyl, phenyl, carbocycle or a heterocycle optionally substituted by one or more groups selected from halogen, hydroxyl, oxo, carboxyl,1-4of alkyl, C1-4alkoxy, C1-4alkylsulfonyl or amino;
R3represents H or saturated With a1-4alkyl;
R3' represents H;
R4and R4' are independently H or C1-4alkyl;
R5represents H or C1-4alkyl;
G is selected from the group consisting of IVb, IVd and IVe:

where R1represents H;
R5' not only is em a H or C 1-4alkyl;
R6and R6' each represent H;
R7in each case represents N;
A1represents a 5-membered heterocycle containing 1 to 3 heteroatoms selected from zero to 1 sulfur atom, and from zero to 3 nitrogen atoms, optionally substituted by one or two groups Q1;
each Q1independently represents H, C1-4alkyl, phenyl or 5 - or 6-membered saturated or unsaturated heterocycle containing 1-3 heteroatoms selected from zero to 1 sulfur atom, and from zero to 3 nitrogen atoms; where one CH2the group of alkyl optionally replaced by-C(O)-NR8- or-NR8-C(O)-; where each phenyl or heterocycle is optionally substituted by one or more groups selected from C1-4of alkyl, hydroxyl, halogen, mercapto, oxo, carboxyl, halogen-substituted alkyl, amino or cyano;
where R8represents H or C1-4alkyl;
X3represents O or S;
Y represents CH2;
Zirepresents S;
one of Z2, Z3and Z4represents N and the others are CQ2;
Q2represents H or phenyl;
M represents a linking group: a) covalently linking group, R2from U1with a group R2from U2; or (b) covalently linking the th group G from U 1with a group G of U2; where M is selected from the group comprising-C(O)NH-(CH2)2-12-NH-C(O)-, -C(O)-NH-CH2-[C≡C]1-4-CH2-NH-C(O)-, -O-CH2-C≡C-C=C-CH2-O-, -O-CH2-Ph-C≡C-C=C-Ph-CH2-O-, -C(O)-NH-(CH2)1-6-(CHOH)-(CH2)1-6-NHC(O)-, -C(O)NH-(CH2)1-4-[O(CH2)1-4]0-8-NH-C(O)-, -C(O)NH-(CH2)1-6-(C(CH3)2)-(CH2)1-6-NHC(O)-, -C(O)NH-[(CH2)1-4NRx]1-2-C(O)-, -C(O)NH-(CH2)1-4NH]1-2-C(O)-, -C(O)NH-CH2-Ph-CH2-NH-C(O)- and-C(O)NH-(CH2)3-NRy-(CH2)3-NHC(O)-;
where each Rxindependently represents H, alkyl or acetyl, and Ryrepresents-C(O)-(CH2)1-6-(3-(2-amino-2-carboxyethyl)-2,5-dioxopiperidin-1-yl); and n is 1;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where G is a group of formula IVd

where Q2represents phenyl.

3. The compound according to claim 1, where G is a group of the formula IVb:

where A1has the formula A1:

where R'5represents H;
X3represents O;
Q'1represents S;
Q'2represents CR9or N;
Q'3represents N;
Q'4represents CR9;
R9before the hat is H.

4. The compound according to claim 1, where R2represents a C1-4alkyl, celexin or saturated 5 - or 6-membered heterocycle.

5. The compound according to claim 1, where R2selected from the group consisting of tert-butyl, isopropyl, cyclohexyl, tetrahydropyran-4-yl, N-methylsulfonylmethane-4-yl, tetrahydrothiopyran-4-yl, tetrahydrothiopyran-4-yl (where S is the oxidised form of SO or SO2), cyclohexane-4-it 4-hydroxycyclohexane, 4-hydroxy-4-methylcyclohexane, 1-methyl-tetrahydropyran-4-yl, 2-hydroxyprop-2-yl, buta-2-yl, thiophene-3-yl, piperidine-4-yl, pyridine-3-yl, phenyl and 1-hydroxic-1-yl.

6. The compound according to claim 1, where R3represents methyl.

7. The compound according to claim 1, where R4represents H or methyl, and R4' represents H.

8. The compound according to claim 1, where R5represents H or methyl.

9. The compound according to claim 1, where R2represents isopropyl, tert-butyl, cyclohexyl or tetrahydropyranyl; R3represents methyl; R4represents methyl; R4' represents H; and R5represents H.

