Hemiasterlyn derivatives and application thereof for at cancer treatment

FIELD: chemistry; pharmacology.

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

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

55 cl, 19 ex

 

The present application claims the priority date of the provisional application for U.S. patent No. 60/366592 filed March 22, 2002, the complete contents of which are incorporated in this application by reference.

Hemiasterlin (1) was first isolated from the sponge Hemiasterella minor (class School; detachment Hadromedidia, family Hemiasterllidae)collected in Sodwana Bay, South Africa (see Kashman et al. U.S. patent No. 5661175). It was reported that hemiasterlin exhibits antitumor activity against several cell lines, including the human lung carcinoma, carcinoma human colon and melanoma of the person.

After the first allocation and the message about the connection were allocated additional hemiasterlin, and were synthesized several derivatives hemiasterlin, and also to study their biological activity. Later it was reported that hemiasterlin and some of its analogues are antimitoticescoe activity and, thus, can be used to treat certain types of cancer (see U.S. patent No. 6153590 and PCT application WO 99/32509). However, it received only a limited number of analogues hemiasterlin, half of whom were themselves natural products isolated from species Cymbastela, or they were obtained by modification of natural products. Thus, the number and types of derivatives, is the quiet, it was possible to assess in terms of biological activity, were limited.

It is clear that there remains a need in the development of synthetic methodologies to access and study therapeutic effect of a variety of new derivatives hemiasterlin, in particular those which cannot be obtained by modifications of the natural product.

Thus, there is particular interest in the development of new compounds that exhibit a favorable therapeutic profile in vivo (for example, are safe and effective, at the same time maintaining stability in biological environments).

There is a need for the development of new analogues hemiasterlin to assess their potential as therapeutic agents for cancer treatment. The present invention relates to new compounds of General formula (I),

as well as to methods for their preparation and to their use in the treatment of cancer, where R1-R7X1X2, R, Q and n have the meanings specified below. Compounds of the invention are also suitable for the prevention of restenosis of blood vessels affected by such injuries as angioplasty and stenting.

Recognizing the need for access and further study of the biological activity of new derivatives hemiasterlin and this class of peptides in General, the present invention relates to new peptide is idnum compounds as described in more detail in the present description, which exhibit antitumor activity. Thus, the compounds of the invention and their pharmaceutical compositions can be used to treat cancer. In some embodiments of compounds of the present invention can be used to treat diseases and disorders, including but not limited to, prostate cancer, breast, colon, bladder, cervix, skin, testes, kidney, ovarian, stomach, brain, liver, pancreas or esophagus, lymphoma, leukemia and multiple myeloma. In some other embodiments of compounds of the invention also find application in the prevention of restenosis of blood vessels, prone to injury such as angioplasty and stenting.

1) a General description of the compounds of the invention

Compounds of the invention include compounds of General formula (I), as further defined below:

where n is 0, 1, 2, 3 or 4;

each X1and X2independently represents CRARBC(=O) or-SO2-; where each occurring RAand RBrepresents independently hydrogen or an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl;

each R 1and R2independently represents hydrogen, -(C=O)RCor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; where each occurring RWithindependentlyrepresents hydrogen, HE, ORDor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; RDrepresents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl;

each found R3and R4represents independently hydrogen or an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; or where any two of the groups R1,R2, R3and R4taken together can form an alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) part or aryl or heteroaryl;

each R5, R6and R7independently represents hydrogen, -(C=O)REor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; where each occurring RErepresents adored, HE, ORFor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; or where any two of the groups R5, R6and R7taken together, form an alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) part or aryl or heteroaryl; RFrepresents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; or R7absent when NR7linked to R via a double bond;

Rrepresents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; and

Q represents ORQ', SRQ', NRQ'RQN3, =N-OH or an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; where each RQ'and RQindependently represent hydrogen or an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; or RQ'and RQtaken together with the nitrogen atom to which they are attached, can form an alicyclic, heteroalicyclic the th, alicyclic(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) part or aryl or heteroaryl; and

and their pharmaceutically acceptable derivatives.

In some embodiments of the compounds of formula (I) and compounds described in classes and subclasses do not represent hemiasterlin occurring in nature.

In some embodiments of the compounds of formula (I) and compounds described in classes and subclasses do not have the following structure:

In some embodiments of compounds directly above, and compounds as described in some of the classes and subclasses of the description, the compounds do not include more than 4 consecutive α-amino acid residue, and/or one or more of the following groups do not occur simultaneously as defined:

(a) n=1;

each X1and X2represent C(=O);

each R1and R2independently represents hydrogen, aliphatic, alicyclic, heteroaromatics, heteroalicyclic, Ar-aliphatic, Ar-alicyclic part and where at least one of R1and R2represents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, Ar-aliphatic, Ar-alicyclic the massive part, and none of them represents Ar, Ar-aliphatic, Ar-alicyclic part; R1and R2taken together can form a three - to semichasnoho ring; where Ar is defined as substituted or unsubstituted phenyl, naphthyl, antracol, tenantry, furyl, pyrrolyl, thiophenyl, benzofuran, benzothiophene, hinely, ethanolic, imidazolyl, thiazolyl, oxazolyl or pyridyl;

R3represents hydrogen;

R4represents-CR4aR4bR4cwhere each R4aand R4bindependently represents hydrogen, aliphatic, alicyclic, heteroaromatics, heteroalicyclic, Ar-aliphatic, Ar-alicyclic part and where at least one of R4aand R4brepresents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, Ar-aliphatic, Ar-alicyclic part, and none of them represents Ar, Ar-aliphatic or Ar-alicyclic part; R4aand R4btaken together can form a three - to semichasnoho ring; and R4Srepresents hydrogen, aliphatic, alicyclic, heteroaromatics, heteroalicyclic, Ar-aliphatic, Ar-alicyclic part and Ar, where Ar is defined above;

each R5, R6and R7independently represents hydrogen, aliphatic, alicyclics is, heteroaromatics, heteroalicyclic, Ar-aliphatic, Ar-alicyclic part and Ar;

R represents the portion selected from the group consisting of linear, saturated or unsaturated, substituted or unsubstituted alkyl group containing from 1 to 6 carbon atoms; and

Q represents-ORG, -SRG, -NRGRH, -NHCH(RK)CO2H or-NRCH(RK)CO2H, where each RGand RHindependently represents hydrogen, aliphatic, alicyclic, heteroaromatics, heteroalicyclic part; RKrepresents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic part or the part having the structure -(CH2)tNRK1RK2where t=1-4 and RK1and RK2independently represents hydrogen, aliphatic, alicyclic, heteroaromatics, heteroalicyclic part or-C(NH)(NH2);

(b) n=1;

each X1and X2represent C(=O);

R1represents an optionally substituted methylene or a group-CH=related indole part, forming through this tricyclic part;

R2represents hydrogen, optionally substituted alkyl or acyl group or absent when R1represents-CH=as defined above;

R3presented yet a hydrogen or is absent, when CR3and CRyRzas defined above, linked by a double bond;

R4represents the portion having the structure:

where each Rw, Ryand Rzindependently represents hydrogen, optionally substituted alkyl or acyl, or Rzno, when CR3and CRyRzas defined, are connected by a double bond; Rxrepresents hydrogen or an optional Deputy or absent when R1represents an optionally substituted methylene or a group-CH=as defined above; Y is an optional Deputy; and m is 0, 1, 2, 3 or 4;

R5represents hydrogen, HE or optionally substituted alkyl or acyl group;

R6represents hydrogen or optionally substituted alkyl group;

R7represents hydrogen or alkyl; and

-R-X2-Q together represent optionally substituted alkyl part;

(c) n=1;

each X1and X2represent C(=O);

R1represents hydrogen, optionally substituted alkyl or acyl group or optionally substituted methylene or-CH= group associated with the indole part, forming through this tricyclic part;

R2not only is em a hydrogen, optionally substituted alkyl or acyl group or absent when R1represents-CH=as defined above;

R3represents hydrogen or is absent, when CR3and CRyRzas defined above, linked by a double bond;

R4represents the portion having the structure:

where each Rw, Ryand Rzindependently represents hydrogen or optionally substituted alkyl or acyl, or Rzno, when CR3and CRyRzas defined in the description, are connected by a double bond; with the limitation that Ryand Rzat the same time do not represent hydrogen; Rxrepresents hydrogen or an optional Deputy or absent when R1represents an optionally substituted methylene or a group-CH=as defined above; Y is an optional Deputy; and m is 0, 1, 2, 3 or 4;

R5represents hydrogen, HE or optionally substituted alkyl or acyl group;

R6represents hydrogen or optionally substituted alkyl group;

R7represents hydrogen or alkyl; and

-R-X2-Q together represent optionally substituted alkyl part, or-Q'-C(O)X, where Q' represents obazatelno substituted-CH 2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH=CH-, -CH2C=C - or fenelonov part, where X is an-OR', -SR', or-NR'r R", and each found R' and R" independently represents hydrogen or optionally substituted alkyl;

(d) n=1;

X1represents the C=O;

R1represents methyl;

R2and R3taken together, constitute piperidinol part;

each R4and R5represents hydrogen,

R6represents a-CH(CH3)CH2CH3;

R7represents-CH2OC(=O)CH2CH(CH3)2, -CH2OC(=O)CH2CH2CH3or-CH2OC(=O)CH2CH3; and

-R-X2-Q together represent the part having the structure:

(e) n=1;

X1represents the C=O;

each R1, R2and R7represents methyl;

each R3and R5represents hydrogen;

each R4and R6represents isopropyl; and

-R-X2-Q together represent the part having the structure:

where RXrepresents hydrogen or 2-thiazolyl; and/or

(f) n=1;

X1represent C=O;

each R1and R2independently represents hydrogen or C1-4alkyl;

each is th R 3and R5represents hydrogen;

each R4and R6represents isopropyl;

R7represents methyl; and

-R-X2-Q together represent the part having the structure:

where v=0, 1, or 2;

R' represents hydrogen or C1-4alkyl;

Rrepresents a C1-6alkylamino; hydroxy; C3-7cycloalkenyl, optionally substituted phenyl or benzyl; arylamino; C1-4alkoxy; benzhydrazide; heterocyclyl, optionally substituted from one to three substituents selected from the group consisting of benzyl, benzhydryl, alkyl, hydroxy, alkoxy, alkylcarboxylic, amino, mono - or dialkylamino, acylamino, alkoxycarbonyl, phenyl or halogen; heterocyclisation; heterocyclochain with the heterocyclic group, optionally substituted from one to three substituents selected from the group consisting of benzyl, benzhydryl, alkyl, hydroxy, alkoxy, alkylcarboxylic, amino, dialkylamino, acylamino, alkoxycarbonyl or halogen; Arakelov or aralkyl, both optionally substituted from one to three substituents selected from the group consisting of halogen, alkoxycarbonyl, sulfamoyl, alkylcarboxylic, cyano, mono - or dialkylamino, alkyl, alkoxy, phenyl, phenoxy trifloromethyl, triptoreline, alkylthio, hydroxy, alkoxycarbonyl, heterocyclyl, 1,3-dioxolane, 1,4-dioxolane, amino, aminosulfonyl or benzyl; or aralkylamines a1-4alkylenes and aryl group, optionally substituted from one to three substituents selected from the group consisting of halogen, alkoxycarbonyl, sulfamoyl, alkylcarboxylic, carbamoylated, cyano, mono - or dialkylamino, alkyl, alkoxy, phenyl, phenoxy, trifloromethyl, triptoreline, alkylthio, hydroxy, alkoxycarbonyl, heterocyclyl, 1,3-dioxolane, 1,4-dioxolane, amino or benzyl; and

R"'represents hydrogen, alkyl, optionally substituted from one to three substituents selected from the group consisting of hydroxy, alkoxy, amino, mono - or dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, alkylcarboxylic, carbamoylated or halogen; alkenyl; quinil; C3-7cycloalkyl; aryl, optionally substituted from one to three substituents selected from the group consisting of halogen, alkoxycarbonyl, sulfamoyl, alkylcarboxylic, cyano, mono - and dialkylamino, alkyl, alkoxy, phenyl, phenoxy, trifloromethyl, triptoreline, alkylthio, hydroxy, alkoxycarbonyl, heterocyclyl, 1,3-dioxolane, 1,4-dioxolane, amino or benzyl; aralkyl with aryl group, not necessarily Thames is authorized from one to three substituents, selected from the group consisting of halogen, alkoxycarbonyl, carbamoyl, sulfamoyl, alkylcarboxylic, cyano, mono - or dialkylamino, alkyl, alkoxy, phenyl, phenoxy, trifloromethyl, triptoreline, alkylthio, hydroxy, alkoxycarbonyl, heterocyclyl, 1,3-dioxolane, 1,4-dioxolane, amino or benzyl; or geterotsiklicheskikh;

where the groups specified in paragraph (f), defined as follows:

alkyl refers to a linear or razvetvlennoy hydrocarbon group, optionally substituted hydroxy, alkoxy, amino, mono - or dialkylamino, acetoxy, alkylcarboxylic, alkoxycarbonyl, carbamoylated, carbamoyl or halogen;

alkenyl refers to a hydrocarbon chain as defined above for alkyl having at least one double bond;

quinil refers to a hydrocarbon chain as defined above for alkyl having at least one triple bond;

With3-7cycloalkyl refers to saturated cyclic hydrocarbon group having 3-7 carbon atoms, optionally substituted by alkyl, phenyl, amino, hydroxy or halogen;

With1-4alkylene refers to biradicaloid linear or branched hydrocarbon chain containing 1-4 carbon atoms;

aralkyl refers to an aryl group attached to alkalinous group;

heterocyclyl applies to feast upon Nomo, unsaturated or aromatic monovalent cyclic radical having one to three heteroatoms selected from O, N and S, or combinations thereof, optionally substituted by one or more substituents of the benzyl, benzhydryl, alkyl, hydroxy, alkoxy, alkylaromatics, amino, mono - or dialkylamino, acylamino, alkoxycarbonyl or halogen;

amino refers to-NH2and includes amino groups, which are optionally substituted by lower alkyl groups or attitudinise groups known in the field;

cyclooctylamino refers to cycloalkyl groups, as defined above, attached to the structure through amino radical;

arylamino defined as aryl-NH-;

aralkylamines defined as aralkyl-NH-;

carbarnoyl refers to the group-C(=O)-NH2;

carbamoylated refers to the group-O-C(=O)-NH-;

alkylcarboxylic refers to the group-O-C(=O)-NH-alkyl;

alkylcarboxylic refers to the group-O-C(=O)-alkyl;

aralkylated refers to the group-O-aralkyl; and

Alkylthio refers to the group alkyl-S-.

In some other embodiments of the compounds described in (a) above, and compounds described in some of the classes and subclasses of description, the following groups do not occur simultaneously as defined:

n=1; each X1and X2represents C(=O); each R and R2represents independently hydrogen, methyl, ethyl, propyl, n-butyl, acetyl; or R1and R2taken together, form a part selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; R3represents hydrogen; R4represents-CR4aR4bR4cwhere each R4aandR4bindependently represent methyl, ethyl, n-propyl, or n-butyl; or R4aandR4btaken together, form a part selected from the group consisting of β-cyclopropyl, β-cyclobutyl, β-cyclopentyl and β-cyclohexyl; and R4crepresents phenyl, naphthyl, antracol or pyrrolyl; each R5and R7represents independently hydrogen or methyl; R6represents a branched alkyl group containing from three to six carbons; and R-X2-Q together represent the part having the structure:

where R' represents methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, or sec-butyl; R" represents hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, or sec-butyl; and Q represents OH or orGwhere RGrepresents a linear or branched alkyl group containing from one to six carbon atoms.

In some the other embodiments of the compounds, described in (a) above, and compounds described in certain classes and subclasses of description, the following groups do not occur simultaneously as defined:

n=1; each of X1and X2represents C(=O); each R1, R3and R5represents hydrogen; R2represents methyl; R4represents-CR4aR4bR4c, R6represents tert-butyl; and R-X2-Q together represent a part having the structure:

where R' represents isopropyl; and R" represents methyl; and Q represents IT; and

(a) each R4aandR4brepresents methyl; R4Srepresents a methyl or phenyl; and R7represents hydrogen or methyl;

(b) each R4aandR4brepresents methyl; R4Srepresents hydrogen; and R7represents methyl;

or

(C) each R4aandR4brepresents hydrogen; R4Srepresents phenyl; and R7represents methyl.

In some embodiments of the compounds of formula (I) and compounds described in classes and subclasses descriptions that do not have the structure of any one or more of the compounds described from line 28 to page 8 to line 9 on p.25, line 1 on page 28 to line 9 n is p.32 from line 16 on page 39 to line 20 on p.80 WO 03/008378, which is fully incorporated in the description by reference.

In some embodiments of the compounds of formula (I) and compounds described in classes and subclasses descriptions that do not have the structure of any one or more of the compounds described from line 24 on page 10 to line 18 on page 17, from line 26 on page 17 to line 3 on page 19, from line 10 on page 19 to line 3, page 20, line 17, page 20 to line 9 on page 21, lines 14-29 on page 21, lines 1-12 on page 22, lines 16-18 on page 22, lines 22-27 on page 22, from line 1 on page 23 to line 21 on page 24, line 26 to page 24 to line 9 on p.25 and line 1 on page 28 to line 9 on page 32 WO 03/008378.

In some embodiments of the compounds of formula (I) and compounds described in classes and subclasses descriptions that do not have the structure of any one or more of the compounds described in J. Nieman et al., "Synthesis and Antitumotic/Cytotoxic Activity of Hemiasterlin Analogues", Journal of Natural Products, 2003,66(2):183-199, which is fully incorporated here by reference.

In some embodiments of the compounds of formula (I) and compounds described in classes and subclasses descriptions that do not have any one or more of the following structures:

In some embodiments of the compounds of formula (I) defined as follows:

each of X1and X2represents independently CHRARBO 2or C=O; where each of RAandRBindependently represents hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

each R1andR2independently represents hydrogen or linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, lower heteroalkyl or acyl part or aryl or heteroaryl; where the alkyl, heteroalkyl and the aryl part can be substituted or unsubstituted; or

R1andR2taken together, may form a saturated or unsaturated, substituted or unsubstituted ring of 5-8 atoms;

each found R3andR4represents independently hydrogen or a linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, lower heteroalkyl, lower-alkyl(aryl), lower-heteroalkyl(aryl) part, or aryl or heteroaryl; where the alkyl, heteroalkyl, -alkyl(aryl), heteroalkyl(aryl), aryl and heteroaryl can be substituted or unsubstituted; or

R3andR4taken together, may form a saturated or unsaturated substituted or unsubstituted ring of 3-8 atoms;

bearing carbon atom of R3andR4can have the S configuration;

n=1;

R5represents hydrogen or a protective group; where the protective group can be astonishing group;

R6represents hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or heteroalkyl; or substituted or unsubstituted aryl or heteroaryl;

bearing carbon atom of R6can have the S configuration;

R7represents hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or heteroalkyl; or substituted or unsubstituted aryl or heteroaryl; or R7absent when NR7linked to R via a double bond;

R represents a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated alkyl part; or heteroaromatics part containing 1-10 carbon atoms, 1 to 4 nitrogen atoms, 0 to 4 oxygen atoms and 0 to 4 sulfur atoms; whereby heteroaromatics part may be substituted or not substituted, linear or razvetvlenno the th, cyclic or acyclic, or saturated or unsaturated;

where (i) the alkyl part may have the structure:

where each R8a, R9aand R10aindependently absent, represents hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or heteroalkyl; or substituted or unsubstituted aryl or heteroaryl; where any two groups of R7, R8a, R9aand R10amay form a substituted or unsubstituted, saturated or unsaturated cyclic alkyl, heteroalkyl, alkyl(aryl) or heteroalkyl(aryl); or aryl or heteroaryl; and where the carbon atom bearing R8acan have the S configuration;

(ii) heteroalkyl part can have the structure:

where each R8b, R9b, R10band R11bindependently absent, represents hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl or acyl; or substituted or unsubstituted aryl or heteroaryl; where any two groups of R7, R8b, R9b, R10band R11bmay make obyvaci substituted or unsubstituted, saturated or unsaturated cyclic alkyl, heteroalkyl, alkyl(aryl) or heteroalkyl(aryl); or substituted or unsubstituted aryl or heteroaryl; where each group NR7and CR8b, CR8band CR9b, CR9band NR10b, NR10band CR11bindependently associated with single or double bond, as valency; and where the carbon atom bearing R8bcan have the S configuration;

(iii) or heteroalkyl part can have the structure:

where each R8s, R9c, R10s, R11Sand R12sindependently absent, represents hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or heteroalkyl; or substituted or unsubstituted aryl or heteroaryl; where any two groups of R7, R8s, R9cR10s, R11Sand R12smay form a substituted or unsubstituted, saturated or unsaturated cyclic alkyl, heteroalkyl, alkyl(aryl) or heteroalkyl(aryl); or substituted or unsubstituted aryl or heteroaryl; where each group NR7and CR8s, CR8sand CR9c, CR9cand CR10s, CR10sand CR11Sregardless what about the associated single or double bond, as valence allows; and where the carbon atom bearing R8scan have the S configuration; and

Q represents ORQ', SRQ', NRQ'RQwhere each group RQ'andRQindependently represents hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or heteroalkyl part; or substituted or unsubstituted aryl or heteroaryl; or RQ'andRQtaken together, may form a substituted or unsubstituted, saturated or unsaturated cyclic alkyl or heteroalkyl part or substituted or unsubstituted aryl or heteroaryl; and

their pharmaceutically acceptable derivatives.

In some embodiments of the present invention defines certain classes of compounds that are of particular interest. For example, one class of compounds of special interest includes compounds having the structure of formula (I)in which R represents a-CH(R8a)C(R9a)=C(R10a)-and the compound has the structure (Ia):

where R1-R7X1X2, Q and n are defined in classes and subclasses description;

each R8A, R9aand R10Aillegal is ASIMO represents hydrogen or an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; and where any two of the groups R7, R8A, R9aand R10Amay form a substituted or unsubstituted, saturated or unsaturated alicyclic heteroalicyclic, alicyclic(aryl), heterocyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl); or aryl or heteroaryl part.

Otherthe class of compounds of special interest, referred to by class (Ib)consists of compounds having the structure of formula (I)in which X2represents C=O, and R represents heteroaromatics part containing 1-10 carbon atoms, 1 to 4 nitrogen atom and 0-4 oxygen atoms and 0-4 sulfur atom, whereby heteroaromatics part may be substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated.

Otherthe class of compounds of special interest consists of compounds having the structure of formula (I)in which X1represents C=O, n=1; R1and R4taken together form a cyclic heterocyclic or heteroaryl; R3represents hydrogen or is absent when the carbon atom carrying the R3connected is N or E through a double bond; and the compound has the structure (Ic):

where R2,R5-R7, R, X2and Q are defined in the description in classes and subclasses;

each occurring G, J, L and M independently represents CHRiv, CRivRv, O, S, NRivRvwhere each occurring RivandRvindependently absent or represents hydrogen, -C(=O)Rvior aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; or where any two adjacent groups R2, Riv, Rvor Rvitaken together, form a substituted or unsubstituted, saturated or unsaturated alicyclic or heteroalicyclic part containing 3-6 atoms, or aryl or heteroaryl; where each common group Rvirepresents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl;

each N and G, G and J, J and L, L, and M, M and CR3and CR3and N independently associated single or a double bond, to the extent permitted by valence; and

each g, j, l and m independently equal 0, 1, 2, 3, 4, 5 or 6, where the sum of g, j, l and m is 3-6.

Otherthe class of compounds of special interest consists of compounds having the structure of formula (I), W is X 1represents C=O, n=1; each R3and R4independently represents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or, when taken together, form an alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl); and the compound has the structure (Id):

where R1, R2,R5-R7, R, X2and Q are defined in the description of classes and subclasses.

The following structures illustrate severalexemplary types of compounds of class (Ia). Additional connections are described in detail in the "Examples"section.

The following structures illustrate severalexemplary types of compounds of class (Ib). Additional connections are described in detail in the "Examples"section.

The following structures illustrate severalexemplary types of compounds of class (Ic). Additional connections are described in detail in the "Examples"section.

The following structures illustrate severalexemplary types of compounds of class (Id). Additional compounds described in OPI is offering in the "Examples"section.

Other compounds of the invention will be obvious.

A number of important subclasses of each of the classes mentioned above deserves special mention; for example, one important subclass of class (Ia) include those compounds that have the structure of formula (Ia)in which X2represents the C=O; and the compound has the following structure:

where R1-R7, n and Q are defined in the description of classes and subclasses.

each R8a, R9aand R10aindependently represents hydrogen or alkyl, heteroalkyl, aryl or heteroaryl; and where any two of the groups R7, R8a, R9aand R10amay form a cyclic alkyl, heteroalkyl, -alkyl(aryl), -heteroalkyl(aryl), -alkyl(heteroaryl) or-heteroalkyl(heteroaryl) part, or aryl or heteroaryl; and

X1represents CRARB, SO2or C=O; where each RAandRBindependently represents hydrogen, alkyl, heteroalkyl, aryl or heteroaryl.

Another important subclass of class (Ia) include compounds which have the structure of formula (Ia)in which X1represents the C=O; and the compound has the following structure:

where R -R7, n and Q are defined in the description of classes and subclasses.

each R8a, R9aand R10aindependently represents hydrogen or alkyl, heteroalkyl, aryl or heteroaryl; and where any two of the groups R7, R8a, R9aand R10amay form a cyclic alkyl, heteroalkyl, -alkyl(aryl), -heteroalkyl(aryl), -alkyl(heteroaryl) or-heteroalkyl(heteroaryl) part, or aryl or heteroaryl; and

X2represents CRARB, SO2or C=O; where each RAandRBindependently represents hydrogen, alkyl, heteroalkyl, aryl or heteroaryl.

Another important subclass of class (Ia) include those compounds that have the structure of formula (Ia)in which each X1andX2represents the C=O; n=1; R3represents hydrogen; R4represents the portion, having the structure-CR4aR4bR4c; and the compound has the following structure:

where R1-R2, R5-R7and Q are defined in the description in classes and subclasses; and

each R4aand R4bindependently represents hydrogen or lower alkyl or heteroalkyl, and R4Srepresents aryl or heteroaryl; and

each R8a, R9aand R1a independently represents hydrogen or alkyl, heteroalkyl, aryl or heteroaryl; and where any two of the groups R7, R8a, R9aand R10amay form a cyclic alkyl, heteroalkyl, -alkyl(aryl), -heteroalkyl(aryl), -alkyl(heteroaryl) or-heteroalkyl(heteroaryl) part, or aryl or heteroaryl part.

Another important subclass of class (Ia) include those compounds that have the structure of formula (Ia)in which each X1andX2represents the C=O; Q is an optionally substituted nitrogen-containing cyclic portion; and the compound has the following structure:

where R1-R7and n are defined in the description in classes and subclasses;

each R8a, R9aand R10aindependently represents hydrogen or alkyl, heteroalkyl, aryl or heteroaryl; and where any two of the groups R7, R8a, R9aand R10amay form a cyclic alkyl, heteroalkyl, -alkyl(aryl), -heteroalkyl(aryl), -alkyl(heteroaryl) or-heteroalkyl(heteroaryl) part, or aryl or heteroaryl;

each found a, b, D and E independently represents CHRi, CRiRii, O, S, NRiRiiwhere each of the first found R iandRiiindependently absent, represents hydrogen, -C(=O)Riiior aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; or where any two adjacent groups Ri,Riior Riiitaken together, form an alicyclic or heteroalicyclic part containing 3-6 atoms, or aryl or heteroaryl; where each occurring Riiirepresents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl;

each N and A, A and B, B and D, D and E and E and N are independently associated single or double bond, as valency; and

each a, b, d and e are independently equal 0, 1, 2, 3, 4, 5, 6 or 7, where the sum of a, b, d and e is equal to 4-7.

Another important subclass of class (Ia) include those compounds that have the structure of formula (Ia)in which each X1andX2represents the C=O; Q is an optionally substituted nitrogen-containing cyclic part; n=1; R3represents hydrogen; R4represents the portion, having the structure-CR4aR4bR4c; and the compound has the following structure:

where R1, R2, R5-R7A , b, D, E, a, b, d and c are defined in the description in the CL is SSH and subclasses;

each R4aand R4bindependently represents hydrogen or lower alkyl or heteroalkyl, and R4Srepresents a substituted or unsubstituted aryl or heteroaryl group;

each R8a, R9aand R10aindependently represents hydrogen or alkyl, heteroalkyl, aryl or heteroaryl; and where any two of the groups R7, R8a, R9aand R10amay form a cyclic alkyl, heteroalkyl, -alkyl(aryl), -heteroalkyl(aryl), -alkyl(heteroaryl) or-heteroalkyl(heteroaryl) part, or aryl or heteroaryl part.

A number of important subclasses of each of the above subclasses of class (Ia) deserve separate mention; these subclasses include subclasses of the above subclasses of class (Ia)in which:

i-a. R1and R2independently represent hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl;

ii-a. R1represents hydrogen and R2represents a substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl;

iii-a. R1the present is the focus of a hydrogen and R 2represents a substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl;

iv-a. R1represents hydrogen and R2represents methyl, ethyl, propyl, butyl, pentyl, tert-butyl, isopropyl, -CH(CH3)CH2CH3, -CH(CH3)CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)2CH2CH3, -CH(CH3)cyclobutyl, -CH(Et)2, -CH(CH3)2C-CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

v-a. Each R1and R2represents hydrogen;

vi-a. The carbon atom carrying the R3and R4has the S configuration;

vii-a. R3represents hydrogen and R4represents a substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl, heteroalkyl or-alkyl(aryl) or substituted or unsubstituted aryl or heteroaryl;

viii-a. R3represents hydrogen and R4represents-CR4aR4bR4c; where R4aandR4bindependently represent hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl part, and R4 is represents a substituted or unsubstituted aryl or heteroaryl;

ix-a. R3represents hydrogen and R4represents-CR4aR4bPh; where R4aandR4bindependently represent hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl part;

x-a. R4represents a substituted or unsubstituted 3-indole part;

xi-a. R3represents hydrogen;

xii-a. R1and R4taken together, form a substituted or unsubstituted pyrolidine group;

xiii-a. R1and R4taken together, form a substituted or unsubstituted piperidino group;

xiv-a. R1and R4taken together, form a substituted or unsubstituted thiazolidinone group;

xv-a. R1and R4taken together, form a substituted or unsubstituted morpholino group;

xvi-a. R1and R4taken together, form a substituted or unsubstituted thiomorpholine group;

xvii-a. R1and R4taken together, form a substituted or unsubstituted indole group;

xviii-a. Each R3and R4are independently substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated is lower alkyl, heteroalkyl or-alkyl(aryl) or substituted or unsubstituted aryl or heteroaryl;

xix-a. Each R3and R4are independently substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, -alkyl(aryl) or substituted or unsubstituted aryl;

xx-A. Each R3and R4are independently substituted or unsubstituted lower alkyl, aryl or heteroaryl;

xxi-A. Each R3and R4represent independently methyl, ethyl, propyl, butyl, pentyl, tert-butyl, isopropyl, -CH(CH3)CH2CH3, -CH(CH3)CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)2CH2CH3, -CH(CH3)cyclobutyl, -CH(Et)2, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl, -C1-6ORa- 1-6SRaor-CRaRbRc; where RaandRbare independently hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, and Rwithrepresents a substituted or unsubstituted aryl or heteroaryl;

xxii. Each R3and R4represent independently methyl, ethyl, propyl, bout the l, pentyl, tert-butyl, isopropyl, -CH(CH3)CH2CH3, -CH(CH3)CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)2CH2CH3, -CH(CH3)cyclobutyl, -CH(Et)2, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl, -C1-6ORa- 1-6SRaor-CRbRcPh; where Rarepresents hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl and each RbandRcare independently substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

xxiii. Each R3and R4represents ethyl;

xxiv. R3represents phenyl and R4represents lower alkyl;

xxv. R3represents phenyl and R4represents ethyl;

xxvi. R3and R4taken together, form a substituted or unsubstituted cycloalkyl group;

xxvii. R3and R4taken together, constitute tsiklogeksilnogo group;

xxviii. R3and R4taken together, form a substituted or unsubstituted cycloalkyl(aryl) group;

xxix. R5represents hydrogen;

p> xxx-A. R6represents a substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl;

xxxi. R6represents methyl, ethyl, propyl, butyl, pentyl, tert-butyl, isopropyl, -CH(CH3)CH2CH3, -CH2CH(CH3)2, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

xxxii. R6represents tert-butyl;

xxxiii. The carbon atom carrying the R6has the S configuration;

xxxiv-a. R7represents a substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl;

xxxv-a. R7represents methyl;

xxxvi-a. R represents a-CH(R8a)C(R9a)=C(R10a)-; and

a) R8Arepresents a substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl;

b) R8Arepresents isopropyl;

C) the carbon atom carrying the R8Ahas the S configuration;

d) R9arepresents hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl;

e) R9arepresents hydrogen;

f) R10Arepresents hydrogen or alseny or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl;

g) R10Arepresents methyl;

xxxvii-a. n=1;

xxxviii-a. X1represents the C=O;

xxxix-a. X1represents CH2;

lx-a. X1represents the SO2;

lxi-a. X2represents the C=O;

lxii-a. X2represents CH2;

lxiii-a. X2represents the SO2;

lxiv-a. Q represents ORQ', SRQ', NRQ'RQN3, =N-OH or part selected from the group consisting of

where everyone found r=0, 1, or 2; s and t independently represent an integer from 0 to 8; X represents O, S or NRK; occurring every RQ1and RQ2represents independently hydrogen, halogen, -CN, -S(O)hRJ, -NO2,-CORJ, -CO2RJ, -NRJCORJ, -NRJCO2RJ, -CONRJRJ, -CO(NORJRJ, aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or Z1RJ; where h=1 or 2; and Z1is an independently-O-, -S-, NRK, -C(O)-, where each occurring RJandRKrepresents independently hydrogen, CORL, COORL, CONRLRM, -NRLR , -S(O)2RLor aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part and where each occurring RLandRMrepresents independently hydrogen or an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; and RQ'andRQrepresents independently hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl part, or substituted or unsubstituted aryl or heteroaryl; or RQ'andRQtaken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl; and

lxv-a. Q represents ORQ', SRQ', NRQ'RQ,N3, =N-OH, or part selected from the group consisting of

where everyone found r=0, 1, or 2; s and t independently represent an integer from 0 to 8; each occurring RQ1and RQ2represents independently hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl part, or substituted or unsubstituted the arilje the th or heteroaryl part, or RQ1andRQ2taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic; and RQ'andRQare independently hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl part, or substituted or unsubstituted aryl or heteroaryl; or RQ'andRQtaken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl; and/or

lxvi-a. Q represents ORQ', SRQ', NRQ'RQ,N3, =N-OH, or part selected from the group consisting of

where everyone found r=0, 1, or 2; and RQ'andRQare independently hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl part, or substituted or unsubstituted aryl or heteroaryl; or RQ'andRQtaken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl part.

An important subclass of class (Ib) include those with the unity, which have the structure of formula (Ib)in which R represents-C(R8b)C(R9b)N(R10b)C(R11b)-; and the compound has the following structure:

where R1-R7n, X1and Q are defined in the description in classes and subclasses;

each R8b, R9b, R10band R11bindependently absent or represents hydrogen, -(C=O)RLor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part where everyone found RLindependently represent hydrogen, HE, ORMor aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or where any two of the groups R8b, R9b, R10band R11btaken together, form an alicyclic or heteroalicyclic part or aryl or heteroaryl; RMrepresents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; and

each NR7and CR8b, CR8band CR9b, CR9band NR10b, NR10band CR11bindependently associated single or double bond, as valency.

Another important subclass of class (Ib) include those compounds that have the structure of formula (Ib), the X 1represents the C=O; R represents-C(R8b)C(R9b)N(R10b)C(R11b)-; n=1; R3represents hydrogen; R4represents the portion, having the structure-CR4aR4bR4c; and the compound has the following structure:

where R1-R2, R5-R7and Q are defined in the description in classes and subclasses; and

each R4Aand R4bindependently represents hydrogen or lower alkyl, and R4Srepresents aryl or heteroaryl;

each R8b, R9b, R10band R11bindependently absent or represents hydrogen, -(C=O)RLor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part where everyone found RLindependently represents hydrogen, HE, ORMor aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or where any two of the groups R8b, R9b, R10band R11btaken together, form an alicyclic or heteroalicyclic part, or aryl or heteroaryl; RMrepresents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; and

each NR7The CR 8b, CR8band CR9b, CR9band NR10b, NR10band CR11bindependently associated single or double bond, as valency.

Another important subclass of class (Ib) include those compounds that have the structure of formula (Ib)in which R represents-C(R8b)C(R9b)N(R10b)C(R11b)-; R10band R11btaken together, form a substituted or unsubstituted cyclic heteroalkyl or heteroaryl; and the compound has the following structure:

where R1-R7,n and Q are defined in the description in classes and subclasses;

p=1, 2, 3 or 4;

q=0-12;

each meeting S1independently represents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or any two adjacent of S1taken together can form an alicyclic, heteroalicyclic, aryl or heteroaryl;

each R8band R9bindependently absent or represents hydrogen, -(C=O)RLor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part where everyone found RLindependently represents hydrogen, HE, ORMor an aliphatic, alicyclic, heteroclita is practical, heteroalicyclic, aryl or heteroaryl part, or where R8band R9btaken together, form an alicyclic or heteroalicyclic part, or aryl or heteroaryl; RMrepresents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; and

each NR7and CR8and CR8band CR9bindependently associated single or double bond, as valency.

Another important subclass of class (Ib) include those compounds that have the structure of formula (Ib)in which n=1; R represents-C(R8b)C(R9b)N(R10b)C(R11b)-; R10band R11btaken together, form a substituted or unsubstituted cyclic heteroalkyl or heteroaryl; R4represents the portion, having the structure-CR4aR4bR4c; and the compound has the following structure:

where R1-R7X1and Q are defined in the description in classes and subclasses;

p=1, 2, 3 or 4;

q=0, 1, 2, 3, 4, 5 or 6;

each meeting S1independently represents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or any two adjacent of S1taken together, may form and iceslideshow, heteroalicyclic, aryl or heteroaryl;

each R4band R4bindependently represents hydrogen or lower alkyl or heteroalkyl; and R4Srepresents aryl or heteroaryl;

each R8band R9bindependently represents hydrogen, -(C=O)RLor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part where everyone found RLindependently represents hydrogen, HE, ORMor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or where R8band R9btaken together, form an alicyclic or heteroalicyclic part, or aryl or heteroaryl; RMrepresents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; and

each NR7and CR8band CR8band CR9bindependently associated single or double bond, as valency.

Another important subclass of class (Ib) include those compounds that have the structure of formula (Ib)in which R represents-C(R8c)C(R9c)With(R10s)With(R11c)OC(R12c)- and the compound has the following structure:

where R1 -R7n, X1and Q are defined in the description in classes and subclasses;

each R8c, R9c, R10s, R11cand R12cindependently absent or represents hydrogen, -(C=O)RLor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part where everyone found RLindependently represents hydrogen, HE, ORMor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or where any two of the groups R8c, R9c, R10s, R11cand R12ctaken together, form an alicyclic or heteroalicyclic part, or aryl or heteroaryl; RMrepresents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; and

each NR7and CR8s, CR8sand CR9c, CR9cand CR10sand CR10sand CR11Sindependently associated single or double bond, as valency.

Another important subclass of class (Ib) include those compounds that have the structure of formula (Ib)in which X1represents the C=O; n=1; R3represents hydrogen; R4represents the portion, having the structure-CR4aR4bR4c; R is the Wallpaper-C(R 8c)C(R9c)With(R10s)With(R11c)OC(R12cand the compound has the following structure:

where R1, R2, R5-R7and Q are defined in the description in classes and subclasses;

each R4Aand R4bindependently represent hydrogen or lower alkyl or heteroalkyl; and R4crepresents aryl or heteroaryl;

each R8c, R9c, R10s, R11cand R12cindependently absent or represents hydrogen, -(C=O)RLor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part where everyone found RLindependently represents hydrogen, HE, ORMor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or where any two of the groups R8c, R9c, R10s, R11cand R12ctaken together, form an alicyclic or heteroalicyclic part or aryl or heteroaryl; RMrepresents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; and

each NR7and CR8s, CR8sand CR9c, CR9cand CR10sand CR10sand CR11Sindependently associated single or dual bound is o, as valence allows.

A number of important subclasses of each of the above subclasses of class (Ib) deserve separate mention; these subclasses include subclasses of the above subclasses of class (Ib)in which:

i-b. R1and R2independently represent hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl;

ii-b. R1represents hydrogen and R2represents a substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl;

iii-b. R1represents hydrogen and R2represents a substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl;

iv-b. R1represents hydrogen and R2represents a methyl, ethyl, propyl, butyl, pentyl, tert-butyl, isopropyl, -CH(CH3)CH2CH3, -CH(CH3)CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)2CH2CH3, -CH(CH3)cyclobutyl, -CH(Et)2, -CH(CH3)2C-CH, cyclohexyl, cyclopentyl, cyclobutyl Il is cyclopropyl;

v-b. Each R1and R2represents hydrogen;

vi-b. The carbon atom carrying the R3and R4has the S configuration;

vii-b. R3represents hydrogen and R4represents a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl or-alkyl(aryl) or substituted or unsubstituted aryl or heteroaryl;

viii-b. R3represents hydrogen and R4represents-CR4aR4bR4c; where R4aandR4bindependently represent hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl part, and R4Srepresents a substituted or unsubstituted aryl or heteroaryl;

ix-b. R3represents hydrogen and R4represents-CR4aR4bPh; where R4aandR4bindependently represent hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl part;

x-b. R4represents a substituted or unsubstituted 3-indole part;

xi-b. R3represents hydrogen;

xii-b. R1and R4taken together, they form the substituted or unsubstituted pyrolidine group;

xiii-b. R1and R4taken together, form a substituted or unsubstituted piperidino group;

xiv-b. R1and R4taken together, form a substituted or unsubstituted thiazolidinone group;

xv-b. R1and R4taken together, form a substituted or unsubstituted morpholino group;

xvi-b. R1and R4taken together, form a substituted or unsubstituted thiomorpholine group;

xvii-b. R1and R4taken together, form a substituted or unsubstituted indole group;

xviii-b. Each R3and R4represents independently a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl or-alkyl(aryl) or substituted or unsubstituted aryl or heteroaryl;

xix-b. Each R3and R4represents independently a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, -alkyl(aryl) or substituted or unsubstituted aryl;

xx-b. Each R3and R4represents independently a substituted or unsubstituted lower alkyl, aryl or heteroaryl;

xxi-b. Each R3and R4represents independently methyl, ethyl, propyl, butyl, pentyl, tert-butyl, isopropyl, -CH(CH3)H 2CH3, -CH(CH3)CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)2CH2CH3, -CH(CH3)cyclobutyl, -CH(Et)2, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl, -C1-6ORa- 1-6SRaor-CRaRbRc; where RaandRbare independently hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, and Rwithrepresents a substituted or unsubstituted aryl or heteroaryl;

xxii-b. Each R3and R4represents independently methyl, ethyl, propyl, butyl, pentyl, tert-butyl, isopropyl, -CH(CH3)CH2CH3, -CH(CH3)CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)2CH2CH3, -CH(CH3)cyclobutyl, -CH(Et)2, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl, -C1-6ORa- 1-6SRaor-CRbRcPh; where Rarepresents hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl and each RbandRcare illegal the performance of substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

xxiii-b. Each R3and R4represents ethyl;

xxiv-b. R3represents phenyl and R4represents lower alkyl;

xxv-b. R3represents phenyl and R4represents ethyl;

xxvi-b. R3and R4taken together, form a substituted or unsubstituted cycloalkyl group;

xxvii-b. R3and R4taken together, constitute tsiklogeksilnogo group;

xxviii-b. R3and R4taken together, form a substituted or unsubstituted cycloalkyl(aryl) group;

xxix-b. R5represents hydrogen;

xxx-b. R6represents a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

xxxi-b. R6represents methyl, ethyl, propyl, butyl, pentyl, tert-butyl, isopropyl, -CH(CH3)CH2CH3, -CH2CH(CH3)2, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

xxxii-b. R6represents tert-butyl;

xxxiii-b. The carbon atom carrying the R6has the S configuration;

xxxiv-b. R7represents a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or Nene is sydeny lower alkyl;

xxxv-b. R7represents methyl;

xxxvi-b. R represents-C(R8b)C(R9b)N(R10b)CR11b-; and

a) R8brepresents a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

b) R8brepresents isopropyl;

C) the carbon atom carrying the R8bhas the S configuration;

d) R9brepresents hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

e) R10brepresents hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or acyl;

f) R10brepresents hydrogen, methyl or acetyl;

g) R10band R11btaken together, form a substituted or unsubstituted pyrolidine ring; or

h) R9band R11btaken together, form a substituted or unsubstituted thiazole ring;

xxxvii-b. R represents-C(R8c)C(R9c)C(R10c)CR11cOCR12cand

a) R8srepresents a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

b) R8sp is ecstasy an isopropyl;

C) the carbon atom carrying the R8shas the S configuration;

(d) each R9cand R10sindependently represents hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

e) CR9cand CR10slinked through a double bond;

f) CR9cand CR10slinked through a double bond and R9crepresents hydrogen; or

g) CR9cand CR10slinked through a double bond and R10srepresents methyl;

xxxviii-b. n=1;

xxxix-b. X1represents the C=O;

xl-b. X1represents CH2;

xli-b. X1represents the SO2;

xlii-b. Q represents ORQ', SRQ', NRQ'RQN3, =N-OH or part selected from the group consisting of

where everyone found r=0, 1, or 2; s and t independently represent an integer from 0 to 8; X represents O, S or NRK; occurring every RQ1and RQ2represents independently hydrogen, halogen, -CN, -S(O)hRJ, -NO2,-CORJ, -CO2RJ, -NRJCORJ, -NRJCO2RJ, -CONRJRJ, -CO(NORJRJ, aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl the ing part, or-Z1RJ; where h=1 or 2; and Z1is an independently-O-, -S-, NRK, -C(O)-, where each occurring RJandRKrepresents independently hydrogen, CORL, COORL, CONRLRM, -NRLRM, -S(O)2RLor aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, and where each occurring RLandRMrepresents independently hydrogen, or an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; and RQ'andRQrepresents independently hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl part, or substituted or unsubstituted aryl or heteroaryl; or RQ'andRQtaken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl;

xliii-b. Q represents ORQ', SRQ', NRQ'RQ,N3, =N-OH or part selected from the group consisting of

where everyone found r=0, 1, or 2; s and t independently represent an integer from 0 to 8; calystegia R Q1and RQ2represents independently hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl part, or substituted or unsubstituted aryl or heteroaryl; or RQ1and RQ2taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic; and RQ'andRQrepresents independently hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl part, or substituted or unsubstituted aryl or heteroaryl; or RQ'andRQtaken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl; and/or

xliv-b. Q represents ORQ', SRQ', NRQ'RQ,N3, =N-OH, or part selected from the group consisting of

where everyone found r=0, 1, and RQ'andRQrepresents independently hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl part, or substituted or unsubstituted aryl or hetaerae the aryl part, or RQ'andRQtaken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl part.

An important subclass of class (Ic) includes those compounds that have the structure of formula (Ic)in which X2represents the C=O; R represents a-CH(R8a)With(R9a)=C(R10a)-; j=0; each of l and m is equal to 1; R3represents hydrogen; G is a CRG1; M represents CRM1RM2and the compound has the structure:

where R2, R5-R7and Q are defined in the description in classes and subclasses;

g=1, 2, 3 or 4;

each R8A, R9aand R10Aindependently represents hydrogen or alkyl, heteroalkyl, aryl or heteroaryl; and where any two of the groups R7, R8A, R9aand R10Amay form a cyclic alkyl, heteroalkyl, -alkyl(aryl), -heteroalkyl(aryl), -alkyl(heteroaryl) or-heteroalkyl(heteroaryl) part, or aryl or heteroaryl;

L represents CRL1RL2, S, Oor NRL3where each occurring RL1,RL2and RL3represents independently hydrogen or an aliphatic, alicyclic, heteroaromatics, g is carolinelucas, aryl or heteroaryl;

each found RG1, RM1and RM2represents independently hydrogen or an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl;

where any two adjacent groups RL1,RL2, RL3, RG1, RM1or RM2taken together, form a substituted or unsubstituted alicyclic or heteroalicyclic part containing 3-6 atoms, or aryl or heteroaryl part.

Another important subclass of class (Ic) includes those compounds that have the structure of formula (Ic)in which X2represents the C=O; each G, J and M is CH2; each j, l, and m is 1; R represents a-CH(R8a)With(R9a)=C(R10a)-; R3represents hydrogen; and the compound has the structure:

where R2, R5-R7and Q are defined in the description in classes and subclasses;

g=1, 2, or 3;

each R8A, R9aand R10Aindependently represents hydrogen or alkyl, heteroalkyl, aryl or heteroaryl; and where any two of the groups R7, R8A, R9aand R10Amay form a cyclic alkyl, heteroalkyl, -alkyl(aryl), -heteroalkyl(aryl), -alkyl(heteroaryl), and the and-heteroalkyl(heteroaryl) part, or aryl or heteroaryl;

RL1and RL2are independently hydrogen or aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part.

Another important subclass of class (Ic) includes those compounds that have the structure of formula (Ic)in which X2represents the C=O; R represents-C(R8b)With(R9b)N(R10b)C(R11b)-; j=0; each of l and m is equal to 1; R3represents hydrogen; G is a CHRG1M represents CRM1RM2and the compound has the structure:

where R2, R5-R7and Q are defined in the description in classes and subclasses;

g=1, 2, or 3;

L represents CRL1RL2, S, Oor NRL3where each occurring RL1,RL2and RL3represents independently hydrogen or an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl;

each found RG1, RM1and RM2represents independently hydrogen or an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl;

any two adjacent groups RL1,RL2, RL3, RG1, RM1or RM2 taken together, may form a substituted or unsubstituted alicyclic or heteroalicyclic part containing 3-6 atoms, or aryl or heteroaryl;

each R8b, R9b, R10band R11bindependently represents hydrogen, -(C=O)RLor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part where everyone found RLrepresents independently hydrogen, HE, ORMor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or where any two adjacent groups R8b, R9b, R10band R11btaken together, form an alicyclic or heteroalicyclic part; or aryl or heteroaryl; RMrepresents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; and

where each NR7and CR8b, CR8band CR9b, CR9band NR10b, NR10band CR11bindependently associated with single or double bond, as valency.