10. The compound according to claim 1, selected from the group consisting of:

























and its pharmaceutically acceptable salt.

11. The compound according to claim 1, which has the General formula I':

where each group G1and G2independently represents a group G as defined in claim 1.

12. The compound according to claim 1, where each U1and U2has the formula II-d:

where the group Q is a group Q2such as defined in claim 1.

13. The compound according to claim 1, which is a

where each group G1and G2is a group G and the group G is the same as defined in claim 1 or 12.

14. The compound according to claim 1, which is a

where each group G1and G2is a group G and the group G is the same as defined in claim 1 or 12.

15. The compound according to claim 1, which is a

where each group G1and G2is a group G and the group G is the same as defined in claim 1 or 12.

16. The compound according to claim 1, which is a

where each group G1and G2is a group G and the group G is the same as defined in claim 1 or 12.

17. The compound according to claim 1, which is a

18. The compound according to claim 1, which is a

19. The compound according to claim 1, which is a

20. The compound according to claim 1, which is a

21. The compound according to claim 1, which is a

22. The compound according to claim 1, which is a

23. The compound according to claim 1, which is a

24. The compound according to claim 1 for inducing apoptosis in a cell by introducing a connection to the specified cell.

25. The compound according to claim 1 for sensibilizirovannoy cells to the apoptotic signal by introducing a connection is in the specified cell.

26. Connection A.25 where specified induce the apoptosis signal by contacting the specified cell with a compound selected from the group consisting of citarabinom, fludarabine, 5-fluoro-2'-dose irradiation on neurogenesis, gemcitabine, methotrexate, bleomycin, cisplatin, cyclophosphamide, adriamycin (doxorubicin), mitoxantrone, camptothecin, topotecan, colcemid, colchicine, paclitaxel, vinblastine, vincristine, tamoxifen, finasteride, Taxotere and mitomycin C, or exposure to radiation.

27. Connection A.25 where specified induce the apoptosis signal contacts of the specified cells to Apo2L/TRAIL.

28. The compound according to claim 1 for the inhibition of IAP binding protein with protein caspase by contacting the specified protein IAP with the connection.

29. The compound according to claim 1 for the treatment of a disease or condition associated with overexpression of IAP in a mammal by introducing a specified mammal an effective amount of the compounds.

30. The compound according to claim 1 for the treatment of cancer by introducing a specified mammal an effective amount of the compounds.

31. The use of compounds according to claim 1 for the production of medicines for inducing apoptosis in a cell by introducing a connection to the specified cell.

32. The use of compounds according to claim 1 for the manufacture of a medicinal product for sensibilize the Finance cell to an apoptotic signal by introducing a connection to the specified cell.

33. Use p where specified induce the apoptosis signal by contacting the specified cell with a compound selected from the group consisting of citarabinom, fludarabine, 5-fluoro-2'-dose irradiation on neurogenesis, gemcitabine, methotrexate, bleomycin, cisplatin, cyclophosphamide, adriamycin (doxorubicin), mitoxantrone, camptothecin, topotecan, colcemid, colchicine, paclitaxel, vinblastine, vincristine, tamoxifen, finasteride, Taxotere and mitomycin C, or exposure to radiation.

34. Use p where specified induce the apoptosis signal contacts of the specified cells to Apo2L/TRAIL.

35. The use of compounds according to claim 1 for the production of pharmaceuticals for inhibition of IAP binding protein with protein caspase by contacting the specified protein IAP with the connection.

36. The use of compounds according to claim 1 for the manufacture of a medicinal product for the treatment of a disease or condition associated with overexpression of IAP in a mammal by introducing a specified mammal an effective amount of the compounds.

37. The use of compounds according to claim 1 for the manufacture of a medicinal product for the treatment of cancer by introducing a specified mammal an effective amount of the compounds.



 

Same patents:

FIELD: chemistry; biochemistry.

SUBSTANCE: invention relates to biotechnology and specifically to biologically active substances of peptide nature which modulate activity of certain growth factors relative stimulation of proliferation of thyroxine producing follicular cells of the thyroid gland. The invention can be used in medicine and experimental biochemistry. Proteins which are highly homologous to the thyrotropic hormone are sought for. After that a functional TSH site is built up in silico based on the spatial structure of the complex of the β2 adrenoceptor/antibody to the β2 adrenoreceptor taking into account homology of the TSH and antibodies to the β2 adrenoreceptor. Chemical synthesis of the identified amino acid residues of antibodies to the β2 adrenoreceptor is then carried out. Further, the synthesised oligopeptides are biologically tested. The said oligopeptide has general formula X1-X2-X3 (I), where X1 is Trp or Tyr; X2 is Gly, Gin, Glu, or Asp, X3 is Tyr or Trp.