Another important subclass of class (Ic) includes those compounds that have the structure of formula (Ic)in which X2represents the C=O; R represents-C(R8b)With(R9b)N(R10b)C(R11b )-; j=0; each of l and m is equal to 1; R3represents hydrogen; G is a CHRG1M represents CRM1RM2; R10band R11btaken together form a cyclic heteroalkyl group; and the compound has the structure:

where R2, R5-R7and Q are defined in the description in classes and subclasses;

g=1, 2, 3 or 4;

q=0-12;

each meeting S1represents independently an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or any two adjacent of S1taken together can form an alicyclic, heteroalicyclic, aryl or heteroaryl;

each R8band R9bindependently absent or represents hydrogen, -(C=O)RLor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part where everyone found RLindependently represents hydrogen, HE, ORMor aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or where R8band R9btaken together, form an alicyclic or heteroalicyclic part, or aryl or heteroaryl; RMrepresents the Alif is practical, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; and

each NR7and CR8band CR8band CR9bindependently associated with single or double bond, as valency.

Another important subclass of class (Ic) includes those compounds that have the structure of formula (Ic)in which X2represents the C=O; each G, J and M is CH2; each j, l, and m is 1; R represents-C(R8b)With(R9b)N(R10b)C(R11b)-; R3represents hydrogen; and the compound has the structure:

where R2, R5-R7and Q are defined in the description in classes and subclasses;

g=0, 1, 2 or 3;

RL1and RL2are independently hydrogen or aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl;

each R8b, R9b, R10band R11bindependently absent or represents hydrogen, -(C=O)RLor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part where everyone found RLindependently represents hydrogen, HE, ORMor aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl the second part, or where any two adjacent groups R8b, R9b, R10band R11btaken together, form an alicyclic or heteroalicyclic part, or aryl or heteroaryl; RMrepresents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; and

each NR7and CR8b, CR8band CR9b, CR9band NR10b, NR10band CR11bindependently associated with single or double bond, as valency.

Another important subclass of class (Ic) includes those compounds that have the structure of formula (Ic)in which X2represents the C=O; each G, J and M is CH2; each j, l, and m is 1; R represents-C(R8b)With(R9b)N(R10b)C(R11b)-; R3represents hydrogen; R10band R11btaken together form a cyclic heteroalkyl group; and the compound has the structure:

where R2, R5-R7and Q are defined in the description in classes and subclasses;

p=1, 2, 3 or 4;

q=0-12;

g=1, 2, or 3;

RL1and RL2are independently hydrogen or aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl;

each meeting S1the submitted is an independently aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or any two adjacent of S1taken together can form an alicyclic, heteroalicyclic, aryl or heteroaryl;

each R8band R9bindependently represents hydrogen, -(C=O)RLor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part where everyone found RLindependently represents hydrogen, HE, ORMor aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or where R8band R9btaken together, form an alicyclic or heteroalicyclic part, or aryl or heteroaryl; RMrepresents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; and

each NR7and CR8band CR8band CR9bindependently associated with single or double bond, as valency.

Another important subclass of class (Ic) includes those compounds that have the structure of formula (Ic)in which X2represents the C=O; R represents-C(R8s)With(R9c)C(R10s)C(R11S)OC(R12s)-; j=0; each l and m=1; R3PR is dstanley a hydrogen; G represents CHRG1M represents CRM1RM2; and the compound has the structure:

where R1, R2, R5-R7and Q are defined in the description in classes and subclasses;

g=1, 2, or 3;

L represents CRL1RL2, S, Oor NRL3where each occurring RL1,RL2and RL3represents independently hydrogen or an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl;

each found RG1, RM1and RM2represents independently hydrogen or an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl;

any two adjacent groups RL1,RL2, RL3, RG1, RM1or RM2taken together, may form a substituted or unsubstituted alicyclic or heteroalicyclic part containing 3-6 atoms, or aryl or heteroaryl;

each R8c, R9c, R10c, R11cand R12cindependently absent or represents hydrogen, -(C=O)RLor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part where everyone found RLis the fight independently hydrogen, HE, ORMor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or where any two adjacent groups R8c, R9c, R10c, R11cand R12ctaken together, form an alicyclic or heteroalicyclic part, or aryl or heteroaryl; RMrepresents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; and

where each NR7and CR8s, CR8sand CR9c, CR9cand CR10sand CR10sand CR11Sindependently associated with single or double bond, as valency.

Another important subclass of class (Ic) includes those compounds that have the structure of formula (Ic)in which X2represents the C=O; R represents-C(R8s)With(R9c)C(R10s)C(R11S)OC(R12s)-; each G, J and M is CH2; each of j, l and m=1; R3represents hydrogen; and the compound has the structure:

where R1, R2, R5-R7and Q are defined in the description in classes and subclasses;

g=0, 1, 2 or 3;

RL1and RL2represents independently hydrogen or an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl is inuu part;

each R8c, R9c, R10c, R11cand R12cindependently absent or represents hydrogen, -(C=O)RLor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part where everyone found RLrepresents independently hydrogen, HE, ORMor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or where any two of the groups R8c, R9c, R10c, R11cand R12ctaken together, form an alicyclic or heteroalicyclic part, or aryl or heteroaryl; RMrepresents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; and

where each NR7and CR8s, CR8sand CR9c, CR9cand CR10sand CR10sand CR11Sindependently associated with single or double bond, as valency.

A number of important subclasses of each of the above subclass of class (Ic) deserve separate mention; these subclasses include subclasses of the above subclass of class (Ic)in which:

i-c. R2represents hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic, or on sennou or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl;

ii-c. R2represents a substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl;

iii-c. R2represents a substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl;

iv-c. R2represents methyl, ethyl, propyl, butyl, pentyl, tert-butyl, isopropyl, -CH(CH3)CH2CH3, -CH(CH3)CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)2CH2CH3, -CH(CH3)cyclobutyl, -CH(Et)2, -CH(CH3)2CCH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

v-c. R2represents hydrogen;

vi-c. R2represents hydrogen, methyl or benzyl;

vii-c. R2represents methyl;

viii-c. R2represents acyl, where the acyl group represents a group protecting the nitrogen;

ix-c. R3represents hydrogen;

x-c. R1and R4taken together, form a substituted or unsubstituted pyrolidine group;

xi-c. R1and R4taken together, form a substituted or unsubstituted piperidino group;

xii-c. R 1and R4taken together, form a substituted or unsubstituted thiazolidinone group;

xiii-c. R1and R4taken together, form a substituted or unsubstituted morpholino group;

xiv-c. R1and R4taken together, form a substituted or unsubstituted thiomorpholine group;

xv-c. R1and R4taken together, form a substituted or unsubstituted indole group;

xvi-c. R5represents hydrogen;

xvii-c. R6represents a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

xviii-c. R6represents methyl, ethyl, propyl, butyl, pentyl, tert-butyl, isopropyl, -CH(CH3)CH2CH3, -CH2CH(CH3)2, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

xix-c. R6represents tert-butyl;

xx-c. The carbon atom carrying the R6has the S configuration;

xxi-c. R7represents a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

xxii-c. R7represents methyl;

xxiii. R represents a-CH(R8a)C(R9a)=C(R10a)-; and

a) R8Arepresents a substituted or unsubstituted, linear or branched, CEC is practical or acyclic, or saturated or unsaturated lower alkyl;

b) R8Arepresents isopropyl;

C) the carbon atom carrying the R8Ahas the S configuration;

d) R9arepresents hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

e) R9arepresents hydrogen;

f) R10Arepresents hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; or

g) R10Arepresents methyl;

xxiv-c. R represents-C(R8b)C(R9b)N(R10b)CR11band

a) R8brepresents a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

b) R8brepresents isopropyl;

C) the carbon atom carrying the R8bhas the S configuration;

d) R9brepresents hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

e) R10brepresents hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated n is SCHOU alkyl or acyl;

f) R10brepresents hydrogen, methyl or acetyl;

g) R10band R11btaken together, form a substituted or unsubstituted pyrolidine ring; or

h) R9band R11btaken together, form a substituted or unsubstituted thiazole ring;

xxxv-d. R represents-C(R8c)C(R9c)C(R10c)CR11cOCR12cand

a) R8srepresents a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

b) R8srepresents isopropyl;

C) the carbon atom carrying the R8shas the S configuration;

(d) each R9cand R10sindependently represents hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

e) CR9cand CR10slinked through a double bond;

f) CR9cand CR10slinked through a double bond and R9crepresents hydrogen; or

g) CR9cand CR10slinked through a double bond and R10srepresents methyl;

xxv-c. -C(R3)(R4)N(R1)(R2) together represent the part having the structure:

and

a) R2represents hydrogen, or substituted or nezamedin the Yu, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl;

b) R2represents methyl, ethyl or propyl;

(C) RG1represents hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or substituted or unsubstituted phenyl;

d) RG1represents hydrogen, methyl or phenyl;

e) RG1and the substituents on L, taken together, form a substituted or unsubstituted phenyl group;

f) each of RM1and RM2independently represents hydrogen, hydroxyl, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; substituted or unsubstituted phenyl portion, or RM2no, when RM1and the substituents on L, taken together, form a substituted or unsubstituted aryl or heteroaryl;

g) g=1 or 2; or

h) L represents CH2, S, or O;

xxvi-c. -C(R3)(R4)N(R1)(R2) together represent the part having the structure:

and

a) R2represents hydrogen, or substituted or unsubstituted, linear is whether branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl;

b) R2represents methyl;

(C) each RL1and RL2independently represents hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or substituted or unsubstituted phenyl;

(d) each RL1and RL2represents hydrogen;

(e) each RL1and RL2independently represents a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; or

f) g=1 or 2;

xxvii-c. X2represents the C=O;

xxviii-c. X2represents CH2;

xxix-c. X2represents the SO2;

xxx-c. Q represents ORQ', SRQ', NRQ'RQN3, =N-OH or part selected from the group consisting of:

where each occurring r is 0, 1 or 2; s and t independently represent an integer from 0 to 8; X represents O, S or NRK; occurring every RQ1and RQ2represents independently hydrogen, halogen, -CN, -S(O)hRJ, -NO2,-CORJ, -CO2RJ, -NRJCOR , -NRJCO2RJ, -CONRJRJ, -CO(NORJRJ, aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or Z1RJ; where h=1 or 2; and Z1is an independently-O-, -S-, NRK, -C(O)-, where each occurring RJandRKrepresents independently hydrogen, CORL, COORL, CONRLRM, -NRLRM, -S(O)2RLor aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, and where each occurring RLandRMrepresents independently hydrogen, or an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; and RQ'andRQrepresents independently hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl part, or substituted or unsubstituted aryl or heteroaryl; or RQ'andRQtaken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl;

xxxi-c. Q represents ORQ', SRQ', NRQ'RQN3, =N-OH, or part of, branney from the group consisting of:

where everyone found r=0, 1, or 2; s and t independently represent an integer from 0 to 8; each occurring RQ1and RQ2represents independently hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl part, or substituted or unsubstituted aryl or heteroaryl part, or RQ1andRQ2taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic; and RQ'andRQare independently hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl part, or substituted or unsubstituted aryl or heteroaryl part, or RQ'andRQtaken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl part and/or

xxxii-c. Q represents ORQ', SRQ', NRQ'RQ,N3, =N-OH, or part selected from the group consisting of

where everyone found r=0, 1, or 2; and RQ'andRQrepresent independently waters of the genus, or substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl part, or RQ'andRQtaken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl part.

A number of important subclasses of each of the above subclasses of class (Id)in which R represents a-CH(R8a)C(R9a)=C(R10a)-, X2represents the C=O; and the compound has the following structure:

where each R3and R4independently represents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or when taken together, form an alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl); R1, R2, R5-R7and Q are defined in the description in classes and subclasses; and

each R8a, R9aand R10aindependently represents hydrogen or an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; and where any two of the groups R7, R8a, R9aand R10acan images is to alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) part, or aryl or heteroaryl part.

Another important subclass of class (Id)includes those compounds that have the structure of formula (Id)in which R represents-C(R8b)C(R9b)N(R10b)C(R11b)-, X2represents the C=O; and the compound has the following structure:

where each R3and R4independently represents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or when taken together, form an alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl); R1, R2, R5-R7and Q are defined in the description in classes and subclasses;

each R8b, R9b, R10band R11bindependently absent or represents hydrogen, -(C=O)RLor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part where everyone found RLindependently represents hydrogen, HE, ORMor aliphatic, alicyclic the definition, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or where the group R8b, R9b, R10band R11btaken together, form an alicyclic or heteroalicyclic part, or aryl or heteroaryl; RMrepresents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; and

each NR7and CR8band CR8band CR9b, CR9band NR10b, NR10bandCR11bindependently associated single or double bond, as valency.

Another important subclass of class (Id)includes those compounds that have the structure of formula (Id)in which R represents-C(R8b)C(R9b)N(R10b)C(R11b)-; X2represents the C=O; R10band R11btaken together form a cyclic heteroalkyl group; and the compound has the following structure:

where each R3and R4independently represents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or when taken together, form an alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(g is tervailing) part; R1, R2, R5-R7and Q are defined in the description in classes and subclasses;

p=1, 2, 3 or 4;

q=0-12;

each meeting S1independently represents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or any two adjacent of S1taken together can form an alicyclic, heteroalicyclic, aryl or heteroaryl;

each R8band R9bindependently represents hydrogen, -(C=O)RLor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part where everyone found RLindependently represents hydrogen, HE, ORMor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or where R8band R9btaken together, form an alicyclic or heteroalicyclic part, or aryl or heteroaryl; RMrepresents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; and

each NR7and CR8and CR8band CR9bindependently associated single or double bond, as valency.

Another important subclass of class (Id) includes those compounds which tion, which have the structure of formula (Id)in which X2represents the C=O; R represents-C(R8c)C(R9c)C(R10s)With(R11c)OC(R12c)- and the compound has the following structure:

where each R3and R4independently represents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or, when taken together, form an alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl); R1, R2, R5-R7and Q are defined in the description in classes and subclasses;

each R8c, R9c, R10s, R11cand R12cindependently absent or represents hydrogen, -(C=O)RLor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part where everyone found RLindependently represents hydrogen, HE, ORMor an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or where any two of the groups R8c, R9c, R10s, R11cand R12ctaken together, form an alicyclic or heteroalicyclic part, or riloy or heteroaryl; where RMrepresents an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl; and

each NR7and CR8s, CR8sand CR9c, CR9cand CR10sand CR10sand CR11Sindependently associated single or double bond, as valency.

A number of important subclasses of each of the above subclasses of class (Id) deserve separate mention; these subclasses include subclasses of the above subclasses of class (Id)in which:

i-d. R1and R2independently represent hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl;

ii-d. R1represents hydrogen, and R2represents a substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl;

iii-d. R1represents hydrogen, and R2represents a substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated lower alkyl;

iv-d. R1represents hydrogen and R2represents methyl, ethyl, propyl, butyl, pen the sludge, tert-butyl, isopropyl, -CH(CH3)CH2CH3, -CH(CH3)CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)2CH2CH3, -CH(CH3)cyclobutyl, -CH(Et)2, -CH(CH3)2C CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

v-d. Each R1and R2represents hydrogen;

vi-d. Each R1and R2represents independently hydrogen or methyl;

vii-d. Each R1and R2represents methyl;

viii-d. Each R3and R4represents independently a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl or-alkyl(aryl) or substituted or unsubstituted aryl or heteroaryl;

ix-d. Each R3and R4represents independently a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl or-alkyl(aryl) or substituted or unsubstituted aryl;

x-d. Each R3and R4represents independently a substituted or unsubstituted lower alkyl, aryl or heteroaryl;

xi-d. Each R3and R4represents independently methyl, ethyl, propyl, butyl, pentyl, tert-butyl, isopropyl, -CH(CH 3)CH2CH3, -CH(CH3)CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)2CH2CH3CH(CH3)cyclobutyl, -CH(Et)2, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl, -C1-6ORa- 1-6SRaor-CRaRbRc; where RaandRbare independently hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, and Rwithrepresents a substituted or unsubstituted aryl or heteroaryl;

xii-d. Each R3and R4represents independently methyl, ethyl, propyl, butyl, pentyl, tert-butyl, isopropyl, -CH(CH3)CH2CH3, -CH(CH3)CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)2CH2CH3, -CH(CH3)cyclobutyl, -CH(Et)2, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl, -C1-6ORa- 1-6SRaor-CRbRcPh; where Rarepresents hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl and each RbandRcimagine the fight independently substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

xiii-d. Each R3and R4represent ethyl;

xiv-d. R3represents phenyl and R4represents lower alkyl;

xv-d. R3represents phenyl and R4represents ethyl;

xvi-d. R3and R4taken together, form a substituted or unsubstituted cycloalkyl group;

xvii-d. R3and R4taken together, constitute tsiklogeksilnogo group;

xviii-d. R3and R4taken together, form a substituted or unsubstituted cycloalkyl(aryl) group;

xix-d. R5represents hydrogen;

xx-d. R6represents a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

xxi-d. R6represents methyl, ethyl, propyl, butyl, pentyl, tert-butyl, isopropyl, -CH(CH3)CH2CH3, -CH2CH(CH3)2, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

xxii-d. R6represents tert-butyl;

xxiii-d. The carbon atom carrying the R6has the S configuration;

xxiv-d. R7represents a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated with the first lower alkyl;

xxv-d. R7represents methyl;

xxvi-d. R represents a-CH(R8a)C(R9a)=C(R10a)-; and

i) R8Arepresents a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

j) R8Arepresents isopropyl;

k) the carbon atom carrying the R8Ahas the S configuration;

l) R9arepresents hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

m) R9arepresents hydrogen;

n) R10Arepresents hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; or

o) R10Arepresents methyl;

xxvii-d. R represents-C(R8b)C(R9b)N(R10b)C(R11b- and

p) R8brepresents a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

q) R8brepresents isopropyl;

r) the carbon atom carrying the R8bhas the S configuration;

s) R9brepresents hydrogen or substituted or unsubstituted, linear or branched, cyclic who or acyclic, or saturated or unsaturated lower alkyl;

t) R10brepresents hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or acyl;

u) R10brepresents hydrogen, methyl or acetyl;

v) R10band R11btaken together, form a substituted or unsubstituted pyrolidine ring; or

w) R9band R11btaken together, form a substituted or unsubstituted thiazole ring;

xxviii-d. R represents-C(R8c)C(R9c)C(R10c)CR11cOCR12cand

h) R8srepresents a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

i) R8srepresents isopropyl;

(j) the carbon atom carrying the R8shas the S configuration;

k) for every R9cand R10sindependently represents hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl;

l) CR9cand CR10slinked through a double bond;

m) CR9cand CR10slinked through a double bond and R9crepresents hydrogen; or

n) CR9cand CR10sconnected through dual communications, and R 10srepresents methyl;

xxix-d. X2represents the C=O;

xxx-d. X2represents CH2;

xxxi-d. X2represents the SO2;

xxxii-d. Q represents ORQ', SRQ', NRQ'RQN3, =N-OH or part selected from the group consisting of

where everyone found r=0, 1, or 2; s and t independently represent an integer from 0 to 8; X represents O, S or NRK; occurring every RQ1and RQ2represents independently hydrogen, halogen, -CN, -S(O)hRJ, -NO2,-CORJ, -CO2RJ, -NRJCORJ, -NRJCO2RJ, -CONRJRJ, -CO(NORJRJ, aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, or Z1RJ; where h=1 or 2; and Z1is an independently-O-, -S-, NRK, -C(O)-, where each occurring RJandRKrepresents independently hydrogen, CORL, COORL, CONRLRM, -NRLRM, -S(O)2RLor aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl or heteroaryl part, and where each occurring RLandRMrepresents independently hydrogen, or an aliphatic, alicic is practical, heteroaromatics, heteroalicyclic, aryl or heteroaryl; and RQ'andRQrepresents independently hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl part, or substituted or unsubstituted aryl or heteroaryl; or RQ'andRQtaken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl;

xxxiii-d. Q represents ORQ', SRQ', NRQ'RQ,N3, =N-OH, or part selected from the group consisting of

where everyone found r=0, 1, or 2; s and t independently represent an integer from 0 to 8; each occurring RQ1and RQ2represents independently hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl part, or substituted or unsubstituted aryl or heteroaryl part, or RQ1andRQ2taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic; and RQ'andRQare independently hydrogen, or samisen the Yu or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl part, or substituted or unsubstituted aryl and heteroaryl part, or RQ'andRQtaken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl part and/or

xxxiv-d. Q represents ORQ', SRQ', NRQ'RQ,N3, =N-OH, or part selected from the group consisting of

where everyone found r=0, 1, or 2; and RQ'andRQare independently hydrogen, or substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or heteroalkyl part, or substituted or unsubstituted aryl and heteroaryl part, or RQ'andRQtaken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic, aryl or heteroaryl part.

As should be clear, compounds of interest include among others those connections that share the properties of one or more of the above subclasses. Some of these subclasses are illustrated in the following types of connections:

I) the compounds of formula and f is matemticas acceptable derivatives):

where R1-R2,R4a,R4b, R9a-R10aand Q are as defined in the description above and in subclasses; and Ar represents a substituted or unsubstituted aryl or heteroaryl part.

II) Compounds of the formula (and pharmaceutically acceptable derivatives):

where A, B, D, E, a, b, d, e, R1-R2,R4a,R4band R9a-R10aare as defined in the description above and in subclasses; and Ar represents a substituted or unsubstituted aryl or heteroaryl part.

It should also be understood that for each of the subgroups I-II, described above, of particular interest are a variety of other subclasses, including, but not limited to, those classes i-a, to xliv-a, described above, and classes, subclasses and species of compounds described in the above description and in the examples.

III) Compounds of the formula (and pharmaceutically acceptable derivatives):

where R1-R2,R4a,R4b, R9b-R11band RGare as defined in the description above and in subclasses; and Ar represents a substituted or unsubstituted aryl or heteroaryl part.

IV) Compounds of the formula (and the x pharmaceutically acceptable derivatives):

where A, B, D, E, a, b, d, e, R1-R2,R4a,R4band R9b-R11bare as defined in the description above and in subclasses; and Ar represents a substituted or unsubstituted aryl or heteroaryl part.

V) Compounds of the formula (and pharmaceutically acceptable derivatives):

where R1-R2,R4a,R4b, R9c-R12cand RGare as defined in the description above and in subclasses; and Ar represents a substituted or unsubstituted aryl or heteroaryl part.

It should also be understood that for each subgroup III-V, described above, of particular interest are a variety of other subclasses, including, but not limited to, those classes i-b, XIII-b, described above, and classes, subclasses and species of compounds described in the above description and in the examples.

VI) Compounds of the formula (and pharmaceutically acceptable derivatives):

where L, R9a-R10a, RG1, RM1and RM2are as defined in the description above and in subclasses; g=1 or 2; Q represents ORQ'where RQ'represents hydrogen or lower alkyl; and R2and R6are not avisio substituted or unsubstituted linear or branched lower alkyl.

VII) Compounds of the formula (and pharmaceutically acceptable derivatives):

where g, R9a-R10a, RL1and RL2are as defined in the description above and in subclasses; X1represent CH2or C=O; R2and R6are independently substituted or unsubstituted linear or branched lower alkyl; and Q represents ORQ'or NRQ'RQwhere RQ'represent hydrogen or lower alkyl, or RQ'andRQtaken together with the nitrogen atom to which they are bound, form a substituted or unsubstituted heterocyclic portion, whereby each of the above alkyl parts can be substituted or unsubstituted, linear or branched, cyclic or acyclic.

VIII) Compounds of the formula (and pharmaceutically acceptable derivatives):

where A, B, D, E, L, a, b, d, e, p, R9b, RG1, RM1and RM2are as defined in the description above and in subclasses; g=1 or 2; and R2and R6are independently substituted or unsubstituted linear or branched lower alkyl.

(IX) Compounds of the formula (and pharmaceutically acceptable derivatives):

the de p, R9b, RL1, RL2, RQ'and RQare as defined in the description above and in subclasses; and R2and R6are independently substituted or unsubstituted linear or branched lower alkyl.

It should also be understood that for each of the subgroups VI-IX, described above, of particular interest are a variety of other subclasses, including, but not limited to, those classes i-c to xxxii-c, which are described above, and classes, subclasses and species of compounds described in the above description and in the examples. In some embodiments, the implementation of the compounds of subgroups VI-IX described above, R2represents methyl, isopropyl, sec-butyl or-CH(CH3)CH(CH3)2. In some embodiments, the implementation of the compounds of subgroups VI-IX described above, R6represents tert-butyl or isopropyl. In some embodiments, the implementation of the compounds of subgroups VI-IX described above, R2represents methyl, isopropyl, sec-butyl or-CH(CH3)CH(CH3)2and R6represents tert-butyl or isopropyl. In some illustrative implementations of the compounds of subgroups VI-IX described above, R2represents methyl, and R6represents tert-butyl. In some illustrative implementations of the compounds of subgroups VI-IX, op the sled above, R2represents isopropyl, and R6represents tert-butyl. In some illustrative implementations of the compounds of subgroups VI-IX described above, R2represents sec-butyl, and R6represents tert-butyl or isopropyl. In some illustrative implementations of the compounds of subgroups VI-IX described above, R2represents a-CH(CH3)CH(CH3)2and R6represents tert-butyl.

X) Compounds of the formula (and pharmaceutically acceptable derivatives):

where R1, R9a, R10aand RGare as defined in the description above and in subclasses; and each of R3and R4are independently alkyl, heteroalkyl, heteroalkyl(aryl) or alkyl(aryl) part or R3and R4taken together, constitute the alkyl or heteroalkyl part.

You should also understand that for a subgroup of X, described above, of particular interest are a variety of other subclasses, including, but not limited to, those classes i-d to xxxii-d, which are described above, and classes, subclasses and species of compounds described in the above description and in the examples.