EFFECT: invention widens the range of biologically active substances of peptide nature.

2 dwg, 1 tbl, 4 ex

The invention relates to new compounds which are inhibitors of interleukin-1-converting enzyme (IAP), is characterized by a specific structural formula; to pharmaceutical compositions having the ability to inhibit interleukin-1-converting enzymes, method of treatment and prophylaxis of diseases selected from the group consisting of IL-1-mediated autoimmune inflammatory, neurodegenerative diseases, as well as the selection method of the IAP inhibitor

The invention relates to compounds of the formula a-b-D-E-F-G, where the values of the radicals presented in the description in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts

The invention relates to new derivatives of substituted purine with immune modulating, in particular immunostimulatory activity in vivo and in vitro and does not exhibit toxicity, to pharmaceutical compositions and method of slowing tumor growth

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and salts thereof wherein R1 represents -A11-A12-; R2 represents tetrahydrofurylmethyl, tetrahydropyranylmethyl or tetrahydropyranyl; A11 represents a single bond, methylene or 3,2-ethylene; A12 represents C1-6 alkyl, C3-6 cycloalkyl or C3-6 cycloalkyl containing methyl; R3 represents methoxy, cyano, cyclobutyloxymethyl, methoxymethyl or ethoxymethyl; and R4 represents methoxy or chlorine. Also, the invention also refers to a pharmaceutical composition possessing corticotrophin-releasing factor (CRF) receptor antagonist activity, containing a compound of formula (I), to a therapeutic/preventive agent, and a method of treating the diseases specified in the patent claim.

EFFECT: there are presented the compounds of formula (I) as corticotropin-releasing factor (CRF) receptor antagonists.

20 cl, 2 dwg, 2 tbl, 51 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1 , where X and T are N or C, Q is a (3-7)-member aromatic ring which contains 0-3 nitrogen atoms as ring members, and which is optionally benzo-condensed and is substituted with oxo; C1-C6-alkyl; halogen- C1-C6-alkyl; hydroxy-C1-C6-alkyl; C1-C6-alkoxy; C6-C10-aryl; or a (3-7)-member heteroaryl containing 1-3 oxygen atoms, P is C1-C6-alkyl, optionally substituted with a halogen, and R is a group selected from: (i) -C1-C6-alkyl-R1, (ii) -NR2R3, (iii) -O-R4, (iv) -S-R5, (v) -C (=O))-R6, (vi) optionally substituted (3-7)-member heteroaryl containing 1-4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulphur atom, (vi) optionally substituted (3-7)-member heteroatom containing 1-4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulphur atom, (vii) optionally substituted, saturated or partially unsaturated, separate or condensed (3-10)-member heterocyclic ring containing 1-4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulphur atom, (viii) azido; where each R1, R2, R3, R4, R3, R6, is as described in the claim. The invention also relates to a pharmaceutical composition for preventing and treating a vascular disease, which contains a compound of formula 1.

EFFECT: compounds of formula 1 with inhibitory activity with reference to aggregation of thrombocytes.

7 cl, 7 dwg, 2 tbl, 519 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a 2-aza-bicyclo[3.3.0]octane derivative of formula , with stereogenic centres in a (1S,3S,5S)-configuration, where A is a thiazolyl which is unsubstituted or monosubstituted, where the substitute is independently selected from a group comprising C1-4alkyl, C3-6cycloalkyl and NH2; B is phenyl which is unsubstituted or mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, trifluoromethyl, NHC(O)CH3 and halogen; and R1 is an imidazo[2,1·b]thiazolyl or benzoisoxazolyl group, where said groups are independently unsubstituted or monosubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl; or R1 is a 2,3-dihydrobenzofuranyl group; or a pharmaceutically acceptable salt. The 2-aza-bicyclo[3.3.0]octane derivative of formula (I) is as a medicinal agent having the activity of orexin receptor antagonists.

EFFECT: obtaining novel 2-aza-bicyclo[3,3,0]octane derivatives as orexin receptor antagonists.