Some of the above compounds can include one or more asymmetric centers and therefore may exist in different isomeric forms, for example, the stereoisomers and/or diastereomers. It should be understood that the invention covers every possible isomers such as geometrical isomer, optical isomer, a stereoisomer and tautomer based on asymmetric carbon, which can occur in the structures of the compounds of the invention, and mixtures of such isomers, and not limited to a specific stereochemistry shown for compounds described in the present description. It should, furthermore, be understood that the absolute stereochemistry of some of the compounds described under the section "Examples"was not defined, and that when the stereochemistry was determined for these compounds, it is understood that it is experimental and indicates that for these compounds, there is a set of diastereomers and/or that the diastereoisomer was isolated in pure form. Thus, the compounds of the invention and their pharmaceutical compositions can be in the form of an individual enantiomer, diastereoisomer or a geometric isomer, or may be in the form of mixtures of stereoisomers. In some embodiments of compounds of the invention are enantioface connection. In some embodiments of the provided mixture of stereoisomers or diastereomers.

In addition, no other indications, some compounds, as described in the description, can have the one or more double bonds, which may exist in the form or Z-or E-isomer. The invention additionally encompasses compounds in the form of individual isomers, essentially devoid of other isomers, and alternative in the form of mixtures of different isomers, for example racemic mixtures of stereoisomers. The invention also includes tautomers of some compounds, as described above. In addition to the above compounds as such, the invention also includes pharmaceutically acceptable derivatives of these compounds and compositions comprising one or more compounds of the invention and one or more pharmaceutically acceptable excipients or additives.

Compounds of the invention can be obtained by crystallization of the compounds of formula (I) in various conditions, and they can exist in the form of one or a combination of polymorphs of compounds of General formula (I)constituting part of this invention. For example, different polymorphs can be identified and/or obtained using different solvents or mixtures of solvents for recrystallization; by performing recrystallization at different temperatures or by using different types of cooling, ranging from very fast to very slow cooling during kristallizatsii. Polymorphs may also be obtained by heating or melting of the is placed, followed by gradual or fast cooling. The presence of polymorphs may be determined by NMR spectroscopy, solid probe, infrared spectroscopy, differential scanning calorimetry, x-ray diffraction pattern of the powder and/or other techniques. Thus, the present invention includes compounds of the invention, their derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate and a pharmaceutically acceptable compositions containing them.

2) Connection and definitions

As described above, this invention relates to new compounds with a range of biological properties. The compounds of this invention have biological activity, suitable for the treatment of diseases or disorders, such as proliferative diseases, including cancer, but not limited to them. In some embodiments of compounds of the invention also find application in the prevention of restenosis of blood vessels exposed to trauma, such as angioplasty and stenting.

The compounds of this invention include compounds disclosed above and described in the description and partly illustrated by the various classes, subgenera, and species disclosed in the description in other places.

In addition, the present invention relates to pharmaceuticas and acceptable derivatives of the compounds of the invention and methods of treatment of an individual with the use of these compounds, their pharmaceutical compounds or any of them in combination with one or more additional therapeutic agents. Used in the phrase "pharmaceutically acceptable derivative" means any pharmaceutically acceptable salt, a simple ester, or salt of such a simple ester of such compound, or any adduct or derivative which, after administration to a patient are capable of providing (directly or indirectly) a compound as otherwise described in the description, or its metabolite or residue. Thus, pharmaceutically acceptable derivatives include, among other compounds are prodrugs. A prodrug is a derivative, usually at a significantly reduced pharmacological activity, which contains an additional part, which is susceptible to destruction in vivo, giving the parent molecule in the form of the pharmacologically active species. An example of a prodrug is a simple ester which is cleaved in vivo, giving the desired compound. Prodrugs of various compounds and materials and methods of obtaining derivatives of the parent compounds to create prodrugs are known and can be adapted to the present invention. Some illustrative pharmaceutical compositions and pharmaceutically acceptable derivatives will be discussed in the description below.

Numerous is suitable proletarienne parts and information, concerning their selection, synthesis and application, are well known in this field. Examples are interested proletarienne parts include, among others, proletarienne part that can be attached to the containing primary or secondary amine functional groups. Examples of such proletarienne parts include the following:

< / br>
R1= all natural, unnatural amino acids
Synthesis proletarienne groups, see Borchardt, R. T. et. al.,J. Org. Chem.1997, 43,3641-3652.
< / br>
R1= C1-C4 alkyl, cycloalkyl, oxyalkyl, aminoalkyl etc.

R2= all natural, unnatural amino acids
Synthesis proletarienne groups, see Zhou, X-X. et. al., PCT WO 99/51613.
< / br>
R1, R2= all natural, unnatural amino acids
Synthesis proletarienne groups, see Ezra, A. et. al.,J. Med. Chem.2000,43,3641-3652.

Other examples of interest proletarienne fragments are proletarienne fragments, which can be linked with hydroxyl-containing functional groups. Such proletarienne fragments are well known in this field and can easily be identified special is a shrub in a related technical field. The present invention covers any Palekastro the form of compounds described in the description.

Some compounds of the present invention and determine the specific functional groups are also described in more detail below. In this invention, the chemical elements are identified in accordance with the Periodic table of the elements, CAS version, 75th edition of the Handbook of chemistry and physics, inside cover, and specific functional groups are generally defined as defined in the description. In addition, General principles of organic chemistry, as well as specific functional parts and reactivity are described in the publication "Organic Chemistry", Thomas Sorell, University Science Books, Sausalito: 1999, the full contents of which are incorporated here by reference. In addition, the person skilled in the art will understand that in synthetic methods, as described in the description, use a variety of protective groups. Under used in the description, the term "protective group" is meant that a particular functional group, for example, O, S, or N, is temporarily blocked so that a reaction can take place selectively at another reactive site in a multifunctional compound. In preferred embodiments of the protective group reacts selectively in good yield to obtain a secure substrate, which ostoich is in protected reactions; the protective group must be selectively removed in good yield readily available, preferably nontoxic reagents that do not attack the other functional groups; protective group forms an easily separable derivative (preferably without creating a new stereogenic centers); and the protective group has a minimum of additional functionality to avoid further sites of reaction. As discussed in detail in the description, you can use group advocating oxygen, sulfur, nitrogen, and carbon. For example, in some embodiments, the implementation uses some illustrative group advocating oxygen. Data illustrative group advocating oxygen include, but are not limited to, simple methyl ethers, substituted simple methyl esters (for example, IOM (simple methoxymethyl ether), MTM (simple methylthiomethyl ether), VOM (simple benzyloxyethanol ether), RMVB (simple pair-methoxybenzylamine ether), as a few examples), substituted simple ethyl ethers, substituted simple benzyl ethers, simple Silovye esters (e.g., TMS (simple trimethylsilyloxy ether), TES (simple triethylsilyl ether), TIPS (simple triisopropylsilyl ether), TBDMS (simple tert-butyldimethylsilyloxy ether), a simple tribotechnology ether, TBDPS (simple tert-butyldiphenylsilyl the FYR), as a few examples), esters (e.g., formate, acetate, benzoate (Bz), triptorelin, dichloracetate, as a few examples), carbonates, cyclic acetals and ketals. In some other illustrative embodiments of used group protecting the nitrogen. Data group protecting the nitrogen include, but are not limited to, carbamates (including carbamates, methyl, ethyl and substituted ethyl (for example, Troc), as a few examples), amides, cyclic kidnie derivatives, N-alkyl and N-aryl amines, minovia derivatives and enaminone derivative as a few examples. Some other illustrative protective group discussed in detail in the description, but it should be understood that the present invention is not limited to these protective groups; using the above criteria can be easily identified and used in the present invention a variety of additional equivalent protective group. In addition, a variety of protective groups described in the publication "Protective Groups in Organic Synthesis", Third Ed. Greene, T.W. and Wuts, P.G., Eds., John Wiley & Sons, New York: 1999, the full contents of which are incorporated here by reference.

Compounds disclosed in the description, can be replaced with any number of substituents or functional parts. The term "substituted" or with the term "optional what about the", or not, and substituents contained in formulas of this invention, refers to the replacement of hydrogen radicals in a given structure with the radical of a particular Deputy. When more than one position in any given structure may be substituted by more than one Deputy, selected from a particular group, the Deputy may be either the same or different in each position. Used in the description, the term "substituted" includes all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. In accordance with this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described in the description, which correspond to the valences of the heteroatoms. In addition, the invention is not limited by the permissible substituents of organic compounds. Combinations of substituents and variables provided by this invention preferably are those that lead to the formation of stable compounds used in the treatment of, for example, cancer. Used the term "sustainable" predpochtitel what about the refers to compounds that which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time so that they can be used for the purposes discussed in detail in the description.

Used the term "aliphatic" includes both saturated and unsaturated, linear (i.e. unbranched) or branched aliphatic hydrocarbons, which are optionally substituted by one or more functional groups. The term "aliphatic" includes alkyl, alkeline, alkyline radicals, but is not limited to them. Thus, used the term "alkyl" includes linear and branched alkyl groups. Similar applies to the common generic terms, such as "alkenyl", "quinil" and the like. In addition, used the term "alkyl", "alkenyl", "quinil" and similar covers, and substituted and unsubstituted groups. In some implementations, the term "lower alkyl" is used to determine the alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched, containing 1-6 carbon atoms.

In some embodiments of alkyl, alkeline and alkyline group, COI is Lithuania in the invention, contain 1-20 aliphatic carbon atoms. In some embodiments of alkyl, alkeline and alkyline group used in the invention contain 1-10 aliphatic carbon atoms. In other embodiments of alkyl, alkeline and alkyline group used in the invention contain 1-8 aliphatic carbon atoms. In still some other embodiments of alkyl, alkeline and alkyline group used in the invention contain 1-6 aliphatic carbon atoms. In still some other embodiments of alkyl, alkeline and alkyline group used in the invention contain 1-4 carbon atoms. Thus, the illustrative aliphatic groups include, for example, methyl, ethyl, n-sawn, ISO-propyl, allyl, n-butylene, second-butylene, isobutylene, tert-butylene, n-Pintilie, second-Pintilie, isopentyl, tert-Pintilie, n-hexylene, second-hexylene parts and the like, which again, may bear one or more substituents, but are not limited to. Alkeneamine groups include, for example, ethynyl, propenyl, butenyl, 1-methyl-2-butene-1-yl and the like, but are not limited to. Representative alkyline group include ethinyl, 2-PROPYNYL (propargyl), 1-PROPYNYL and the like, but are not limited to.

Used the term "alicycle the ical" refers to compounds that which combine the properties of aliphatic and cyclic compounds and include but are not limited to, cyclic, or polycyclic aliphatic hydrocarbons and cycloalkyl connection with bridging ties, which are optional substituted with one or more functional groups. The term "alicyclic" includes cycloalkenyl, cycloalkenyl and cycloalkenyl radicals, which are optionally substituted by one or more functional groups, but are not limited to. Thus, the illustrative alicyclic groups include, but are not limited to, for example, cyclopropyl, -CH2-cyclopropylidene, cyclobutyl, -CH2-cyclobutyl, cyclopentyl, -CH2-cyclopentyl-n, tsiklogeksilnogo, -CH2-tsiklogeksilnogo, cyclohexylaniline, cyclohexylaniline, norbornylene radicals and the like, which again, may bear one or more substituents.

Used the term "alkoxy" (or "alkyloxy") or "thioalkyl" refers to an alkyl group as previously defined, attached to the parent molecular part through an oxygen atom or through a sulfur atom. In some embodiments of the alkyl group contains 1-20 aliphatic carbon atoms. In some other embodiments of the alkyl group contains 1-10 aliphatic ATO is s carbon. In some embodiments of alkyl, Alchemilla and Alchemilla group used in the invention contain 1-8 aliphatic carbon atoms. In some embodiments of the alkyl group contains 1-6 aliphatic carbon atoms. In some embodiments of the alkyl group contains 1-4 aliphatic carbon atoms. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentane and n-hexose. Examples of thioalkyl include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio and the like.

The term "alkylamino" refers to a group having the structure-other', where R' is an alkyl, as defined in the description. The term "aminoalkyl" refers to a group having the structure NH2R'-, where R' is an alkyl, as defined in the description. In some embodiments of the alkyl group contains 1-20 aliphatic carbon atoms. In some other embodiments of the alkyl group contains 1-10 aliphatic carbon atoms. In some embodiments of alkyl, Alchemilla and Alchemilla group used in the invention contain 1-8 aliphatic carbon atoms. In some embodiments of the alkyl group contains 1-6 aliphatic carbon atoms. In another VA who Ianto implementation alkyl group contains 1-4 aliphatic carbon atoms. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, isopropylamino and the like.

Some examples of substituents of the above described aliphatic (and other) radicals of the compounds of the invention include, but are not limited to aliphatic; alicyclic; heteroaromatics, heteroalicyclic; aryl; heteroaryl; alcylaryl; alkylether; alkoxy; aryloxy; heteroatomic; heteroaromatic; alkylthio; aaltio; heteroalkyl; heteroaromatic; F; Cl; Br; I; -IT; -NO2; -CN; -CF3; -CH2CF3; -CHI2; -CH2OH; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)Rx; -CO2(Rx); -CON(Rx)2; -OC(O)Rx; -OCO2Rx; -OCON(Rx)2; -N(Rx)2; -S(O)2Rx; -NRx(CO)Rxwhere each occurring Rxindependently includes, but is not limited to, aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl, heteroaryl, alcylaryl or alkylchlorosilanes group, where any of the aliphatic, alicyclic, heteroalicyclic, heteroalicyclic, aryl, heteroaryl, alcylaryl or alkylglycerols substituents described above may be substituted or unsubstituted, branched or unbranched, cyclic or acicle the definition and where any of the aryl or heteroaryl substituents, as described above, may be substituted or unsubstituted. Additional examples of generally applicable substituents are illustrated some of the options for implementation in the examples described in the description.

In General, used the terms "aryl" and "heteroaryl" refer to stable mono - or polycyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated radicals having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted. You should also understand that defined in the description of the aryl and heteroaryl portion may be attached through an aliphatic, alicyclic, heteroaromatics, heteroalicyclic, alkyl or heteroalkyl part and, thus, also include -(aliphatic)aryl, -(heteroaromatics)aryl, -(aliphatic)heteroaryl, -(heteroaromatics)heteroaryl, -(alkyl)aryl, -(heteroalkyl)aryl and -(heteroalkyl)heteroaryl part. Thus, used in the phrase "aryl and heteroaryl and aryl, heteroaryl -(aliphatic)aryl, -(heteroaromatics)aryl, -(aliphatic) heteroaryl, -(heteroaromatics)heteroaryl, -(alkyl)aryl, -(heteroalkyl)aryl and -(heteroalkyl)heteroaryl" are interchangeable is. Substituents include, but are not limited to, any of the previously mentioned substituents, i.e. substituents listed for aliphatic parts, or other parts, as disclosed in the description, leading to the formation of stable compounds. In some embodiments of the present invention, the term "aryl" refers to mono - or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. In some embodiments of the present invention used in the description, the term "heteroaryl" refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; zero, one, or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical is attached to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, chinoline, ethenolysis and the like.

It should be understood that aryl and heteroaryl groups (including the BIC is licencie aryl groups) can be unsubstituted or substituted, where the substitution includes replacement of one, two or three hydrogen atoms in the group is independently any one or more of the following groups, including, but not limited to, aliphatic; alicyclic; heteroaromatics; heteroalicyclic; aryl; heteroaryl; alcylaryl; alkylchlorosilanes; alkoxy; aryloxy; heteroatomic; heteroaromatic, alkylthio; aaltio; heteroalkyl; heteroaromatic; F; Cl; Br; I; -OH; -NO2; -CN; -CF3; -CH2CF3; -CHCl2; -CH2OH; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)Rx; -CO2(Rx); -CON(Rx)2; -OC(O)Rx; -OCO2Rx; -OCON(Rx)2; -N(Rx)2; -S(O)2Rx; -NRx(CO)Rxwhere each occurring Rxindependently includes, but is not limited to, aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl, heteroaryl, alcylaryl or alkylchlorosilanes group, where any of the aliphatic, alicyclic, heteroalicyclic, heteroalicyclic, aryl, heteroaryl, alcylaryl or alkylglycerols substituents described above may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and where any of the aryl or heteroaryl substituents described you the e, may be substituted or unsubstituted. Additional examples of generally applicable substituents are illustrated some of the options for implementation in the examples described in the description.

Used the term "cycloalkyl" refers specifically to the group, having from 3 to 7, preferably from 3 to 10 carbon atoms. Suitable cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the case of other aliphatic, heteroalicyclic or heterocyclic parts may optionally be substituted with substituents including, but not limited to, aliphatic; alicyclic; heteroaromatics; heteroalicyclic; aryl; heteroaryl; alcylaryl; alkylchlorosilanes; alkoxy; aryloxy; heteroatomic; heteroaromatic; alkylthio; aaltio; heteroalkyl; heteroaromatic; F; Cl; Br; I; -OH; -NO2; -CN; -CF3; -CH2CF3; -CHCl2; -CH2OH; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)Rx; -CO2(Rx); -CON(Rx)2; -OC(O)Rx; -OCO2Rx; -OCON(Rx)2; -N(Rx)2; -S(O)2Rx; -NRx(CO)Rxwhere each occurring Rxindependently includes, but is not limited to, aliphatic, alicyclic, heteroaromatic the ski, heteroalicyclic, aryl, heteroaryl, alcylaryl or alkylchlorosilanes group, where any of the aliphatic, alicyclic, heteroalicyclic, heteroalicyclic, aryl, heteroaryl, alcylaryl or alkylglycerols substituents described above may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and where any of the aryl or heteroaryl substituents described above may be substituted or unsubstituted. Additional examples of generally used substituents illustrated some of the options for implementation in the examples described in the description.

Used the term "heteroaromatics" refers to aliphatic parts, in which one or more carbon atoms in the main chain have been replaced by a heteroatom. Thus, heteroaromatics group refers to an aliphatic chain which contains one or more atoms of oxygen, sulfur, nitrogen, phosphorus or silicon, for example, instead of carbon atoms. Heteroaromatics parts may be branched or linear, unbranched. In some embodiments of heteroaromatics part substituted by independent replacement of one or more hydrogen atoms of one or more parts, including but not limited to, aliphatic; Alice is symbolic; heteroaromatics; heteroalicyclic; aryl; heteroaryl; alcylaryl; alkylchlorosilanes; alkoxy; aryloxy; heteroatomic; heteroaromatic; alkylthio; aaltio; heteroalkyl; heteroaromatic; F; Cl; Br; I; -OH; -NO2; -CN; -CF3; -CH2CF3; -CHCl2; -CH2OH; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)Rx; -CO2(Rx); -CON(Rx)2; -OC(O)Rx; -OCO2Rx; -OCON(Rx)2; -N(Rx)2; -S(O)2Rx; -NRx(CO)Rxwhere each occurring Rxindependently includes, but is not limited to, aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl, heteroaryl, alcylaryl or alkylchlorosilanes group, where any of the aliphatic, alicyclic, heteroalicyclic, heteroalicyclic, alcylaryl or alkylglycerols substituents described above may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and where any of the aryl or heteroaryl substituents described above may be substituted or unsubstituted. Additional examples of generally used substituents illustrated some of the options for implementation in the examples described in the description.

Used the term "getrole ilycheskie" refers to compounds that which combine the properties heteroalicyclic and cyclic compounds and include but are not limited to, saturated and unsaturated mono - or polycyclic heterocycles, such as morpholino, pyrrolidinyl, furanyl, thiofuran, pyrrolyl etc. that are optional substituted with one or more functional groups.

Used the term "halogen" refers to an atom selected from fluorine, chlorine, bromine and iodine.

The term "halogenated" means an alkyl group, as defined in the description, containing 1, 2 or 3 halogen atom attached to it, and illustrated by such groups as chloromethyl, bromacil, trifluoromethyl and the like.

Used the term "heteroseksualci" or "heterocycle" refers to non-aromatic, 5-, 6 - or 7-membered ring or a polycyclic group, including, without limitation, bi - or tricyclic group comprising a condensed six-membered rings that have 1 to 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, where (i) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (ii) the heteroatoms nitrogen and sulfur may be optionally oxidized, (iii) the nitrogen heteroatom may be optionally stereoselectivity, and (iv) any of the above rings may be condensed to an aryl or heteroaryl the th ring. Examples of heterocycles include, but are not limited to, pyrrolidinyl, pyrazolyl, pyrazolidine, imidazoline, imidazolidine, piperidine, piperazinil, oxazolidinyl, isoxazolidine, morpholine, thiazolidine, isothiazolinones and tetrahydrofuryl. In some implementations used the term "substituted heterocytolysine or heterocyclic group" refers to geteroseksualnoe or heterocyclic group, as defined in the description, in which independently of one, two or three hydrogen atoms substituted on the aliphatic; alicyclic; heteroaromatics; heteroalicyclic; aryl; heteroaryl; alcylaryl; alkylchlorosilanes; alkoxy; aryloxy; heteroatomic; heteroaromatic; alkylthio; aaltio; heteroalkyl; heteroaromatic; F; Cl; Br; I; -OH; -NO2; -CN; -CF3; -CH2CF3; -CHCl2; -CH2OH; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)Rx; -CO2(Rx); -CON(Rx)2; -OC(O)Rx; -OCO2Rx; -OCON(Rx)2; -N(Rx)2; -S(O)2Rx; -NRx(CO)Rxwhere each occurring Rxindependently includes, but is not limited to, aliphatic, alicyclic, heteroaromatics, heteroalicyclic, aryl, heteroaryl, alcylaryl or alkylchlorosilanes group, where I is th of aliphatic, alicyclic, heteroalicyclic, heteroalicyclic, aryl, heteroaryl, alcylaryl or alkylglycerols substituents described above may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and where any of the aryl or heteroaryl substituents described above may be substituted or unsubstituted. Additional examples of generally applicable substituents are illustrated some of the options for implementation in the examples described in the description.

Used the terms "aliphatic", "heteroaromatics", "alkyl", "alkeneamine", "alkyline", "heteroalkyl", "heteroalkyl", "heteroalkyl" and the like include substituted and unsubstituted, saturated and unsaturated, linear and branched groups. Similarly, the term "alicyclic", "heteroalicyclic", "heterocytolysine", "heterocycle" and the like include substituted and unsubstituted, saturated and unsaturated groups. In addition, the terms "aliphatic(aryl), "heteroaromatics(aryl)", "aliphatic(heteroaryl)", "heteroaromatics(heteroaryl)", "alicyclic(aryl)", "heteroalicyclic(aryl)", "alicyclic(heteroaryl)", "heteroalicyclic(heteroaryl)", "-Ala is l(aryl)", "heteroalkyl(aryl)", "-alkyl(heteroaryl), heteroalkyl(heteroaryl)" and the like include substituted and unsubstituted, and saturated or unsaturated (i.e. non-aromatic component part of the molecule) group. In addition, unless otherwise indicated, the terms "cycloalkyl", "cycloalkenyl", "cycloalkenyl", "heterocytolysine", "heterocyclization", "heterocytolysine", "aryl", "heteroaryl" and the like include both substituted and unsubstituted groups.

3) Methodology synthesis

In accordance with the present invention can use any available method for manufacturing or producing compounds of the invention or compositions comprising them. For example, you can use a variety of synthesis methods, such as methods, described in detail below. Alternative or additional compounds of the invention can be obtained using any of a variety of combined methods of parallel synthesis and/or methods of synthesis in the solid phase, known in this field.

In one aspect the present invention relates to new peptides having the formula (I)as described above. Examples of methods for producing compounds in accordance with the invention presented below, as shown in detail in schemes 1-12 and in the "Examples" section in this description. Should Wed the mother, that disclosed in the description of the methods can be used for each of the described compounds and their equivalents. In addition, the reagents and starting materials known to experts in this field. Although the following schemes describe some illustrative connection, it should be understood that the use of other source materials will allow you to get other analogs of compounds of the invention. For example, the compounds described below, where each X1and X2represents C=O, R5represents hydrogen, R6represents tert-butyl and R7represents methyl; however, it should be understood that other source materials and/or intermediate compounds can be used to produce compounds where, for example, X1and X2can independently represent C=O, CH2, SO2and R5-R7may represent fragments other than the fragments depicted in the description, such as alkyl, heteroalkyl, aryl, heteroaryl etc. Should also be understood that any available methods known in this field can be used to obtain the compounds of the invention or compositions comprising them. The person skilled in the art will understand that suitable methods of synthesis are not limited to those shown below in schemes 1-12, and that any suitable means which Intesa, known in this field can be used to obtain the compounds of the invention.

In some embodiments of compounds of the invention have the General structure (I'), as shown in scheme 1, where R, R' and Q represent aliphatic, heteroaromatics, aryl or heteroaryl part. In preferred embodiments of R, R' and Q are parts, such as those described in the description of classes and subclasses. Examples of preferred structures for R, R' and Q are depicted in scheme 1.

Scheme 1

Examples of compounds covered by this structural formula include, but are not limited to, compounds in which:

R1= H or Me

R3= Me, Et or forms a 5-6-membered ring with R4

R4= Me, Et or forms a 5-6-membered ring with R3

R10b= H, Me, Ac or forms a 5-6-membered ring with R11b

R11b= H or forms a 5-6-membered ring with R10b

RG= H, Me, Et or forms a 5-6-membered ring with RH1

RH1= H, Me, Et or forms a 5-6-membered ring with RG

RH2= H, CO2H, CO2Me, CONH2, CONHMe, CONHMe2, CONHBn, CH2OMe

RG1= H, Me, or forms a 5-6-membered ring with RG2

RG2= H or forms a 5-6-membered ring with RG1

RG3= H, CO2H, CO2Me, CONH2, CONHMe, COHMe 2, CONHBn, CH2OMe

In some embodiments of compounds according to the invention belong to the class of (Ia) and its subclasses, as described in the description. Scheme 2 shows the synthesis of illustrative compounds of this class (compounds of General structure 11). As shown in scheme 2, the core of the dipeptide can be constructed, for example, from N-Boc-N-methylvaline (2) and N-Boc-tert-leucine (4). N-terminal part of the compounds of the invention (R' in scheme 1) to provide (S)-N-Boc-neopentylene (6). As shown in figure 2, various synthesis methods allow to obtain various analogues, for example esters of carboxylic acids of the General structure 7 carboxylic acid, 8 or amides of General structure 11. For other derivatives of the compounds you can use other methods of synthesis known in the art.

Scheme 2

Examples of compounds of this type include, but are not limited to, compounds in which:

RG1= H, Me, or forms a 5-6-membered ring with RG2

RG2= H or forms a 5-6-membered ring with RG1

RG3= H, CO2H, CO2Me, CONH2, CONHMe, CONHMe2, CONHBn, CH2OMe

Synthesis of obtaining an intermediate compound 6 is depicted in scheme 3. The method allows to obtain (S)-N-Boc-neopentylene (6) with an overall yield of 20%.

Scheme 3

In some embodiments of compounds of the invention belong to the class of (Ib) and its subclasses. In schemes 4-6 depicts the synthesis of representatives of compounds of this class (for example, a complex of amine esters, amino acids, aminimides and N-acetylamino overall structure respectively 18, 20, 23, as seen in figure 4; see also complex amine esters, amino acids, minamide and N-acetylmuramic overall structure respectively 25, 26 and 27 in scheme 5). In some embodiments of R can represent a nitrogen-containing heteroalkyl fragment (see schemes 4 and 5) or unsaturated oxygen-containing heteroalkyl fragment (see scheme 6). Although schemes 4-6 are compounds, including N-terminal portion derived from (S)-N-Boc-neopentylene (6), the specialist in this area should be clear that to obtain the compounds of the invention can use a wide range of organic fragments, other than fragments described in schemes 4-6. Similarly in schemes 4-6 lists the connection, where the C-terminal part may represent esters of carboxylic acids, carboxylic acids or amides. It should be understood that the invention is not limited to these compounds and covers derivatives and analogues of these compounds, or compounds derived from different source materials.

<> Scheme 4

Examples of compounds of this type include, but are not limited to, compounds in which:

R10b= H, Me, or forms a 5-6-membered ring with R11b

R11b= H or forms a 5-6-membered ring with R10b

RG= H, Me, or forms a 5-6-membered ring with RH1

RH1= H, or forms a 5-6-membered ring with RG

RH2= H, CO2H, CO2Me, CONH2, CONHMe, CONHMe2, CONHBn, CH2OMe

Scheme 5

Examples of compounds of this type include, but are not limited to, compounds in which:

RG= forms a 5-6-membered ring with RH1

RH1= forms a 5-6-membered ring with RG

RH2= CO2Me, CONH2

Scheme 6

In some other embodiments of compounds of the invention belong to the class (Ic) and its subclasses. The diagrams 7-10 shows the synthesis of compounds of this class (for example, a complex of amine esters, amino acids and aminoamides overall structure respectively 42, 43 and 45, as seen in figure 7). In some other embodiments of compounds of the invention include nitrogen-containing heterocyclic N-terminal fragment. For example, heterocyclic fragment can be piperidine ring (scheme 7, 8 and 9) or hiazolidinedione ring (scheme 10). Examples of other suitable fragments described in the "Examples" section, or will be apparent to a person skilled in this field. As discussed above, R may represent a nitrogen-containing heteroalkyl fragment (scheme 7) or unsaturated alkyl radical (scheme 8, 9 and 10).

Scheme 7

Examples of compounds of this type include, but are not limited to, compounds in which:

R10b= H, Me, or forms a 5-6-membered ring with R11b

R11b= H or forms a 5-6-membered ring with R10b

RG= H, Me, OMe, or forms a 5-6-membered ring with RH1

RH1= H, i-Pr or form a 5-6-membered ring with RG

RH2= OH, OMe, Obn, O-iPr, O-cyclo-Bu, O-cyclopentyl, O-cyclohexyl, NH2, NHBn, NH(2-naphthyl)

Scheme 8

Conditions: (a) K2CO3CH3I, DMF; (b) TMS-diazomethane, MeOH, CH2Cl2; (c) DIBAL, PhCH3, -78°C; (d) Ph3P=C(CH3)CO2Et, CH2Cl2; (e) HCl in 1,4-dioxane; (f) BOC-Tle-OH, CMC,HOAt,NMM, DMF; (g) N-methylpiperidine acid, CMC,HOAt,NMM, DMF (h) LiOH, aq. MeOH; (i) HCl·L-Pro-OMe, DEPC, NMM, DMF

Analogues methylpiperidino acid

Scheme 9

Scheme 10

In some other embodiments of compounds invented the I belong to the class (Id) and its subclasses, as described in the description. The person skilled in the art should be understood that the illustrative heterocyclic starting materials described in schemes 7-10, which were used to obtain the compounds of class (Ic) (namely, compound 38, 60 and 65), can be substituted in the acyclic α-amino acid fragments to obtain the compounds of class (Id), as shown below in scheme 11:

Scheme 11

Examples of compounds of this type include, but are not limited to, compounds in which:

R1= H or Me

R3= Me, Et or forms a 5-6-membered ring with R4

R4= Me, Et or forms a 5-6-membered ring with R3

R10b= H, Me, or forms a 5-6-membered ring with R11b

R11b= H or forms a 5-6-membered ring with R10b

RG= H, Me, or forms a 5-6-membered ring with RH1

RH1= H or forms a 5-6-membered ring with RG

RH2= H, CO2H, CO2Me, CONH2, CONHMe, CONHMe2, CONHBn, CH2OMe

For example, the interaction of diacylglycerol (72) with the HCl salt of amine 49 gives N-terminal heme-complex titilatingly ether 73 or the corresponding carboxylic acid 74 after hydrolysis in suitable conditions (scheme 12).

Scheme 12

It should be understood that each of the reactions described in schemes 2-12 above, is rowedit using reagents and conditions as described for the synthesis of various types of compounds described above, or they can be modified using other available reagents or starting materials. For example, various conditions for the formation of amides, conditions, esterification, hydrolysis and functionalization of the aromatic cores are well known in this field, and can be used in the method of the invention (see generally publication March, Advanced Organic Chemistry, 5thed., John Wiley & Sons, 2001; and "Comprehensive Organic Transformations, a guide to functional group preparations", Richard C. Larock, VCH publishers, 1999; full content of which is included in the description by reference.

As mentioned above, it should be understood that the invention is not limited to the ones listed in the description of compounds. To obtain compounds of the General structure (I) can be used strategy synthesis or original materials, other than those described above. Each of the components/raw materials used in the synthesis of compounds of the invention, it is possible to diversify or before synthesis, or alternatively after receipt of the peptide structure. Used the term "diversification" or "diversify" means the interaction of the compounds of the invention in one or more reactive sites for modification of a functional fragment or to include additional functional groups. For example, when the connection is resultsthe aromatic ring, the aromatic ring can be diversified away (before or after the reaction) or to include a functional group (for example, when there is hydrogen, can be added halogen or other functional group), or modify the functional group (for example, when the aromatic ring is a hydroxyl group, an aromatic ring can be diversified away by interaction with the reagent for protection of hydroxyl group, or to turn it into aliphatic or heteroaromatics group). Below generally describes various schemes that reveal possible ways of synthesis of various analogues or diversification of middleware components, or diversification of the peptide structure.

In some embodiments of producing chemically different derivatives can be achieved by diversifying the C-terminal part of the connection. For example, when the C-terminal part is a carboxylic acid, by reduction reaction of the acid group can be converted into the corresponding aldehyde or alcohol, the corresponding carboxylic acid derivatives can be obtained by amidation reaction, Wittig reaction, decarboxylation, esterification, addition of nucleophiles, turning into ketones, imine, hydrazones, azides, etc. and these reactions are not limiting Examples of such transformations shown in schemes 12 and 13. The person skilled in the art will understand that the possible chemical transformation, is suitable for obtaining derivatives of the compounds of the invention are not limited to those shown in schemes 1-13. Suitable methods of synthesis known in the prior art, can be used to achieve the desired chemical transformations.

Scheme 12A

Scheme 13

4) Application, composition and introduction

In accordance with the present invention the compounds of the invention can be used in any of the available assays known in the prior art for identifying compounds having the predetermined biological activity. For example, the analysis may be cellular or non-cellular, in vivo and in vitro, in the format of high or low material consumption, etc. In some embodiments of compounds of the invention tested in assays to identify those compounds that possess cytotoxic or inhibitory growth effect in vitro or cause regression of tumors and/or inhibition of tumor growth in vivo.

The compounds of this invention which are of particular interest include those that are:

• exhibit cytotoxic and/or inhibitory growth effect on the line of cancer cells supported in vito, or in animal studies using a scientifically acceptable model xenografts of cancer cells;

• preferably cause regression of tumors in vivo;

• show low sensitivity to MDR;

• show low cytotoxicity to non-dividing normal cells; and/or

• have a favorable therapeutic profile (e.g., satisfactory performance and sustainability).

As described in detail in the "Examples"section, in assays to determine the ability of compounds to inhibit the growth lines of tumor cells in vitro, some compounds of the invention exhibit IR5010 μm. In other embodiments of compounds of the invention exhibit IR505 μm. In other embodiments of compounds of the invention exhibit IR501 μm. In other embodiments of compounds of the invention exhibit IR50750 nm. In other embodiments of compounds of the invention exhibit IR50500 nm. In other embodiments of compounds of the invention exhibit IR50250 nm. In other embodiments of compounds of the invention exhibit IR50100 nm. In other embodiments of compounds of the invention exhibit IR5050 nm. In other embodiments of compounds of the invention exhibit IR5025 nm. In other embodiments, the real is in the form of compounds of the invention exhibit IR 5010 nm. In other embodiments of compounds of the invention exhibit IR50of 7.5 nm. In other embodiments of compounds of the invention exhibit IR505 nm. In other embodiments of compounds of the invention exhibit IR502.5 nm. In other embodiments of compounds of the invention exhibit IR501 nm. In other embodiments of compounds of the invention exhibit IR50of 0.75 nm. In other embodiments of compounds of the invention exhibit IR500.5 nm. In other embodiments of compounds of the invention exhibit IR50of 0.25 nm. In other embodiments of compounds of the invention exhibit IR500.1 nm. In some embodiments of compounds of the invention exhibit IR50inhibition of growth of cultured human cancer cells the range from 0.1 nm to 10 nm.

In some other embodiments of compounds of the invention exhibit low sensitivity to MDR (resistance to many drugs). In some embodiments of compounds of the invention have a ratio of [inhibition of cell growth in MDR-positive cells]/[inhibition of cell growth in MDR-negative cells] (i.e. the ratio of resistance) 10. In some embodiments of compounds of the invention have a ratio of resistance 9. In some of the s embodiments of the compounds of the invention have a ratio of resistance 8. In some embodiments of compounds of the invention have a ratio of resistance 7. In some embodiments of compounds of the invention have a ratio of resistance 6. In some embodiments of compounds of the invention have a ratio of resistance 5. In some embodiments of compounds of the invention have a ratio of resistance 4.

In some other embodiments of compounds of the invention exhibit low cytotoxicity against non-dividing normal cells. In some embodiments of compounds of the invention exhibit low cytotoxicity or do not show cytotoxicity against non-dividing normal cells at concentrations up to 1,000 times the concentration at which they inhibit the growth of cancer cells. In some embodiments of compounds of the invention exhibit low cytotoxicity or do not show cytotoxicity against non-dividing normal cells at concentrations in the range of 1-10 microns.

In some other embodiments of compounds of the invention exhibit stability in mouse serum.

In some other embodiments of compounds of the invention exhibit a low value of reversibility of mitotic block. In some embodiments of compounds of izopet the deposits show a ratio of reversibility of mitotic block from 1 to about 30. In some embodiments of compounds of the invention exhibit a ratio of reversibility of mitotic block from 1 to about 25. In some embodiments of compounds of the invention exhibit a ratio of reversibility of mitotic block from 1 to about 20. In some embodiments of compounds of the invention exhibit a ratio of reversibility of mitotic block from 1 to about 15. In some embodiments of compounds of the invention exhibit a ratio of reversibility of mitotic block from 1 to about 10. In some embodiments of compounds of the invention exhibit a ratio of reversibility of mitotic block from 1 to about 5. In some embodiments of compounds of the invention exhibit a ratio of reversibility of mitotic block from 1 to about 3.

In some embodiments of compounds of the invention cause regression of tumors in vivo. In some illustrative embodiments of the compounds of the invention cause regression of tumors in vivo in suitable models xenografts of mouse tumors. In some illustrative embodiments of the compounds of the invention cause a reduction in tumor size to below 70% of the size at the beginning of the introduction of a connection on a suitable xenograft models of cancer cells. In some illustrative embodiments of joint the invention cause a reduction in tumor size to below 65% of the size at the beginning of the introduction of a connection on a suitable xenograft models of cancer cells. In some illustrative embodiments of the compounds of the invention cause a reduction in tumor size to below 60% of the size at the beginning of the introduction of a connection on a suitable xenograft models of cancer cells. In some illustrative embodiments of the compounds of the invention cause a reduction in tumor size to below 55% of the size at the beginning of the introduction of a connection on a suitable xenograft models of cancer cells. In some illustrative embodiments of the compounds of the invention cause a reduction in tumor size to below 50% of the size at the beginning of the introduction of a connection on a suitable xenograft models of cancer cells. In some illustrative embodiments of the compounds of the invention cause regression of tumors in some xenograft models, resistant to many drugs.

In some illustrative embodiments of the compounds of the invention cause the inhibition of tumor growth in vivo. In some illustrative embodiments of the compounds of the invention cause a significant inhibition of tumor growth on suitable models xenografts of cancer cells. In some illustrative embodiments of the compounds of the invention cause a significant inhibition of tumor growth on suitable models of xenograft the cancer cells, resistant to many drugs. In some illustrative embodiments of the compounds of the invention cause the inhibition of tumor growth in treated animals at >50% compared to growth in control animals (i.e. "treatment" tumour size <50% "control" the size of the tumor; or the value of T/C <50%) on suitable models xenografts of cancer cells. In some embodiments of compounds of the invention have values of T/C <70%. In some embodiments of compounds of the invention have values of T/C <65%. In some embodiments of compounds of the invention have values of T/C <60%. In some embodiments of compounds of the invention have values of T/C <55%.

In some embodiments of compounds of the invention inhibit the growth of cancer cells in vitro, show low sensitivity to MDR (i.e. low ratio of resistance), show low cytotoxicity to non-dividing normal cells, are resistant in mouse serum, have a low ratio of reversibility of mitotic block, cause regression of tumors in vivo, and/or cause inhibition of tumor growth in vivo.

In some embodiments of compounds of the invention inhibit the growth of cancer cells in vitro, show low sensitivity to MDR (i.e. low sootnoshenie the resistance) show low cytotoxicity to non-dividing normal cells, are resistant in mouse serum, have a low ratio of reversibility of mitotic block, cause regression of tumors in vivo and cause inhibition of tumor growth in vivo.

In some embodiments of compounds of the invention are any one or more of the following properties:

(i) show values IR50inhibition of growth of cultured human cancer cells the range from 0.1 nm to 10 nm;

(ii) have a ratio of resistance preferably 10, preferably 9, preferably 8, preferably 7, preferably 6, preferably 5, preferably 4;

(iii) show little cytotoxicity or absence of cytotoxicity in non-dividing normal cells at concentrations in the range of 1-10 microns;

(iv) show stability in mouse serum;

(v) show the ratio of the reversibility of mitotic block from 1 to about 30, preferably from 1 to about 25, preferably from 1 to about 20, preferably from 1 to about 15, preferably from 1 to about 10, preferably from 1 to about 5, most preferably from about 1 to about 3;

(vi) cause the tumor size decreased to below 70%, preferably below 65%, preferably lower than 60%, preferably 55%or below, most preferably, the who 50% of the size at the beginning of the introduction of the compounds in suitable models of xenotransplantation cancer cells; and/or

(vii) cause significant inhibition of tumor growth in a suitable model of xenotransplantation cancer cells (for example, have a value of T/S, preferably <70%, preferably <65%, preferably <60%, preferably <55%, most preferably <50%).

In some embodiments of compounds of the invention have the following properties:

(i) show values IR50inhibition of growth of cultured human cancer cells the range from 0.1 nm to 10 nm;

(ii) have a ratio of resistance preferably 10, preferably 9, preferably 8, preferably 7, preferably 6, preferably 5, preferably 4;

(iii) show little cytotoxicity or absence of cytotoxicity in non-dividing normal cells at concentrations in the range of 1-10 microns;

(iv) show stability in mouse serum;

(v) show the ratio of the reversibility of mitotic block from 1 to about 30, preferably from 1 to about 25, preferably from 1 to about 20, preferably from 1 to about 15, preferably from 1 to about 10, preferably from 1 to about 5, most preferably from about 1 to about 3;

(vi) cause the tumor size decreased to below 70%, preferably below 65%, preferably lower than 60%, preferably 55%or below, most preferably nige% of the size at the beginning of the introduction of the compounds in suitable models of xenotransplantation cancer cells; and

(vii) cause significant inhibition of tumor growth in a suitable model of xenotransplantation cancer cells (for example, have a value of T/S, preferably <70%, preferably <65%, preferably <60%, preferably <55%, most preferably <50%).

Examples of compounds exhibiting desirable properties include ER-805913, ER-805736, ER-807102, ER-807328, ER-806925, ER-807850, ER-807904, ER-807974, ER-808368, ER-808662, ER-808824, and their salts (see table below).

As discussed above, the compounds of the invention show activity, inhibitory growth of tumor cells. Compounds of the invention as such can be used to treat a variety of disorders, including but not limited to, as some examples, glioblastoma, retinoblastoma, breast cancer, cervical cancer, cancer of the colon and rectum, leukemia, lung cancer (including, but not limited to, small cell lung cancer), melanoma, multiple myeloma, nahodkinskuju lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and stomach cancer. In some embodiments of compounds of the invention can be used for treatment of solid and solid tumors. In some embodiments of interest, the compounds of the invention can in particular be used to treat breast cancer, prostate cancer, p the CA of the colon, lung cancer, leukemia and lymphoma.

In one embodiment, the implementation of the method involves the introduction of a therapeutically effective amount of the compound or its pharmaceutically acceptable derivative needs it to an individual (including, but not limited to, human or animal). In some embodiments of compounds of the invention can be used to treat cancer (including, but not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon cancer and rectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to, small cell lung cancer), melanoma, and/or skin cancer, multiple melanoma, nahodkinskuju lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and stomach cancer, bladder cancer, uterine cancer, kidney cancer, cancer of the testes, stomach cancer, cancer brain, liver cancer or esophageal cancer).

The pharmaceutical composition

As discussed above, this invention relates to new compounds with biological properties that can be used to treat cancer. In some embodiments of some compounds, as described in the description, act as inhibitors of tumor growth and, thus, they can be used in the treatment of cancer and the inhibition of tumor growth and destruction of cancer cells. In kotoryj embodiments of the compounds of the invention can be used for the treatment of solid tumors or solid tumors. In some interesting embodiments of the compounds of the invention can be used for the treatment of glioblastoma, retinoblastoma, breast cancer, cervical cancer, cancer of the colon and rectum, leukemia, lymphoma, lung cancer (including, but not limited to, small cell lung cancer), melanoma, multiple melanoma, nahodkinskuju lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and stomach cancer, as some examples. Compounds of the invention also find application in the prevention of restenosis of blood vessels exposed to trauma, such as angioplasty and stenting.

Accordingly, in another aspect, the present invention relates to pharmaceutical compositions that include any of the compounds described in the description (or its prodrug, pharmaceutically acceptable salt or other pharmaceutically acceptable derivative), and optionally include a pharmaceutically acceptable carrier. In some embodiments of compounds are able to inhibit the growth of or to kill cancer cells. In some embodiments of these compositions optionally also include one or more additional therapeutic agents. The alternate connection of the present invention can type needs it the patient in combin, the tion with the introduction of one or more therapeutic agents. For example, the additional therapeutic agent for the joint implementation or inclusion in a pharmaceutical composition with a compound of this invention can be a cytotoxic agent or an anti-cancer agent approved for the treatment of cancer, as discussed in more detail in the description, or it can represent any of a number of funds, subject to the approval of the administration of food and drug administration that ultimately obtain approval for the treatment of immune disorders or cancer. You should also understand that some of the compounds of the present invention can exist in free form for treatment, or whenever appropriate, as their pharmaceutically acceptable derivative. In accordance with the present invention pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salt, ester, salt of such ester or prodrug, or other adduct or derivative compound of the present invention that after the introduction of a needy patient is able to provide, directly or indirectly, a compound as otherwise described in the description, or its metabolite or residue.

Used the term "pharmaceutically acceptable salt" refers to those salts which are suitable for use in contact with parodentium and humans and lower animals without little or no undesirable toxicity, irritation, allergic response and the like and meet the reasonable value of the benefit/risk. Pharmaceutically acceptable salts of amines, carboxylic acids and other types of connections are well known in this field. For example, S.M.Berge et al. describe pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 66: 1-19 (1977), included here as a reference. Salt can be obtained in situ during the final isolation and purification of the compounds of the invention or separately by the reaction of free primary or free acid functions with a suitable reagent, as described in General below. For example, the free base can react with a suitable acid. Further, when the compounds of the invention are the acid part, suitable pharmaceutically acceptable salts may include metal salts, such as alkali metal salts, for example sodium or potassium, salts of alkaline earth metals such as calcium salt or magnesium. Examples of pharmaceutically acceptable, nontoxic acid additive salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid, Perlina acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, limo is Naya acid, succinic acid or malonic acid or by using other methods used in this field, as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ashkabat, aspartate, bansilalpet, benzoate, bisulfate, borate, butyrate, comfort, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulphate, aconsultant, formate, fumarate, glucoheptonate, glycerol, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonic, lactobionate, lactate, laurate, lauryl, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, para-toluensulfonate, triptorelin, undecanoate, valerate salt and the like. Representative salts of alkaline or alkaline earth metals include sodium, lithium, potassium, calcium, magnesium and the like. Additional pharmaceutically acceptable salts include, as appropriate, nontoxic ammonium cations, Quaternary ammonium and amine formed using counterions such as halide compound, hydroxide, carboxylate, sulfate, phosphate, nitrate, sulfonate lower alkyl and aryl sulfonate.

In addition, use isoamyl the term "pharmaceutically acceptable ester" refers to esters, which units are hydrolyzed in vivo and include esters, which easily break down in the body to leave the parent compound or its salt. Suitable group of esters include, for example, groups derived from pharmaceutically acceptable aliphatic carboxylic acids, in particular alanovoy, cycloalkanones and landiolol acid in which each alkyl or Alchemilla group is mostly not more than 6 carbon atoms. Some examples of esters include formate, acetate, propionate, butyrate, acrylates and ethylsuccinate.

In addition, used the term "pharmaceutically acceptable prodrugs" refers to those prodrugs of the compounds of the present invention, which is suitable for use in contact with the tissues of humans and lower animals without unwanted toxicity, irritation, allergic response and the like, correspond to the reasonable value of the benefit/risk and effective for their intended use, as well as zwitterionic forms, when possible, of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo, giving the parent compound of the above formula, for example, by hydrolysis in blood. A detailed discussion is presented in the publications of T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vl. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are included here as a reference.

As described above, the pharmaceutical compositions in accordance with the present invention also include pharmaceutically acceptable carrier, which includes any and all solvents, diluents, or other carriers, dispersion or suspension materials, surface active agents, isotonic agents, thickening agents or emulsifying agents, preservatives, solid binding agents, lubricating agents and the like that are suitable for the particular desired dosage form. Remington''s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in the preparation of pharmaceutical compositions and known techniques for getting them. Except in those cases where any of the usual environment of the media is incompatible with the compounds of the invention, for example, causing any undesirable biological effect or otherwise interacting harmful manner with any other component (components) of the pharmaceutical composition, provided that its use is within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, n is not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragakant; malt; gelatin; talc; excipients such as cocoa butter and waxes for suppositories; oils such as peanut oil, cotton seed; sunflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols, such as propylene glycol; esters, such as etiloleat and tillaart; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethyl alcohol and the solution with phosphate buffer, and other non-toxic compatible lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, covering agents, sweeteners, perfuming and flavouring agents, preservatives and antioxidants can also be present in the composition.

Use and compositions comprising the compounds of the invention

The present invention generally relates to compositions that can be used for the treatment of cancer and proliferative disorders.

As described above, some the connection, described in this application, act as inhibitors of tumor growth and, thus, they can be used in the treatment of cancer and the inhibition of growth of tumors and destroy cancer cells. The invention also relates to a method of inhibiting tumor growth and/or metastasis of tumors. The method includes the introduction of a therapeutically effective amount of the compound or its pharmaceutically acceptable derivative needs it to an individual (including, but not limited to, human or animal). In some embodiments of the invention the compounds of the invention can be used for the treatment of solid tumors or solid tumors. Other interest embodiments of the compounds of the invention can be used for the treatment of glioblastoma, retinoblastoma, breast cancer, cervical cancer, cancer of the colon and rectum, leukemia, lymphoma, lung cancer (including, but not limited to, small cell lung cancer), melanoma, multiple myeloma, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and stomach cancer.