8 cl, 1 tbl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of general formula:

or its pharmaceutically acceptable salt wherein the ring A represents a phenyl group which can contain 1-3 substitutes specified in a group of substitutes, or a thienyl group which can contain 1-3 substitutes specified in a group of substitutes α; L represents a single bond or a group of formula -NRC CO- (wherein Re represents a hydrogen atom), the ring B represents C6-14 aryl group which can contain 1-3 substitutes specified in a group of substitutes α, or a 5-10-member heterocyclic group which can contain 1-3 substitutes specified in a group of substitutes α; the X, Y, Z , R1 and R2 , R3, R4, R5 and R6 radical values are presented in cl.1 of the patent claim which possess an effect of Aβ protein production inhibition or an effect of BACE1 inhibition.

EFFECT: preparing the compound which is applicable as a preventive or therapeutic agent for neurodegenerative disease caused by Aβ.

13 cl, 35 tbl, 285 ex

FIELD: chemistry.

SUBSTANCE: invention relates to bicyclosulphonyl acid (BCSA) compounds of formula: where: where each of -Rpw, -Rpx, -RPY, and -RPZ independently denotes H or -RRS1; each -RRS1 independently denotes -F, -Cl, -Br, -I, -RA1, -CF3, -OH, -OCF3 or -ORA1; where each RA1 independently denotes C1-4alkyl, phenyl or benzyl; and additionally, two neighbouring -RRS1 groups can together form -OCH2O-, -OCH2CH2O- or -OCH2CH2CH2O-; -RAK independently denotes a covalent bond, -(CH2)- or -(CH2)2-; -RN independently denotes -RNNN, or -LN-RNNN; the rest of the values of the radicals are given in claim 1, which act as inhibitors of inhibitors of tumor necrosis factor-α converting enzyme (TACE).

EFFECT: compounds are useful in treating TNF-α mediated conditions.

36 cl, 303 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 3-aza-bicyclo[3.3.0]octane derivatives of formula , where R1 and R2 are hydrogen, C1-4alkyl or fluorine; R3 is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl, trifluoromethoxy group and halogen; 2,3-dihydrobenzofuranyl; 2,3-dihydrobenzo[1,4]dioxynyl; or isoxazolyl, pyridyl, indazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, pyrrolo[2,1b]thiazolyl, imidazo[ 1,2-a]pyridinyl or imidazo[2,1-b]thiazolyl, where said groups are unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, halogen and trifluoromethyl; A is or ; R4 is C1-4alkyl or -NR6R7; R6 is hydrogen or C1-4alkyl; R7 is hydrogen or C1-4alkyl; and D is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl and halogen; or a pharmaceutically acceptable salt of such a compound. 3-aza-bicyclo[3.3.0]octane derivatives or a pharmaceutically acceptable salt thereof are used as a medicinal agent having the activity of orexin receptor antagonists.

EFFECT: novel 3-aza-bicyclo[3,3,0]octane derivatives as nonpeptide antagonists of human orexin receptors.

9 cl, 1 tbl, 85 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

wherein R1 represents halogen or alkoxy group; each U and W represents N; V represents CH, and R2 represents H or F, or each U and V represents CH; W represents N, and R2 represents H or F, or U represents N; V represents CH; W represents CH or CRa, and R2 represents H, or also when W represents CH, may represent F; Ra represents CH2OH or alkoxycarbonyl; A represents group CH=CH-B, a binuclear heterocyclic system D, phenyl group which is mono-substituted in the position 4 by C1-4 alkyl group, or phenyl group which is di-substituted in positions 3 and 4 wherein each of two substitutes is optionally specified in a group consisting of C1-4 alkyl and halogen; B represents mono- or di-substituted phenyl group wherein each substitute is a halogen atom; D represents group

wherein Z represents CH or N, and Q represents O or S; or to salts of such compounds.

EFFECT: compounds are used for treating bacterial infections.

13 cl, 2 tbl, 25 ex

FIELD: medicine.

SUBSTANCE: invention refers to an agent for activation of lipoprotein lipase containing a benzene derivative of general formula (1) which is used for preventing and treating hyperlipidemia and obesity. The invention also refers to the benzene derivatives of general formula (1a).

EFFECT: composition improvement.