As discussed in more detail in the description, the present invention relates to compositions that can be used for the treatment of cancer, in particular solid and solid tumors. In particular, as the show is but some compounds of the invention inhibit the growth of several lines of tumor cells in vitro, as described in more detail in the description. And they can be used for the treatment of cancer, including solid and solid tumors.

As discussed above, the compounds of the invention also find application in the prevention of restenosis of blood vessels, subject to injury such as angioplasty and stenting. For example, it is envisaged that the compounds of the invention can be used as coatings for implanted medical devices such as tubes, shunts, catheters, artificial implants, nails, electrical implants such as electrical stimulators, and, in particular, for arterial or venous stents, including stents, raspylyaemye cylinders. In some embodiments of compounds of the invention may be associated with an implantable medical device, or, alternatively, they can be passively adsorbed on the surface of the implantable device. In some other embodiments of compounds of the invention can be formulated for inclusion in or can be released surgical or medical device or implant, such as, for example, a stent, suture materials, introduce catheters, prostheses and the like.

In some illustrative embodiments of the of soedineniya of the invention can be applied as coatings for stents. The stent is typically an open tubular structure that has the form (or species) of holes extending from the outer surface of the stent to the lumen. Conventional produce stents made of biocompatible metallic materials with structures that are carved on the surface of the laser. The stent may be electrically polished to minimize surface irregularities, as these irregularities can trigger adverse biological reaction. However, stents can nevertheless stimulate reaction to a foreign body, which lead to thrombosis or restenosis. In order to avoid these complications in the literature of the prior art have been proposed a variety of coating stents and composition and to reduce the occurrence of these complications or other complications, and to restore the function of the tissue or the delivery of therapeutic compounds into the lumen. For example, drugs with antiproliferative and anti-inflammatory activities were evaluated as coatings, stents, and they turned out to be promising in the prevention of restenosis (see, for example, Presbitero P.et al., "Drug eluting stents do they make the difference?",Minerva Cardioangiol, 2002,50(5):431-442; Ruygrok wellet al., "Rapamycin in cardiovascular medicine",Intern. Med. J., 2003,33(3):103-109; and S.O. Marxet al., "Bench to bedside: the development of rapamycn and its application to stent restenosis", Circulation, 2001,104(8):852-855), each of these references are fully incorporated here by reference). Accordingly, the applicant proposes that the compounds of the invention possess anti-proliferative effects, can be applied as coatings of stents and/or sentovich devices, drug delivery, among other purposes, to prevent restenosis. This area is known for a variety of compositions and methods related to the coating of stents and/or local Stanovoy delivery of drugs to prevent restenosis (see, for example, U.S. patents№№ 6517889; 6273913; 6258121; 6251136; 6248127; 6231600; 6203551; 6153252; 6071305; 5891507; 5837313) and in published patent application U.S. No. US2001/0027340, each of these documents are fully incorporated in the description by reference). For example, the stents may be coated with conjugates of polymers-drugs immersion of the stent in the solution of polymer-drug or aerosol coating the stent with a solution. In one embodiment, the implementation of suitable materials for implantable devices include biologically compatible and non-toxic materials, and may be selected from metals, such as Nickel-titanium alloys, steel or biocompatible polymers, hydrogels, polyurethane, polyethylene, copolymers acetate ethylenevinyl etc. some in the ways of realization of the connection of the invention is applied in the form of a coating on a stent for insertion into an artery or vein after balloon angioplasty.

Therefore, the invention can be described in certain broad aspects as a way of inhibiting restenosis of the artery or occlusion of arteries after vascular injury, including the introduction needs it to an individual a composition comprising a compound of the invention conjugated with a suitable polymer or polymeric material. In the process the individual can be, for example, a patient undergoing coronary artery bypass surgery, vascular surgery, organ transplantation, or any other arterial angioplasty, and the composition can be administered intravenously or even it is possible to cover the stent to be implanted in the injured portion of the vessel.

In another aspect the invention relates to dental implants and surgical or medical devices, including stents and grafts, covered or designed in some other way for content and/or release of any of the disclosed in the description of the compounds of the invention. In some embodiments of compounds have antiproliferative activity. In some other embodiments of compounds inhibit the proliferation of smooth muscle cells. Representative examples of implants and surgical or medical devices of the invention include cardiovascular devices (for example, the implant is planned venous catheters, venous cannula venous catheters with tunnels, highways or cannula for continuous injection, including catheter for infusion into the hepatic artery, the wire electrical cardiac pacemakers, implantable defibrillators); neurologic/neurosurgical devices (for example, zheludochno-peritoneal shunts, zheludochno-arterial shunts, devices to stimulate nerves, patches Dura and implants for the prevention of fibrosis after laminectomy, devices for permanent subarachnoid infusions); gastrointestinal devices (e.g., chronic implantable catheters, tubes for feeding, Porto-systemic shunts, shunts about ascites, peritoneal implants for drug delivery, catheters for peritoneal deleasa, implantable mesh over the hernia, suspensions or solid implants to prevent surgical adhesions, including grid); genitourinary device (e.g., uterine implants, including intrauterine devices (IUD) and devices to prevent endometrial hyperplasia, implants in the fallopian tube, the device including reversible sterilization, fallopian tube stents, artificial sphincters and periuretralnuu implants about incontinence, ureteral stents, chronic implantable catheters, lighting is obline to increase bladder capacity or wrappers or cotter pins to vasovasostomy); ocular implants (for example, multiple implants and other implants about neovascular glaucoma, contact lenses, produce medicines over the pterygoid Maidenhead, cotter pins about the failed dacrocystorhinostomy, contact lenses, produce medicines over neovascularization corneal implants for podu diabetic retinopathy, contact lenses, produce drugs on corneal grafts at high risk); otolaryngology devices (e.g., implants bones, splints or stents, Eustachian tubes about exudative otitis media or chronic otitis as an alternative to drainage through the ear drum); implants plastic surgery (for example, prevention fibrous contracture in response to implants of the breast containing gel or saline solution, when accesses under the pectoral muscle or behind the breast tissue or after mastectomy, or chin implants), and orthopedic implants (e.g., cemented orthopedic prostheses).

Implants and other surgical or medical devices may be coated with (or adapted to release otherwise) compositions of the present invention in a variety of ways, including, for example: (a) direct fixation to the implant or the mouth is oistu compounds or compositions of the invention (for example, or the coating film of the polymer/drug to the implant or device, or by dipping the implant or device into the polymer solution/drug or other covalent or noncovalent means); (b) coating the implant or device substance such as a hydrogel, which in turn must absorb the compound or composition of the invention; (C) intertwining strands, covered with a compound or composition of the invention (or of the polymer embedded in the thread), the implant or device; (d) inserting the implant or device into a sleeve or mesh which is comprised of or coated with a compound or composition of the invention; (e) the design of the implant or device connection or composition of the invention; or (f) device implant or device to release the connection of the invention in other ways. In some embodiments of the composition should be firmly attached to the implant or device during storage and during injection. The compound or composition of the invention also preferably should not decompose during storage before the introduction or by warming to body temperature after insertion into the body (if required). In addition, they should preferably cover the implant or device smoothly and evenly, at the same in EMA without changing the contour of the stent. Within the preferred variants of the invention, the implant or device of the invention should provide a uniform, predictable, long-lasting release of the compounds or compositions of the invention into the tissue surrounding the implant or device as soon as it was posted. For vascular stents in addition to the above properties, the composition should not thrombogenic stent (causing the formation of blood clots), or to cause substantial turbulence of the blood flow (more than, as one might expect, would cause the stent, if not covered).

In the case of stents, you can develop a variety of stents for the content and/or release of compounds or compositions of the invention disclosed in the description, including esophageal stents, gastrointestinal stents, vascular stents, biliary stents, colonic stents, pancreatic stents, ureteric and urethral stents, lacrimal stents, the stents of the Eustachian tube, fallopian tube stents and tracheal/bronchial stents (see, for example, U.S. patent No. 6515016, the full contents of which are included in the description by reference). Stents can be easily obtained from commercial sources or constructed in accordance with well known techniques. Representative examples of stents include stents, described in the patent With The And No. 4768523, entitled "Hydrogel adhesive"; U.S. patent No. 4776337, entitled "Expandable intraluminal graft, and method and apparatus for implanting an expandable intraluminal graft"; U.S. patent No. 5041126, entitled "Endovascular stent and delivery device"; U.S. patent No. 5052998, entitled "implantable stent and method of use"; U.S. patent No. 5064435, entitled "Self-expanding stent having a stable axial length"; U.S. patent No. 5089606, entitled "water-Insoluble foam of polysaccharide hydrogels for medical applications"; U.S. patent No. 5147370 entitled "Nitinol stent for the hollow channels of the body"; in U.S. patent No. 5176626 entitled "Implicitely stent"; U.S. patent No. 5213580, entitled "Method of intraluminal sealing biodegradable polymer" and in U.S. patent No. 5328471, entitled "Method and apparatus for the treatment of endemic diseases in the hollow tubular organs and other tissue openings".

As discussed above, the stent is coated with (or adapted to release otherwise) compositions of the present invention, can be used to eliminate the obstruction of blood vessels and prevent restenosis and/or reduce the frequency of restenosis. Within other aspects of the present invention the walls of the s, covered with (or adapted to release otherwise) compositions of the present invention, are presented for expanding the lumen of the conduit body. In particular, the stent having a generally tubular structure and the surface covered with (or adapted to release otherwise) of the compound or composition of the present invention, can be introduced into the channel so that the channel extends. In some embodiments of the stent, coated with (or adapted to release otherwise) compositions of the present invention, can be used to eliminate obstruction of the bile ducts, gastrointestinal tract, esophagus, trachea/bronchi, urethra or blood vessels.

In another aspect of the invention presents methods of treatment of cancer, comprising introducing a therapeutically effective amount of the compounds of formula (I), as described in the description who needs it the individual. In some embodiments of compounds of the invention can be used for treatment of solid and solid tumors. It should be understood that the compounds and compositions in accordance with the method of the present invention can be administered using any amount and any route of administration effective for treating cancer. Thus, used in the description, the expression "effective amount" refers to the amount rises the mu for destroying or inhibiting the growth of tumor cells, or refers to the amount sufficient to reduce the growth of tumor cells. The exact quantity required will vary from individual to individual depending on the species, age and General condition of the individual, the severity of infection, specific anti-cancer tools, method of its introduction, and similar factors. Compounds of the invention are preferably prepared in a standard dosage form for ease of administration and uniformity of dosage. Used in the description, the expression "standard dosage form" refers to physically discrete unit of a therapeutic agent, suitable for a subject to treatment of the patient. However, it should be understood that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the range of sound medical judgment. A certain level therapeutically effective dose for any particular patient or organism will depend on various factors, including the subject of the treatment of the disorder and the severity of the disorder; activity of the specific connections in use; the specific compositions used; the age, body weight, General health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular used is soedineniya; the duration of the treatment; drugs used in combination or simultaneously used with a specific connection and like factors well known in the medical fields (see, for example, Goodman and Gilman''s, "The Pharmacological Basis of Therapeutics, Tenth Edition, A. Gilman, J.Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001, which is fully incorporated in the description by reference).

In some embodiments of the methods of use of implants and other surgical or medical devices of the invention, coated with (or adapted to release otherwise) compounds and compositions of the present invention. In some embodiments of the methods of preventing restenosis, including the introduction of a stent in a blocked blood vessel, the stent has a generally tubular structure, the surface structure is covered (or is adapted to release otherwise) of the compound or composition of the invention so that the obstruction is removed, and the compound or composition of the invention is delivered in amounts effective to prevent restenosis and/or reduce the frequency of restenosis. In other embodiments of the methods of preventing restenosis, including the introduction of a stent in a blocked blood vessel, the stent has a generally tubular structure, the surface of which tructure covered (or is adapted to release otherwise) of the compound or composition of the invention so what the obstruction is removed and the compound or composition of the invention is delivered in amounts effective for inhibiting proliferation of smooth muscle cells.

In the volume of other aspects of the present invention presents methods for expanding the lumen of the channel of the body, including the introduction of the stent into the channel, and the stent has a generally tubular structure, the surface structure is covered (or is adapted to release otherwise) of the compound or composition of the invention so that the channel extends. In some embodiments of the lumen of the conduit body is expanded to eliminate obstruction of the bile ducts, gastrointestinal tract, esophagus, trachea/bronchi, urethra and/or vessels.

In some embodiments of the presented methods to eliminate the obstruction of the bile ducts, including the introduction of a biliary stent in the bile channel, and the stent has a generally tubular structure, the surface structure is covered (or is adapted to release otherwise) of the compound or composition of the invention so that eliminates obstruction of the bile ducts. In short, the growth of a tumor of the common bile duct leads to progressive cholestatic jaundice, which is incompatible with life. In General, biliary system, which takes bile from the liver into the 12-duodenum, often in which it is sealed (1) tumor, composed of cells of the bile ducts (cholangiocarcinoma), (2) a tumor that is embedded in the bile duct (e.g., pancreatic carcinoma) or (3) tumor that exerts an external pressure and squeezes the bile duct (e.g., enlarged lymph nodes). Primary tumors of the bile ducts, as well as other tumors that cause compression wood of the bile duct, can be treated with the use of stents. Implants and other surgical or medical devices can be coated (or adapted to release otherwise) compositions of the present invention. One example of primary tumors of the bile duct adenocarcinomas (also referred to as tumors of Klatskin when they occur at the bifurcation of the common hepatic duct). These tumors are also called carcinoma of the bile ducts, choledochoenterostomy or adenocarcinomas of the biliary system. Benign tumors that affect the bile duct (e.g., adenoma of the biliary system) and in rare cases, squamous cell carcinoma, bile duct and adenocarcinoma of the gallbladder can also cause compression of the wood of the bile ducts and therefore lead to obstruction of the biliary tract. Compression wood bile duct is most often caused by tumors of the liver and pancreas W is Lesa to compress and therefore clog the ducts. Most tumors of the pancreas develop from cells of the pancreatic ducts. This form of cancer with a high mortality (5% of all cancer deaths; 26000 new cases per year in USA), with an average survival of 6 months and a survival rate at 1 year, which constitutes only 10%. When these tumors are located in the head of the pancreas, they often cause obstruction of the biliary tract, and this significantly reduces the patient's quality of life. Although all types of pancreatic tumors are referred to as "carcinoma of pancreas", there are histological subtypes including adenocarcinoma, adenosquamous carcinoma, cystadenocarcinoma and acinskiego carcinoma. Liver tumors, as discussed above, can also cause compression of the biliary tree and therefore cause obstruction of the bile ducts.

In some embodiments of the stent bile duct is first injected into the bile duct is one of several ways: from the upper end of the needle is inserted through the abdominal wall and through the liver (percutaneous perhepatic cholangiogram or "PCT"); from the lower end of kanalirovaniem bile duct through an endoscope inserted through the mouth, stomach and 12-duodenum (endoscopic retrograde cholangiogram or the ERCP"; or direct incision during the surgical procedure. In some embodiments of the study before the introduction, PTC, ERCP, or direct visualization during surgery is performed to determine the appropriate position for insertion of the stent. Then the guide wire passes through the defeat and conduct the delivery catheter to allow the introduction of a stent in his spasams. If the diagnostic study represented the PCT, the guide wire and the delivery catheter is inserted through the abdominal wall, whereas if the initial study was an ERCP, stent can be placed through the mouth. Then the stent is placed under radiological, endoscopic or direct visual control, taking special precautions to precisely place through the narrowing in the bile duct. Then the delivery catheter is removed, leaving the stent, standing in the form of struts, which holds the bile duct open. Additional cholangiogram can be performed to confirm that the stent placed accordingly.

In some embodiments of the methods of eliminating obstructi of the esophagus, including the introduction esophageal stent in the esophagus, and the stent has a generally tubular structure, the surface structure is covered (or PR is sposoben to release otherwise) of the compound or composition of the invention so that eliminates obstruction of the esophagus. Briefly, the esophagus is a hollow tube that carries food and liquids from the mouth to the stomach. Esophageal cancer or the spreading of cancer originating from the adjacent organs (e.g. stomach cancer or lung) leads to the inability to swallow food or saliva. In some embodiments, be implemented before the introduction of the survey, usually barium swallow or endoscopy, for determining the proper position for insertion of the stent. The catheter or endoscope can then be placed through the mouth, and the guide wire passes through an area of block passage. A catheter for delivering a stent carried on the guide wire under x-ray or endoscopic control, and the stent is placed exactly over the narrowing in the esophagus. You can use the study after the introduction, usually x-rays after a SIP, barium, to confirm the appropriate location.

In some embodiments of the methods of eliminating obstructi colon, including the introduction of a colonic stent in the colon, and the stent has a generally tubular structure, the surface structure is covered (or is adapted to release otherwise) of the compound or composition of the invention so that eliminates obstruction of tools the big intestine. Briefly, the colon is a hollow tube that transports food and waste material from the small intestine to anal hole. Cancer of the rectum and/or colon cancer or the spreading of cancer originating from the adjacent organs (eg, uterine cancer, ovarian cancer, bladder) leads to the inability to expel feces from the intestines. In some embodiments, be implemented before the introduction of the survey, usually barium enema or colonoscopy to determine the appropriate position for insertion of the stent. The catheter or endoscope can then be placed through the anus, and the guide wire passes through an area of block passage. A catheter for delivering a stent carried on the guide wire under x-ray or endoscopic control and the stent is placed exactly over the narrowing in the colon or rectum. You can use the study after the introduction, usually x-ray with barium enema to confirm the appropriate location.

In some embodiments of the methods of eliminating obstructi trachea/bronchi, including the introduction of a tracheal/bronchial stent into the trachea or bronchi, the stent has a generally tubular structure, the surface structure is covered (or is adapted to release otherwise) connect the discharge or composition of the invention so that eliminates obstruction of the trachea/bronchus. Briefly, the trachea and bronchi are tubes that carry air from the mouth and nose into the lungs. Blockage of the trachea cancer, germination cancer originating from the adjacent organs (e.g. lung cancer) or collapse of the trachea or bronchi due to chondromalacia (weakening of the cartilage rings) leads to inability to breathe. In some embodiments, be implemented before the introduction of the survey, usually endoscopy, to determine the appropriate position for insertion of the stent. The catheter or endoscope is then placed through the mouth and the guide wire passes through an area of block passage. A catheter for delivering the stent is then carried out along the guide wire to allow the introduction of spaceghost stent. The stent is placed under x-ray or endoscopic control to fit exactly through the constriction. A catheter for delivery can then be removed, leaving the stent, standing by itself in the form of struts. You can use the study after the introduction, usually bronchoscopy to confirm the appropriate location.

In some embodiments of the methods of eliminating obstructi urethra, including the introduction of a urethral stent in the urethra, and the stent has a generally tubular structure, being the m surface of the structure is covered (or is adapted to release otherwise) of the compound or composition of the invention so that eliminates obstruction of the urethra. In short, the urethra is a tube that drains the bladder through the penis. External constriction of the urethra as it passes through the prostate due to prostate hypertrophy occurs essentially every man over the age of 60 years and causes progressive difficulty urinating. In some embodiments, be implemented before the introduction of the survey, usually first endoscopy or urethrogram, to determine the appropriate position for insertion of the stent, which is higher than the external urethral sphincter at the lower end and close to the same level with the neck of the bladder on the top end. Then the endoscope or catheter is positioned through the hole in the penis, and the guide wire is carried out in the bladder. A catheter for delivering the stent is then carried out along the guide wire to allow the introduction of the stent. A catheter for delivery then removed and the stent is expanded into place. You can use the study after the introduction, usually endoscopy or retrograde urethrogram, to confirm the appropriate location.

In some embodiments of the methods of eliminating obstructi vessels, including the introduction of a vascular stent into a blood vessel, with the UNT has a generally tubular structure, moreover, the surface structure is covered (or is adapted to release otherwise) of the compound or composition of the invention so that eliminates obstruction of the vessel. Briefly, the stents can be placed in a wide variety of blood vessels, and arteries, and veins, to prevent recurrent stenosis in the plot failed angioplasties interventions for the treatment of stenoses, which is likely to be unsuccessful in the treatment of angioplasty, and for the treatment of postoperative narrowing (e.g., stenosis grafts for hemodialysis). Suitable sites include, but are not limited to, iliac, renal, and coronary arteries, upper Vena cava and grafts for hemodialysis. In some embodiments of first perform angiography to determine the localization of the site for placement of the stent. This is usually done by injection of a radiopaque substance through a catheter inserted into an artery or vein when carrying out radiography. Then either percutaneous or through the operation, the catheter can be introduced in the femoral artery, brachial artery, femoral vein, or brachial vein and move into the appropriate blood vessel in the direction of his vascular system under fluoroscopic control. Then the stent can be placed through the vascular stenosis. You can also use angiog is the Amma after administration to confirm appropriate placement.

In addition, after preparation of the composition with an appropriate pharmaceutically acceptable carrier in a desired dosage, the pharmaceutical composition of the present invention can introduce people and other animals orally, rectally, parenterally, nutrizionale, vnutrivlagalischno, intraperitoneally, locally (powders, ointments or drops), buccal, in the form of an oral or nasal spray or similar ways, depending on the severity of the exposed treatment of infection. In some embodiments of compounds of the invention can be entered at a dosage of from about 0.001 mg/kg to about 50 mg/kg, from about 0.01 mg/kg to about 25 mg/kg, or from about 0.1 mg/kg to about 10 mg/kg of body weight of the individual in 1 day, 1 or more times/day, to obtain the desired therapeutic effect. You should also understand that an individual can enter the dosage of less than 0.001 mg/kg and greater than 50 mg/kg (e.g., 50-100 mg/kg). In some embodiments of compounds administered orally or parenterally.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in danniebelle, such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol. 1,3-butyleneglycol, dimethylformamide, oils (in particular, oil seeds, cotton, peanut, corn, seed, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of fatty acids sorbitan and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspendresume agents, sweetening, flavoring agents and fragrances.

Injectable preparations, for example sterile injectable aqueous or oily suspensions, can be in accordance with known methods using suitable dispersing or wetting agents and suspendida agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, in the form of a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, ringer's solution in the US Pharmacopoeia and isotonic Rast is the PR of sodium chloride. In addition, sterile, fixed oils are commonly used as a solvent or suspendida environment. For this purpose you can use any soft fixed oils, including synthetic mono - or diglycerides. In addition, fatty acids such as oleic acid, are used in the preparation of injectable preparations.

Injectable compositions can be sterilized, for example, by filtration through a retaining bacteria filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersing in sterile water or other sterile injectable medium prior to use.

To extend the effect of the drug is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be done by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and shape of the crystals. Alternatively, delayed absorption of parenteral entered the drug form is accomplished by dissolving or suspendirovanie of the drug in an oil carrier. Injectable depot forms are made by forming microinch olyarnik matrices of the drug in biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio between drug and polymer and the nature of the particular polymer used, you can adjust the speed of release of the drug. Examples of other biodegradable polymers include complex poly(orthoevra) and poly(anhydrides). Depot injectable compositions also get a grip of the drug in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal injection preferably represent suppositories, which can be obtained by mixing the compounds of this invention with suitable non-irritating with excipients or carriers such as cocoa butter, polyethylene glycol or wax for suppositories, which are solid at ambient temperature but liquid at body temperature and therefore melt in the cavity of the rectum or vagina and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms the active compound mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and/or a) fillers or agents to increase the volume, such as starches, l is chose, sucrose, glucose, mannitol and silicic acid, b) binding agents, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, C) humectants such as glycerol, d) loosening agents, such as agar-agar, calcium carbonate, potato starch or tapioca starches, alginic acid, certain silicates and sodium carbonate, e) agents, retarding dissolution such as paraffin, f) accelerators suction, such as Quaternary ammonium compounds, g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricating agents such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also include agents that give the buffer properties.

Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as glycols of high molecular weight and the like. Solid dosage forms such as tablets, pills, capsules, pills and granules can be obtained with coatings and shells, such as dissolving in the intestines are covered with the I other coverage well-known in the preparation of pharmaceutical compositions. They may not necessarily contain agents which impart opacity, and can also consist of a composition that releases the active ingredient (the ingredient), or preferably in a certain part of the intestinal tract, optionally deferred. Examples embedded in the media compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as glycols of high molecular weight and the like.

The active compounds can also be a micro-encapsulated form with one or more excipients as noted above. Solid dosage forms such as tablets, pills, capsules, pills and granules can be obtained with coatings and shells, such as dissolving in the intestines cover, cover, regulating the release, and other coatings well known in the field of preparation of pharmaceutical compositions. In such solid dosage forms the active compound may be mixed with at least one inert diluent such as sucrose, lactose and to Ajmal. Such dosage forms can also include, as is common practice, additional substances other than inert diluents, such as lubricating agents for tableting and other tableting AIDS such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also include agents that give the buffer properties. They may not necessarily contain agents which impart opacity, and can also consist of a composition that releases the active ingredient (the ingredient), or preferably in a certain part of the intestinal tract, optionally deferred. Examples embedded in the media compositions that can be used include polymeric substances and waxes.

Dosage forms for local or transdermal injection of the compounds of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, aerosols, inhalation compositions or covers. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic composition, ear drops and eye drops are also prescribed as being within the range of the present invention. In addition, toadie the invention provides for the use of transdermal pads, which have the added advantage of providing controlled delivery of the compound into the body. Such dosage forms are made by dissolving or dispersing the compound in an appropriate environment. Agents that enhance the absorption, can also be used to increase the current connection through the skin. You can adjust the speed or the provision of the membrane, regulating the speed, or by dispersing the compound in a polymer matrix or gel.

It should also be understood that the compounds and pharmaceutical compositions of the present invention can be prepared and used in the methods of combined treatment, i.e. the compounds and pharmaceutical compositions can be or administered simultaneously with one or more other desired therapeutics or medical procedures, before them or after them. A combination of treatments (therapeutic agent or procedure) for use in combination mode should take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. You should also understand that methods of treatment may achieve the desired effect about the same disorder (for example, the compound of the invention it is possible to enter ignoreme is but with another anti-cancer agent), or they may achieve different effects (e.g., elimination of side effects). For example, other methods of treatment or anti-cancer tools that can be used in combination with anticancer means of the present invention include surgery, radiotherapy (as a few examples, γ-irradiation, radiation therapy beam neutron rays, radiation therapy beam electron beams, proton therapy, brachytherapy, and systemic injection of radioactive isotopes), endocrine therapy, biological reaction modifiers (as a few examples, interferons, interleukins and factors of tumor necrosis (TNF), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics) and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide), antimetabolites (methotrexate), purine antagonists and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil, cytarabin, gemcitabine), poisons acting on the nervous spindle (vinblastine, vincristine, vinorelbine, paclitaxel), podophyllotoxins (etoposide, irinotecan, topotecan), antibiotics (doxorubicin, bleomycin, mitomycin), nitrosoanatabine (carmustin, lomustin), inorganic ions (caplat is h, carboplatin), enzymes (asparaginase), and hormones (tamoxifen, leuprolide, flutamide and megestrol), as a few examples. A more extensive discussion of modern methods of cancer treatment are presented in the publication The Merck Manual, the seventeenth Ed. 1999, the full content of which is included in the description by reference. The list approved by the food and drug administration (FDA) oncologic drugs are also presented on the website of the National cancer Institute (NCI) in (www.nci.nih.gov and the FDA website (www.fda.gov/cancer/cder/druglistframe - see Appendix a).

In some embodiments of the pharmaceutical compositions of the present invention, in addition, include one or more additional therapeutically active ingredients (e.g., chemotherapy and/or palliative). For the purposes of the invention, the term "palliative" refers to treatment that focuses on relieving symptoms and/or side effects of the regimen, but it is not healing. For example, palliative care covers painkillers, medicines against nausea. In addition, chemotherapy, and radiation therapy, and surgery can be used palliative (i.e. to reduce symptoms without cure; for example, to reduce the size of tumors and reduce the pressure, bleeding, pain and other symptoms is s cancer).

Medical kits

In other embodiments of the present invention relates to a kit for easy and efficient implementation of methods in accordance with the present invention. In General, the pharmaceutical pack or kit includes one or more containers filled with one or more ingredients of the pharmaceutical compositions of the invention. These kits are specially adapted for the delivery of solid oral forms such as tablets or capsules. Such a kit preferably includes a number of standard dosages and may also include a card with the dosage, oriented in the order of their intended application. If desired, may be provided auxiliary memory means, for example, in the form of numbers, letters, or other marks or calendar pad, marking the days on treatment schedule, in which you can enter the dosage. Alternative dosing placebo or calcium supplements or in the form similar to or different from dosages of the pharmaceutical compositions can be included to provide a set, in which the dosage is taken every day. Optional in conjunction with such container (containers) can be a notice in the form of regulations of the governmental Agency regulating the manufacture, use or sale of pharmaceutical and the ducts, the notice reflects approval by the Agency of manufacture, use or sale for introducing people.

Equivalents

Representative examples that follow are intended to help illustrate the invention and are not intended or should not be considered as limiting the range of the invention. Indeed, various modifications of the invention and many of its further implementation options in addition to those shown and described in the description, will be obvious to specialists in this area of the full contents of this document, including examples that follow, and links to scientific and patent literature cited in the description. In addition, it should be understood that the contents of these references are included in the description as a reference to facilitate the illustration of the prior art.

The following examples contain important additional information, illustration and guidance that can be adapted to practice the present invention in its various embodiments, implementations and equivalents.

Examples

The practitioner is sufficiently entrenched literature of peptide chemistry, from which can be gleaned information contained herein, for guidance on strategies of synthesis, the protective groups and other materials and the ways m which should be used for the synthesis of compounds of this invention.

Various presented in the description references provide useful background information on obtaining the compounds similar to the compounds of the invention described in the description, or the relevant intermediate connections, as well as information on the preparation of the compositions, uses and the introduction of such compounds, which may be of interest.

In addition, the practitioner is directed to a specific guidance and examples presented in this document relating to various illustrative compounds and intermediate compounds.

The compounds of this invention and obtaining them can be further understood from the examples which illustrate some of the ways in which these connections receive or apply. However, it should be understood that these examples do not limit the invention. It is believed that modifications of the invention that are not known or will be developed in the future, fall under the range of the present invention, as described in the description and in the description hereinafter claimed.

In accordance with the present invention can use any of the available techniques for the manufacture or produce compounds of the invention or compositions comprising them. For example, you can use various methods of synthesis in solution phase, such as methods, discussed in detail what's below. Alternative or additional compounds of the invention can be obtained using any of the various combined methods of parallel synthesis and/or methods of synthesis in the solid phase, known in this field.

As described below, it should be understood that many of the compounds of the invention can be synthesized as described in the description of ways. Starting materials and reagents used in the preparation of these compounds, or are suppliers to the trade network, such as Aldrich Chemical Company (Milwaukee, WI), Bachem (Torrance, CA), Sigma (St. Louis, MO), or get their way, well known to the average person skilled in the art, following procedures described in such references as Fieser and Fieser 1991, "Reagents for Organic Synthesis, vols 1-17, John Wiley and Sons, New York, NY, 1991; Rodd 1989 "Chemistry of Carbon Compounds", vols. 1-5 and supps, Elsevier Science Publishers, 1989; "Organic Reactions", vols 1-40, John Wiley and Sons, New York, NY, 1991; March 2001, "Advanced Organic Chemistry", 5th ed. John Wiley and Sons, New York, NY; and Larock 1990, "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 2nded. VCH Publishers. These schemes are merely illustrative of some of the ways in which it is possible to synthesize the compounds of this invention, and in them it is possible to make various modifications to these schemes, which will be offered to the average person skilled in the field relevant to this description.

Raw materials, intermediate and connect the means of the present invention can be extracted and cleaned using conventional techniques, including filtration, distillation, crystallization, chromatography and the like. They can be characterized using conventional methods, including physical constants and spectral data.

Some illustrative compounds of the invention are listed below and indicated by the specified number of connections.

General procedures reactions:

If no specific instructions, the reaction mixture displaced ivali using a bar of magnetic agitator. Inert atmosphere refers or to the dry argon or dry nitrogen. The reaction was controlled or thin-layer chromatography (TLC), proton nuclear magnetic resonance, or high-performance liquid chromatography (HPLC) appropriately obtained sample of the reaction mixture.

The following abbreviations are used for some common organic reagents specified in the description:

BOC or BOC2O:Dicarbonate di-tert-butyl
SMS:1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide
The method of pair-toluensulfonate
DCM:Dichloromethane
DEPC:Diethylphosphoramidite (diethylthiophosphate)
DIBAL:Hydride diisobutylaluminum
DIEA:Diisopropylethylamine
DMF:N,N-dimethylformamide
DMSO:The sulfoxide
Simple broadcast:Simple diethyl ether
HBTU: Hexaphosphate O-(1-N-benzotriazol-1-yl)-N,N,N,N-tetramethylurea
HOAt:1-hydroxy-7-asobancaria
LAH:Hydride layalina
MSA:Methansulfonate acid
NMM:N-methylmorpholin
TBME:Simple tert-butyl methyl ether
TFA:Triperoxonane acid
THF:Tetrahydrofuran
TMEDA:Tetramethylethylenediamine

General handling procedures:

If no specific instructions, the reaction mixture was cooled to room temperature or below, then the reaction is extinguished if necessary, or water, or saturated aqueous ammonium chloride. The desired products were extracted distribution between water and a suitable is not miscible with water solvent (e.g. ethyl acetate, dichloromethane, simple diethyl ether). Desirable products containing extracts were washed properly with water and then saturated saline solution. In cases where it was assumed that the product containing the extract contained the OS is enough oxidants, the extract was washed with a 10% solution of thiophosphate sodium in a saturated aqueous solution of sodium bicarbonate before the above washing procedure. In cases where it was assumed that the product containing the extract contained residual acid, the extract was washed with saturated aqueous sodium bicarbonate solution before the above washing procedure (except those cases, when the desired product had an acid character). In cases where it was assumed that the product containing the extract contained a residual basis, the extract washed with 10% aqueous citric acid solution before the above washing procedure (except those cases, when the desired product had the main character). After washing the desired product containing extracts were dried over anhydrous magnesium sulfate, then filtered. The crude products were then isolated by removing the solvent (solvents) by rotary evaporation under reduced pressure at an appropriate temperature (generally less than 45°).

When the triphenylphosphine oxide was the main side product of the reaction, the reaction mixture was added directly to a large amount of stirring hexane. The precipitate of triphenylphosphine oxide was removed by filtration and the filtrate was treated with the usual about what atom.

General cleaning procedures:

Chromatographic purification is or column flash chromatography on silica using a single solvent or mixed solvent as an eluent or HPLC on a C18 column. Appropriately desired product containing erwerbende compounds were combined and concentrated under reduced pressure at an appropriate temperature (generally less than 45° (C) to constant weight. The final compounds were obtained for biological testing and or) dissolved in 50% aqueous acetonitrile, filtered and transferred into bottles, then dried in high vacuum; or (b) dissolved in methanol, filtered and transferred into bottles, and then concentrated to dryness using a centrifugal vacuum evaporator.

Example 1: Obtaining complex amine ethers 18, 20 amino acids and aminimides 23

The connection 13

To a solution of compound 12 (205 mg) in DMF (3.8 ml) at room temperature was added (S)-N-Boc-neopentylene (6) (140 mg), NMM (0,30 ml), HOAt (0.124 g) and SMS (1,16 g). The reaction mixture was shaken at room temperature for 24 hours of Water treatment, followed by chromatographic purification gave link the 13 (153 mg, 61%).

The connection 14

To a solution of compound 13 (153 mg) in methanol (20 ml) at 0°With portions was added sodium borohydride (3,18 g) with shaking for 3 days. The temperature of the reaction mixture was maintained in the range from 0 to 5°C. when the reaction mixture turned into a hardened mass, to facilitate stirring to the reaction mixture was added THF. The reaction mixture was brought to room temperature, then was cooled to 0°and processed in the usual manner to obtain compound 14 (140 mg, 96%).

The connection 15

To a solution of compound 14 (50 mg) in THF (3 ml) at room temperature was added periodinane Tessa Martin (204 mg) in one portion. The resulting suspension was vigorously stirred for 4.5 hours Water treatment gave the crude compound 15 (50 mg), which was immediately used in the next stage without purification.

A General procedure for obtaining a complex of amine ethers 18

To a solution of compound 15 (1 equivalent) in an appropriate volume of 1,2-dichloroethane at room temperature was added molecular sieves 4Å (crushed and dried) (weight equal to the weight of the amine hydrochloride). Appropriately selected amine hydrochloride (16) (10 equiv is Lento) was added with vigorous stirring followed by the addition of triacetoxyborohydride sodium (1.5 equivalents). The reaction mixture was stirred at the appropriate temperature (20°-50° (C) until such time as the connection 15 had not been spent in a satisfactory degree. Water treatment followed by chromatographic purification gave the corresponding N-Boc amine complex ester 17. Unprotect N-Boc parts in suitable conditions, would give the corresponding unprotected amine 18.

A General procedure for obtaining amino acid 20

To a solution of complex amine ester 17 in a suitable mixture of THF and methanol was added 1M solution of lithium hydroxide (10-50 equivalents). When the N-Boc amine complex ester 17 hydrolysable to a satisfactory degree, the reaction mixture was subjected to water treatment. N-Boc amino acid 19 was purified chromatographically. Unprotect N-Boc parts in suitable conditions, would give the corresponding unprotected amine 20.

A General procedure for obtaining the amides of amines 23

To a solution of N-Boc amino acid 19 in DMF at room temperature was added NMM (20 equivalents). Added appropriately selected amine hydrochloride (21) (20 equivalents) followed by addition of DEPC (20 equivalents). When the N-Boc amino acid 19 came in reaction to a satisfactory degree, N-Boc amide amine 22 was isolated or direct chromatographic purification of the reaction the mixture, or water treatment, followed by chromatographic purification. Unprotect N-Boc parts in suitable conditions, would give the corresponding unprotected amine 23.

Example 2: obtaining the amides of N-acetylamino 27

Obtaining compounds 24

To a solution of aldehyde 13 (50 mg) in 1,2-dichloroethane (2 ml) at room temperature was added molecular sieves 4A (crushed and dried) (50 mg). Hydrochloride complex licensedialog ester (120 mg) was added with vigorous stirring followed by the addition of triacetoxyborohydride sodium (205 mg). The reaction mixture was stirred at 40°C for 2 h Water treatment, followed by chromatographic purification gave compound 24 (31 mg, 46%).

Obtaining compounds 25

To a solution of compound 24 (5.5 mg) in DMF (0.4 ml) at room temperature was added pyridine (0,006 ml) followed by addition of acetic anhydride (0,004 ml). The reaction mixture was shaken for 3 h at room temperature, then concentrated in vacuum to dryness. The residue was dissolved in saturated HCl in methanol (1 ml) and left at room temperature for 15 minutes the Reaction mixture was concentrated in vacuum to obtain compound 25 (4 mg, 90%).

The connection 26

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To a solution of compound 25 (3,35 mg) in methanol (0.2 ml) was added 1 M solution of lithium hydroxide (amount of 0.118 ml). The reaction mixture was stirred at room temperature for 5 hours Chromatographic purification with subsequent treatment of methanolic HCl gave the hydrochloride of compound 26 (1,95 mg, 61%).

A General procedure for obtaining the amides of N-acetylamino 27

To a solution of compound 26 (1 equivalent) in DMF at room temperature was added NMM (20 equivalents). Added appropriately selected amine hydrochloride (21) (20 equivalents) followed by addition of DEPC (20 equivalents). When the connection 26 came in reaction to a satisfactory degree, amide N-acetylamino (27) was isolated by direct chromatographic purification of the reaction mixture.

Example 3: Obtaining connection 33

The connection 28

To a solution of compound 3b (1,94 g) in dry DHM (20 ml) at 0°in an inert atmosphere was added dropwise a 1 M solution of DIBAL (32 ml). The reaction mixture was stirred at 0°C for 2.5 hours, then was added dropwise methanol (4.4 ml) followed by the addition of saturated solution of ammonium chloride (8,8 ml). Added DHM (200 ml) and the reaction mixture is vigorously stirred at room the Oh temperature for 30 minutes Filtration followed by concentration in vacuo gave the crude compound 28 (1.08 g, 65%).

The connection 29

To a solution of compound 28 (207 mg) in THF (5 ml) at 0°in an inert atmosphere portions was added sodium hydride (60%, dispersion in mineral oil, 160 mg). The reaction mixture was stirred at 0°C for 45 min, then was treated with bromoacetate ethyl (0,47 ml). The reaction mixture was brought to room temperature. Water treatment followed by chromatographic purification gave the intermediate BOC compound (185 mg, 67%). Intermediate BOC compound (139 mg) was dissolved in ethanol (2 ml) and was treated with saturated HCl in ethanol (2 ml). The reaction mixture was kept at room temperature for 10 min, then was concentrated in vacuum to dryness to obtain compound 29 (114 mg).

The connection 30

To a solution of compound 29 (114 mg) in DMF (1.8 ml) at room temperature was added (S)-N-Boc-tert-leucine (4) (283 mg), NMM (is 0.135 ml), HOAt (56 mg) and SMS (518 mg). The reaction mixture was shaken at room temperature for 16 hours, Water treatment, followed by chromatographic purification gave the intermediate BOC compound (42 mg, 22%). Intermediate BOC compound (42 mg) was dissolved in saturated HCl in ethanol (5 ml) and kept at room the temperature for 10 minutes Concentration in vacuo gave compound 30 (37 mg).

The connection 31

To a solution of compound 30 (24 mg) in DMF (0,26 ml) at room temperature was added (S)-N-Boc-neopentylene (6) (38 mg), NMM (0,014 ml), HOAt (8,3 mg) and SMS (52 mg). The reaction mixture was shaken at room temperature for 16 hours, Water treatment, followed by chromatographic purification gave the intermediate BOC compound (38 mg, 64%). Intermediate BOC compound (38 mg) was dissolved in saturated HCl in ethanol (5 ml) and kept at room temperature for 10 minutes Concentration in vacuo gave compound 31 in the form of HCl salt.

The connection 32

To a solution of compound 31 (4 mg) in ethanol (2 ml) was treated with 1 M lithium hydroxide (0.5 ml). The reaction mixture was stirred at room temperature for 1.5 hours, Water treatment, followed by chromatographic purification gave compound 32 (2,9 mg, 76%).

The connection 33

To a solution of compound 32 (1.9 mg) in DMF (70 ml) at room temperature was added NMM (3,8 mm), pyrrolidine (2,8 mm) and DEPC (5,2 µl). The reaction mixture was stirred at room temperature for 16 hours the Reaction mixture is chromatographically purified to obtain compound 33 (1.2 mg, 58%).

Example 4: ruchanie complex amine ethers 42, of 43 amino acids and amides amines 45

The connection 39

To a solution of compound 12 (1.25 g) in DMF (21 ml) at room temperature was added the hydrochloride of (R)-N-methylpiperidine (38) (0,38 g), NMM (1,4 ml), HOAt (0,575 g) and SMS (lower than the 5.37 g). The reaction mixture was shaken at room temperature for 24 hours of Water treatment gave the connection 39 (0,511, 63%).

The connection 40

To a solution of compound 39 (0.8 g) in methanol (8 ml) at 0°With portions was added sodium borohydride (7.9 g) for 3 days. The temperature of the reaction mixture was maintained at a level of from 0° to 5°C. when the reaction mixture turned into a hardened mass, to facilitate mixing of THF was added. The reaction mixture was brought to room temperature, then was cooled to 0°and extinguished a saturated solution of sodium bicarbonate. Water treatment made the connection 40.

The connection 41

To a solution of compound 40 (50 mg) in THF (3 ml) at room temperature was added periodinane Tessa Martin (225 mg) in one portion. The resulting suspension was vigorously stirred for 4 h Water treatment gave the crude compound 41 (55 mg), which was immediately used on the trail of the ment stage without purification.

A General procedure for obtaining N-terminal N-heterocyclic amine complex esters 42

To a solution of compound 41 (300 mg) in 1,2-dichloroethane (10 ml) at room temperature was added molecular sieves 4Å (crushed and dried) (1.5 g). Added the hydrochloride of ester amino acids (16) (10 equivalents) and the reaction mixture is vigorously stirred ˜10 min Triacetoxyborohydride sodium (290 mg) was added in one portion and the reaction mixture is vigorously stirred at room temperature. When the compound 41 was spent in a satisfactory degree, the reaction mixture was subjected to water treatment. N-terminal N-heterocyclic amine complex ester 42 was purified chromatographically except when it is not believed necessary.

A General procedure for obtaining N-terminal N-heterocyclic amino acids 43

To a solution of N-terminal N-heterocyclic amine complex esters (42) in a suitable mixture of THF and methanol was added 1 M solution of lithium hydroxide (10-50 equivalents). When N-terminal N-heterocyclic amine complex esters 42 were obtained to a satisfactory degree, the reaction mixture was subjected to water treatment. N-terminal N-heterocyclic amino acid 43 was purified chromatographically for the claim is ucheniem cases, when it is not believed necessary.

A General procedure for obtaining N-terminal N-heterocyclic amides amines 45

To a solution of N-terminal N-heterocyclic complex of 43 amino acids in DMF at room temperature was added NMM (20 equivalents). Appropriately selected amine hydrochloride (44) (20 equivalents) was added, followed by adding DEPC (20 equivalents). When N-terminal N-heterocyclic amino acid 43 was spent in a satisfactory degree, N-terminal N-heterocyclic amide amine 45 allocated or direct chromatographic purification of the reaction mixture or water treatment, followed by chromatographic purification.

Example 5: Receiving connections 51 and 52

Step 1: obtaining a connection 49:

Getting connections 47:

Procedure A.

Compound 46 (1,0405 g, 4,4984 mmol) was dissolved in DMF (8.0 ml). Added To2CO3(0,6258 g, 4,5279 mmol). Was added methyl iodide (0.6 ml, 9,6379 mmol). Milky suspension was stirred at room temperature under nitrogen atmosphere for 3 days. Standard water treatment gave ester 47 in the form of a colorless oil (1,0590 g, 96%).

Getting connection 2:

Compound 47 (0,9447 g, 3,8509 mmol) was dissolved in toluene (15 ml) and the solution was cooled to -78°C in nitrogen atmosphere. DIBAL (6,0 ml of 6.00 mmol, 1.0 M in hexano) was added via syringe over 5 minutes the Solution was stirred for 1 h and the reaction was suppressed Meon (1.0 ml) at -78°C. Bath was removed and added 5.0 ml of a saturated solution of salinetreated. The mixture was stirred for about 1 h and filtered through celite. The filtrate is washed with N2And with brine and dried over Na2SO4, filtered and evaporated to obtain compound 2 (0,8413 g, 101%), sufficiently pure for the next step.

Obtaining compounds 3b:

Compound 2 (0,8413 g, 3,8509 mmol) was dissolved in CH2Cl2(5.0 ml) was added (carletonville)triphenylphosphorane (1,8212 g, 5,0254 mmol). The solution was stirred at room temperature under nitrogen atmosphere overnight. The solution is evaporated and the residue was diluted with EtOAc (70 ml) and washed with H2About (2×25 ml) and saline (25 ml) and dried over Na2SO4, filtered and evaporated to obtain an oil. Purification with flash chromatography on SiO2(FC) gave pure compound 3b (0,7863 g, 68%).

The connection 48:

Compound 3b (0,7863 g, 2,6262 mmol) was dissolved in CH2Cl2(1.0 ml) was added treat Lilan (0,460 g, 2,880 mmol). Triperoxonane acid (TFU) (2.5 ml) was added at room temperature. After 30 minutes (the complete reaction according to HPLC), the solution evaporated to obtain a solid substance (1,1307 g). This solid was dissolved in CH3CN (approximately 10 ml) and was added to 5.5 N HCl (2.4 ml, 13,2 mmol). Evaporation gave the HCl salt, compound 48 (0,618 g, 100%).

Obtaining compounds 5b:

Compound 48 (0,390 g, 1,6543 mmol), L-N-BOC-tert-butylglycol (1,0106 g, 4,3694 mmol), CMC (1,9704 g, 4,6518 mmol), HOAt (0,5905 g, 4,3384 mmol) and NMM (0,490 ml, 4,4567 mmol) were combined and added DMF (4.0 ml). The solution was stirred at room temperature under nitrogen atmosphere for 25 hours the Solution was diluted with EtOAc (70 ml) and washed with H2About (2×25 ml), the pH of the water environment to 7.2 with phosphate buffer (25 ml), N2O (25 ml) and saline (25 ml) and dried over MgSO4, filtered and evaporated to obtain solid, which was purified with flash chromatography to obtain compound 5b (0,4239 g, 62%).

The connection 49:

Compound 5b (0,1159 g, 0,2809 mmol) was dissolved in CH2Cl2(3.0 ml) and triethylsilane (0,050 ml, 0,3130 mmol). Triperoxonane acid (TFU) (2.5 ml) was added at room temperature. After 30 minutes (the complete reaction according to HPLC), the solution evaporated to obtain a solid substance. This t is ardoe substance was dissolved in CH 3CN (approximately 5 ml) and was added to 5.5 N HCl (0.3 ml, of 1.65 mmol). Evaporation gave the HCl salt, compound 49 (0,0662 g, 100%).

Stage 2: Getting connection 51:

The connection 50:

Compound 49 (0,0774 g, 0,2219 mmol), (R)-N-methylpiperidin (0,0705 g, 0,3925 mmol), CMC (0,1752 g, 0,4536 mmol), HOAt (0,0344 g, 0,2527 mmol) and NMM (0,063 ml, 0,5730 mmol) were combined and added DMF (2.0 ml). The solution was stirred at room temperature under nitrogen atmosphere for 20 hours, the Solution was purified directly by reversed-phase HPLC (RP HPLC) to give compound 50 (0,0989 g, 81%).

The connection 51:

Compound 50 (0,0989 g, 0,2086 mmol) was dissolved in 1:1 H2O/MeOH (14 ml) at room temperature. Added LiOH (0,0537 g, 2,2422 mmol). The suspension was stirred at room temperature for 19 hours, the Solution was acidified to 5.5 N HCl (0,50 ml) and was purified RP HPLC with obtaining salt TFU 11 (0,0978 g, 90%). It was dissolved in CH3CN (approximately 5 ml) and treated with 5.5 N HCl (approximately 1 ml, 5.5 mmol) and evaporated to obtain the HCl salt of compound 51 (0.0667 g, 72%).

Stage 2: Getting connection 52:

Compound 51 (0,0062 g, 0,0139 mmol), hydrochloride of complex L-prolongational ether (0,0263 g, 0,1588 mmol) was dissolved in DMF (1.0 ml) at room temperature under nitrogen atmosphere. DEPC (0,017 ml, 0,1120 the mol) was added via syringe. NMM (0,025 ml, 0,2274 mmol) was added via syringe. The solution was stirred overnight, the reaction was suppressed H2O (1.0 ml) and purified RP HPLC to obtain salt TFU connection 52. It was dissolved in CH3CN (approximately 3 ml) and treated with 5.5 N HCl (0.10 ml, 0.55 mmol) and evaporated to obtain the HCl salt of compound 52 (0,0078 g, 100%).