8 cl, 6 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: method is realised by mixing a compound of formula (B) with p-toluenesulphonic acid or a monohydrate of toluenesulphonic acid in less than 1 molar equivalent with respect to the compound of formula (B), in a solvent while heating. An additional amount of p-toluenesulphonic acid or monohydrate of p-toluenesulphonic acid is then added to the mixed solution while cooling in such an amount that their total molar equivalent with p-toluenesulphonic acid or monohydrate of p-toluenesulphonic acid at the mixing step is equal to 1 molar equivalent or more with respect to the compound of formula (B). At the last step, the obtained solution is crystallised to separate a compound of formula (A).

EFFECT: obtaining a compound of formula (A) with stable high output.

12 cl, 1 dwg, 3 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound which exhibits inhibitory effect on the FAAH enzyme having formula I , where n denotes an integer from 1 to 6; A denotes a group X; where when n equals an integer from 2 to 6, groups A are identical or different; X denotes C1-2-alkylene; R1 denotes a hydrogen atom; R2 denotes a hydrogen atom or a group selected from the following groups: phenyl, phenyloxy; R3 denotes either 2,2,2-trifluoroethyl or phenyl, if necessary substituted with one or more halogen atoms or C1-3-alkyl, C1-3-alkoxy, trifluoromethyl; provided that: the formula 1 compound is not 2,2,2-trifluoroethyl benzylcarbamate, when R3 denotes 2,2,2-trifluoroethyl and group -[A]n- denotes a -CH2- group, when R3 denotes phenyl, if necessary substituted, and group -[A]n-denotes a -CH2-, -CH2CH2-,-CH2CH2CH2- group, then R2 is not a hydrogen atom and is in form of a base, an addition salt with a pharmaceutically acceptable acid, as well as to a method for synthesis of the formula I compound and a pharmaceutical composition having inhibitory effect on FAAH, containing at least one formula I compound.

EFFECT: improved method.

5 cl, 6 ex, 1 tbl

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 2-amino-5-methylthiazole used as an intermediate compound in synthesis of drugs. Method for synthesis of 2-amino-5-methylthiazole involves the following steps: chlorination reaction of propionic aldehyde with sulfuryl chloride, successive addition of lower alcohol and alkali aqueous solution to alkaline pH value of medium, separation of organic phase containing 2-chloropropionic aldehyde acetal, condensation of acetal with thiourea. Organic phase is added directly to thiourea in acid aqueous solution. Method provides increasing yield of the end product and to simplify the process.

EFFECT: improved method of synthesis.

1 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel crystalline forms that can be used as components in preparing a solid pharmaceutical antidiabetic composition and antidiabetic medicinal agent. Invention relates to α-form of crystal and β-form of crystal of (R)-2-(2-aminothiazol-4-yl)-4'-{2-(2-hydroxy-2-phenylethyl)amino)]ethyl}acetanilide. α-Form of crystal shows the heat-absorption peak at 142-146°C in DSC-analysis and main peaks of X-rays powdery diffraction 5.32, 8.08, 15.28, 17.88, 19.04, 20.20, 23.16 and 24.34 in 2θ(°) units, it doesn't show hygroscopicity but possesses stability and therefore can be used as a medicinal agent. β-Form of crystal shows heat-absorbing peaks at 90-110°C and 142-146°C in DSC-analysis and main peaks in X-rays powdery diffraction 9.68, 19.76, 20.72, 22.10 and 23.52, it doesn't show hygroscopicity relatively and useful as an intermediate substance in preparing α-form of crystal also.

EFFECT: valuable properties of crystal.

8 cl, 2 tbl, 9 dwg, 4 ex

The invention relates to a method for producing acid salt of (Z)-2-aminothiazole the compounds of formula (I), where R1and R2independently represent an alkyl group having 1-5 carbon atoms, Y represents a halogen atom, m represents the valency of the inorganic acid of the formula (III) and n represents the integer 1 or 2, including the interaction of the acid salt of 2-aminothiazoline the compounds of formula (II), where R1and R2independently represent an alkyl group having 1-5 carbon atoms, X represents a bromine atom or an iodine atom and the wavy line indicates that this compound is a mixture of E - and Z-isomers, with an inorganic acid of the formula HY (III), where Y represents a halogen atom, and where the acid salt of 2-aminothiazoline the compounds of formula (II) is a compound obtained by the interaction of thiourea and halogenated compounds of the formula (VI), where R1, R2X and the wavy line have the same meanings as defined above
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