Example 6: Getting connection a

The connection 54

To a solution of 4-methylpiperidine (53) (600 μl, 5.0 mmol) in Meon (20 ml) was added Et3N (770 μl, 5.5 mmol) followed by addition of Boc2O (1.2 g, 5.5 mmol) at 0°C. After 15 min the reaction mixture was warmed to room temperature and was allowed to mix overnight. Then the reaction solution was diluted with N2O and was extracted several times with simple ether. The ether extracts were combined, dried over MgSO4, filtered and concentrated to obtain compound 54 (926,5 mg) in quantitative yield as a colourless oil.

Obtaining compounds 55

A solution of compound 54 (926,5 mg, 5.0 mmol) in Et2O (10.5 ml) was cooled to -78°and treated With TMEDA (755 μl, 5.0 mmol) followed by slow addition of a 1.3 M solution of sec-utility (4.6 ml, 6.0 mmol) in cyclohexane for 30-min period. Rea the traditional solution is then warmed to -20° C and maintained at this temperature for 30 min, after which the solution was re-cooled to -78°and blowing gaseous carbon dioxide for 15 minutes, the Reaction solution is then slowly warmed to 0°and was poured into a biphasic mixture of 1 N HCl (100 ml) and EtOAc (50 ml). The reaction solution then was extracted with EtOAc several times. The EtOAc extracts were combined, dried over MgSO4, filtered and concentrated to obtain compound 55 (1.07 g) at exit 89% in the form of a colorless oil (mixture of two CIS-enantiomers).

Obtaining compounds 59A

To a solution of compound 55 (292 mg, 1.2 mmol) in CH2Cl2(2.4 ml) at 0°With added TFU (2.4 ml). After 15 min the reaction solution was heated to room temperature and was stirred for 3 hours, the Reaction mixture was then concentrated in vacuum to obtain compound 59A (309 mg) in quantitative yield as a pale yellow oil.

Getting connection 59b

Stage 1:The connection 56

To a solution of compound 55 (780 mg, 3.2 mmol) in DMF (6.4 ml) was added K2CO3(663 mg, 4.8 mmol) followed by addition of MeI (300 μl, 4.8 mmol). The reaction solution was allowed to mix overnight. The reaction mixture is then p is bavlyali H 2O and was extracted several times with simple ether. The ether extracts were combined, dried over MgSO4, filtered and concentrated in vacuum. Purification of the residue by chromatography on silica gel (4% EtOAc in hexano) gave 535 mg (65%) of compound 56 as a colorless oil.

Stage 2:The connection 57

To a solution of compound 56 (463 mg, 1.8 mmol) in Meon (2.6 ml) was added a 25 wt.% solution of NaOMe in MeOH (100 μl). The solution was allowed to mix overnight. The reaction mixture was then diluted with N2O and was extracted several times with simple ether. The ether extracts were combined, dried over MgSO4, filtered and concentrated in vacuum. Purification of the residue by chromatography on silica gel (4% EtOAc in hexano) gave 363,6 mg (79%) of racemic compounds 57 in the form of a colorless oil.

Stage 3:The connection 58

To a solution of compound 57 (360 mg, 1.4 mmol) in a mixture of 2:1 N2On (2,75 ml) and EtOH (5.50 ml) was added to pellets of KOH (786 mg, 14 mmol) and the reaction solution was stirred at room temperature until completion of the reaction according to thin-layer chromatography (TLC). The reaction mixture was then diluted with N2O and was extracted several times with simple ether. The ether extracts were combined, dried over MgSO4was filtered and the oxygen which has demonstrated with obtaining connection 58 (341 mg) in quantitative yield as a white solid.

Stage 4:Getting connection 59b

To a solution of compound 58 (292 mg, 1.2 mmol) in CH2Cl2(2.4 ml). After 15 min the reaction solution was heated to room temperature and was stirred for 3 hours, the Reaction mixture was then concentrated in vacuum to obtain compound 59b (309 mg) in quantitative yield as a pale yellow oil.

Obtaining compounds 60A and 60b

(60A and 60b)

To a solution of compound 59A (or 59b) (283 mg, 1.1 mmol) in Meon (5 ml) was added Pd(OH)2(75 mg) followed by addition of 37 wt.% solution of formaldehyde in N2About (300 μl). Filed gaseous N2(balloon pressure) and the reaction mixture gave the opportunity to mix in the atmosphere of H2throughout the night. The reaction solution is then filtered through a layer of celite and concentrated to obtain compound 60A (or 60b) (173 mg) in quantitative yield as a white solid.

Getting connections 61A and 61b

(61A and 61b)

To a solution of compounds 60A and 60b (11.0 mg, 0.07 mmol) in CH2Cl2(350 μl) was added HBTU (40 mg, 0.11 mmol) and DIEA (37 μl, 0.21 mmol). After 5 min was added amine 49 (22,0 mg, 0.07 mmol). The reaction mixture was stirred for 30 min, filtered and concentrated. Purification of the residue by chromatography on silica gel (2% EtO in CH 2Cl2gave 15,1 mg (96%) of each diastereoisomer 61A and 61b in the form of colourless oils.

Getting connection a

To a solution of diastereoisomer 61A (9.0 mg, 0.02 mmol) in a mixture of 2:1 N2O (80 ml) and EtOH (160 ml) was added LiOH·H2O (840 mg, 0.20 mmol). The reaction solution was allowed to mix overnight. The reaction mixture was then acidified using 1 N HCl up until the pH reached 6,00. The solution was then extracted several times CH2Cl2. Extracts CH2Cl2were combined, dried over MgSO4, filtered and concentrated to obtain a (8,4 mg) in quantitative yield as a white solid.

Example 7: Getting connection 67b

The connection 64

To a suspension of L-penitsillamin (63) (300 mg, 2.0 mmol) in methanol (10 ml) was added benzaldehyde (233 mg, 2.2 mmol) followed by the addition of sodium bicarbonate (336 mg, 4.0 mmol). The mixture was heated to boiling in a vessel under reflux with stirring for 16 hours After cooling to room temperature, it was acidified to pH 5 1N HCl and was extracted with ethyl acetate 3 times. The organic phase was concentrated to obtain a yellow solid as crude product 64 (469 mg, 99%).

Gender is a given compound 65

To a solution of the crude 64 (47 mg, 0.2 mmol) in THF (1 ml) was added aqueous 37% formaldehyde solution (49 μl, 0.6 mmol) followed by addition of NaBH4(38 mg, 0.6 mmol). The mixture was stirred at room temperature for 24 hours After acidification to pH 5, and extraction with ethyl acetate the organic phase was dried and concentrated to obtain the crude product 65 (67 mg, >100%).

Getting connections 66A and 66b

To a mixture of 65 (29 mg, 0,115 mmol), amine HCl salt 49 (15 mg, 0,043 mmol), CMC (55 mg, 0,129 mmol) and HOAt (3 mg, of 0.022 mmol) was added DMF (0.5 ml) followed by addition of NMM (6 ml, by 0.055 mmol). The mixture was stirred at room temperature for 24 h the Reaction was suppressed by addition of water (0.5 ml) and methanol (0.5 ml). Products 66A (32%) and 60b (75%) was obtained after separation OF HPLC (0-100% In 30 minutes: 5% MeCN+0.15% of TFU in N2About; IN: 0.15% OF TFU in MeCN) and lyophilization.

Getting connection 67b

To a solution of 66b (4 mg, 0,0073 mmol) in methanol (0.5 ml) was added aqueous LiOH (1 M, 0.5 ml). The mixture was stirred for 16 h and was acidified using 1N HCl. Product 67b (2,79 mg, 74%) was obtained after RP HPLC purification and lyophilization.

Example 8: Getting connection 74

Getting connection 69

To a solution of diacylglycerol (68) (131 mg, 1.0 mmol) in 1N NaOH (1.5 ml) was added a solution of di-tert-BUTYLCARBAMATE (436 mg, 2.0 mmol) in dioxane (1.0 ml). The mixture was stirred for 16 hours It was acidified to pH 3 1N HCl and was extracted with ethyl acetate 3 times. The organic phases were combined, dried and concentrated to obtain the crude product 69 (135 mg, 58%).

The connection 70

To a solution of the crude 69 (135 mg, of 0.58 mmol) in MeOH (0.5 ml) and THF (0.5 ml) was added trimethylsilyldiazomethane (2 M in hexano, 2.0 mmol). The mixture was stirred at room temperature for 1 h Evaporation gave the crude product 70 (of 0.58 mmol).

The connection 71

To a mixture of sodium hydride (160 mg, 60%, 4 mmol) in DMF (1 ml) was added a solution of compound 70 (of 0.58 mmol) in DMF (1 ml) followed by addition of methyl iodide (188 μl, 3 mmol). The mixture was stirred at room temperature for 24 hours Water was added for quenching the reaction. Product 71 (118 mg, 78% phase 2) were extracted with ethyl acetate and was purified flash chromatography on a column (silica, ethyl acetate/hexane).

The connection 72

A solution of compound 71 (118 mg, 0.46 mmol) in concentrated HCl (1 ml) was stirred at room temperature for 24 hours Product molecule after evaporation of volatile substances.

The connection 73

To a mixture of compound 72 (30 mg, 0,166 mmol), HCl salt of amine 49 (39 mg, 0,166 mmol), CMC (141 mg, of 0.332 mmol) and HOAt (14 mg, 0,103 mmol) was added DMF (1.5 ml) followed by addition of NMM (6 ml, 0,128 mmol). The mixture was stirred at room temperature for 24 h the Reaction was suppressed by addition of water (0.5 ml) and methanol (0.5 ml). Product 73 (27 mg, 34%) was obtained after separation OF HPLC (0-100% In 30 minutes: 5% MeCN+0.15% of TFU in H2O; B: 0.15% OF TFU in MtCN) and lyophilization.

The connection 74

To a solution of compound 73 (18 mg) in methanol (0.5 ml) was added an aqueous solution of LiOH (1 M, 0.5 ml). The mixture was stirred for 16 h and then acidified using 1 N HCl. Product 74 (12.3 mg, 73%) was obtained after RP HPLC purification and lyophilization.

Example 9: Getting connection 78

The connection 76

To a solution of compound 75 (123 mg) in dry DHM (1 ml) at 0°in an inert atmosphere was added dropwise a 1 M solution of DIBAL (1.6 ml). The reaction mixture was stirred at 0°C for 2 h, then was allowed to warm to 10°With, then re-cooled to 0°C. Methanol (0,22 ml) was added dropwise followed by the addition of saturated solution of ammonium chloride (0,44 ml). Added DHM (20 ml) and the reaction is ionic mixture is vigorously stirred at room temperature for 30 minutes Filtration followed by concentration in vacuum gave compound 76 (73 mg, 65%).

Getting connection 77

To a solution of compound 76 (3 mg) in acetonitrile (0.6 ml) was added periodinane Tessa Martin (3.1 mg). The reaction mixture was stirred at room temperature for 1 h, then diluted simple diethyl ether (2 ml). The resulting suspension was filtered through a PTFE syringe filter with a pore size of 0.25 μm and concentrated in vacuum to obtain crude compound 77 (4 mg).

The connection 78

To a solution of compound 77 (3 mg) in DHM (0.5 ml) at room temperature was added ethylcarboxylate (21 mg). The reaction mixture was stirred at room temperature for 16 h, then was concentrated in vacuum to dryness. Chromatographic purification gave compound 78 (1,48 mg, 44%).

Example 10: the connection 81

Getting connection 79

To a solution of compound 7b (10 mg) in dry DHM (0.5 ml) at 0°in an inert atmosphere was added dropwise a 1 M solution of DIBAL (of 0.085 ml). The reaction mixture was stirred at 0°C for 1.5 h, then was added dropwise methanol (0,012 ml) and then added the eat saturated solution of ammonium chloride (0,024 ml). Added DHM (5 ml) and the reaction mixture is vigorously stirred at room temperature for 20 minutes Filtration followed by concentration in vacuo gave the crude compound 79 (9 mg, 95%).

The connection 80

To a solution of compound 79 (5 mg) in THF (0.5 ml) was added sodium bicarbonate (3.6 mg) and peridinin Tessa Martin (7.2 mg). The reaction mixture was stirred at room temperature for 3 h, then concentrated in vacuo to obtain the crude compound 80.

The connection 81

To a solution of compound 80 (4.8 mg) in ethanol (0.5 ml) at room temperature was added hydroxylamine hydrochloride (4 mg) and sodium acetate (6 mg). The reaction mixture was stirred at 40°C for 1.5 h, then concentrated to dryness. The residue was dissolved in DHM (0.2 ml) and treated TFU (0.2 ml) and left at room temperature for 10 minutes Concentration in vacuum to dryness, followed by chromatographic purification gave compound 81 (2,04 mg).

Example 11: the connection 87

The connection 84

To a solution of compound 28 (335 mg) in THF (10 ml) at 0°in an inert atmosphere portions was added sodium hydride (65% dispersion in mineral is cut oil; 144 mg). The reaction mixture was stirred at 0°C for 30 min, then treated with methyl iodide (0,405 ml). The reaction mixture was brought to room temperature and was stirred at room temperature for 3 hours, Water treatment, followed by chromatographic purification gave compound 84 (254 mg, 72%).

Getting connection 85

Compound 84 (189 mg) was treated with saturated HCl in methanol (5 ml). The reaction mixture was left at room temperature for 2 h, then was concentrated in vacuum to dryness to obtain compound 85 (145 mg).

Getting connection 86

To a solution of compound 85 (145 mg) in DMF (3 ml) at room temperature was added (S)-N-Boc-tert-leucine (483 mg), NMM (0,230 ml), HOAt (95 mg) and SMS (884 mg). The reaction mixture was shaken at room temperature for 16 hours, Water treatment, followed by purification gave the intermediate BOC compound (249 mg, 93%). Intermediate BOC compound (60 mg) was dissolved in methanol (1 ml) and was treated with saturated HCl in methanol (3 ml) and left at room temperature for 30 minutes Concentration in vacuo gave compound 86 (49 mg).

Getting connection 87

To a solution of compound 86 (49 mg) in DMF (of 0.44 ml) at room temperature was added (S)-N-Boc-nefenilase is n (94 mg), NMM (34 μl), HOAt (21 mg) and SMS (130 mg). The reaction mixture was shaken at room temperature for 16 hours, Water treatment, followed by chromatographic purification gave the intermediate BOC compound (41 mg, 47%). Intermediate BOC compound (5.5 mg) was dissolved in DHM (1 ml) and treated TFU (1 ml). The reaction mixture was left at room temperature for 30 min, then concentrated in vacuum to dryness. The residue was dissolved in saturated HCl in methanol (1 ml) and left at room temperature, and then concentrated in vacuum to obtain compound 87 (4,39 mg, 89%).

Example 12: the connection 91

The connection 88

To a solution of compound 28 (344 mg) in 0.5 M under Hanning in DHM (8 ml) at 0°in an inert atmosphere was added dropwise chloride methanesulfonyl (0,207 ml). The reaction mixture was stirred at 0°C for 1.5 h, and then subjected to water treatment, followed by chromatographic purification to obtain intermediate nelfinavir (444 mg). Intermediate mesilate was dissolved in DMSO (2 ml) and treated with sodium azide (258 mg). The reaction mixture was heated at 40°C for 6 h Water treatment gave compound 88 (306 mg, 82%).

The connection 89

A solution of 88 (140 mg) is astoral in DHM (1 ml) and treated TFU (1 ml). The reaction mixture was left at room temperature for 30 min, then concentrated in vacuum to dryness. The residue was dissolved in saturated HCl in methanol (1 ml) and left at room temperature, and then concentrated in vacuum to obtain compound 89 (109 mg).

The connection 90

(90)

To a solution of compound 89 (109 mg) in DMF (2 ml) at room temperature was added (S)-N-Boc-tert-leucine (347 mg), NMM (0,165 ml), HOAt (68 mg) and SMS (635 mg). The reaction mixture was stirred at room temperature for 16 hours, Water treatment, followed by chromatographic purification gave the intermediate BOC compound (173 mg, 87%). Intermediate BOC compound (51 mg) was dissolved in methanol (1 ml) and was treated with saturated HCl in methanol (3 ml) and left at room temperature for 30 minutes Concentration in vacuo gave compound 90 (43 mg).

The connection 91

To a solution of compound 90 (42 mg) in DMF (0,37 ml) at room temperature was added (S)-N-Boc-neopentylene (79 mg), NMM (28 μl), HOAt (17 mg) and SMS (108 mg). The reaction mixture was shaken at room temperature for 16 hours, Water treatment, followed by chromatographic purification gave the intermediate BOC compound (88 mg). Intermediate BOC compound (88 mg) was dissolved in saturated HCl (5 ml)and left at room temperature for 30 min, and then was concentrated in vacuum to obtain compound 91 (70 mg, 89%).

Example 13: a General procedure for obtaining C-terminal acidic compounds:

R2= Me or Et

R1= see examples below

To a solution of the corresponding complex methyl or ethyl ester (e.g., compound 7b) in a suitable mixture of methanol and tetrahydrofuran at room temperature was added aqueous 1 M solution of lithium hydroxide (10-50 equivalents). The reaction mixture was stirred or shaken, or kept at room temperature until, until was satisfactory hydrolysis of ester. Conventional treatment followed by chromatographic purification gave the desired C-terminal acidic compound (e.g., compound 82).

Example 14: the connection is ER-807974

The connection is ER-807641

To a stirred solution of N-Boc-N-Me-L-valine (200 g, 0.86 mol), N,O-dimethylhydroxylamine (92,8 g, 0.95 mol, 1.1 equivalents) and DIEA (316,3 ml, 1.82 mol, 2.1 equivalents) in CH3CN (2 l) at 0°With portions was added HBTU (360,7 g, 0.95 mol, 1.1 equivalent). The solution was stirred at 0°C for another 15 min and then for 1 h at 25°C. the Reaction control is whether TLC (heptane/EtOAc 1:1) and considered complete, when not observed, the connection 46. The solution was concentrated by rotary evaporator and then diluted with TBME (1 l). The organic solution was washed with HCl (1N, 500 ml), water (250 ml), NaHCO3(saturated, 250 ml) and with brine (250 ml). The organic solution was dried over MgSO4(˜120 g). The solution was filtered through a layer of silica gel (˜200 g) and concentrated. The crude amide ER-807641 used without any further purification.

The connection is ER-808993

To a stirred solution of amide ER-807641 (207 g, 755 mmol, 1 equivalent) in dry THF (2070 ml) at -78°solution was added LiAlH4(of 1.0 M/THF, 754 ml, 755 mmol, 1.0 equivalent). The solution was stirred at -78°C for 1 h the Reaction was suppressed at -78°by adding the reaction solution to a suspension of Na2SO4·10H2O (243 g) in TBME (1.5 l). The suspension was allowed to warm up to ˜15°and then filtered through a Celite pad. The filtrate was concentrated and the raw aldehyde ER-808993 was obtained as a transparent oil and used without further purification: 157,9 g (97%).

The connection is ER-808995-01

Part a:

To a stirred solution of aldehyde ER-808993 (138 g, 641 mmol, 1 equivalent) in dry THF (1.4 l) at 25°With added Ph3P=CMeCO2Et (256 g, 705,1 mmol, 1.1 equival the NTA). The solution was stirred at room temperature for 18 hours After this time the reaction was not completed. The solution was heated to boiling under reflux for 5 h, after which TLC showed no remaining aldehyde. The solution was cooled to room temperature and was added heptane (1.5 l). Observed precipitation byproduct Ph3P=O. the Mixture was filtered through a plug of silica gel (200 g). The filtrate was concentrated to a minimum volume (˜50 ml) and the residue was dissolved in EtOAc (800 ml).

Part b:

To a stirred solution of the crude ER-808994 in EtOAc (800 ml) was added MSA (80 ml). The mixture was stirred at room temperature for 45 min (to complete according to TLC). MSA salt complex aminoether were extracted from the organic solution with water (2×300 ml). The aqueous layer was neutralized to pH 7-8 with saturated NaHCO3(300 ml). The resulting solution was extracted with EtOAc (2×400 ml), washed with brine (300 ml), dried over MgSO4and filtered. The EtOAc solution free aminoether was barbotirovany HCl (gas) and salt HCl ER-808995 besieged and collected by filtration in an atmosphere of N2.

The connection is ER-803921-01

To a stirred solution of ER-808995 (61,2 g, 259,6 mmol, 1 equivalent), N-Boc-tBu-Gly-OH (90,1 g, 389,4 mmol, 1.5 equivalent) and DIEA (158 ml, 906,6 mmol, 3.5 equivalents) in dry DHM (612 ml) at 25° With added HBTU (a 147.7 g, 389,4 mmol, 1.5 equivalent). The solution was stirred at room temperature for 4 hours After the concentration of the solid residue suspended in TMBE (250 ml). The mixture was filtered through a layer of silica gel (˜120 g) and the filtrate was washed with a solution of aqueous HCl (1N, 200 ml), water (200 ml) and NaHCO3(saturated, 200 ml). The organic layer was dried over MgSO4, filtered and concentrated. Complex N-Boc-aminoethyl ER-908996 was allocated in the form of oil. Specified intermediate compound was re-dissolved in EtOAc (120 ml) and was added to the MSA (75 ml). The solution was stirred at room temperature for 1 h, and at this time, the reaction was considered complete according to TLC. Salt MSA complex aminoether was extracted with water (2×250 ml), followed by neutralization with NaOH solution (approximately 50%, 300 ml) to pH ˜8-9. The free amine was extracted with TBME (2×30 ml). The combined organic solution was washed with water (200 ml) and with brine (200 ml). After drying over MgSO4and filtering HCl (g) was barbotirovany to obtain hydrochloride ER-803921 in the form of a white solid collected by filtration at approximately 5°C.

The connection is ER-808998

To a stirred suspension of D-pipecolinic acid (100.0 g, 0.77 mol, 1 equivalent) and Pd(OH)2(20 wt.% Pd, 10 g) in a mixture of MeOH/acetone (2:1 V/V, 1.5 l), for example, the Ali hydrogenation (H 260 psi) for 24 hours the Reaction was controlled by TLC (ethanol) and was considered complete when the observed D-pipecolinic acid. The mixture was filtered through a layer of Celite (˜50 g). Transparent filtrate was concentrated to approximately 100 ml and added TBME (50 ml). ER-808998 was filtered as a white crystalline solid with a yield of 88%.

The connection is ER-807961

To a stirred solution of the dipeptide ER-803921 (5.0 g, a 16.8 mmol. 1 equivalent), N-iPr-pipecolinic acid ER-808998 (3.7 g, to 21.8 mmol, 1.3 equivalent) and HBTU (8,3 g and 21.8 mmol, equivalent to 1,3) in 50 ml DHM dropwise added DIEA (7.3 ml, a 41.9 mmol, 2.5 equivalents) at 25°C. the Mixture was stirred for 18 h (overnight), and at this time, the reaction was considered complete according to TLC (heptane/EtOAc 1:1). The mixture was concentrated in vacuo and added TBME (50 ml). The residual thick oil was extracted from the ether solution by filtration through a Celite pad. The filtrate is washed with aqueous HCl (1M, 3×25 ml). The combined aqueous phase was neutralized NH4OH to pH 8-9 in the presence of EtOAc (25 ml). The aqueous layer was separated and held back extraction of TME (25 ml). The combined organic phase was washed with brine and dried over MgSO4, filtered and concentrated to obtain a complex ester of tripeptides ER-807961 at exit 93%.

Getting with the unity ER-807974

To a stirred solution of ester ER-807961 (5.0 g, a 16.8 mmol) in 5:1 THF/H2O (50 ml) was added LiOH (3.50 g, is 83.8 mmol) and the mixture was stirred at room temperature for 20 hours the Reaction was controlled by TLC (ethanol) and was considered complete when ER-807961 was not observed. The suspension was acidified H2SO4(˜50 ml) to pH 7. The mixture was extracted with EtOAc (3×25 ml). The combined organic solution was washed with brine (20 ml), dried over MgSO4, filtered and concentrated. The residue was ground into powder with TWO: received 1.8 g (83%) of thick oil free Foundation ER-807974.

Example 15: the connection is ER-808367

Getting connection 2Z

To a suspension of D-pipecolinic acid 1Z (750 mg, of 5.81 mmol) in Meon (23,2 ml) and 2-butanone (to 11.6 ml) was added Pd(OH)2(175 mg). Filed gaseous N2(balloon pressure) and the reaction mixture was stirred in an atmosphere of H2throughout the night. The reaction solution is then filtered through a layer of celite and concentrated to obtain the crude white solid. The crude product was subjected to flash chromatography (SiO2), elwira 100% EtOH. Received connection 2Z (721 mg, white solid) as a mixture of diastereoisomers at exit 67%.

Obtaining compounds 3Z and 4Z

To a solution 2Z (650 mg, 3,51 mmol) in DMF (3.8 ml) was added To a2CO3(728 mg, at 5.27 mmol) and para-nitrobenzylamine (1.1 g, at 5.27 mmol). The reaction mixture was stirred over night. The reaction solution was diluted with water and was extracted several times simple diethyl ether. Extracts simple ether were combined, washed with water and saline solution. The solution was dried over MgSO4, filtered and concentrated in vacuum. The crude mixture of diastereomers was then divided by flash chromatography, elwira 8% EtOAc in hexano for each diastereoisomer in the form of a pale yellow oil. Connection 3Z (360 mg) was obtained from 32% yield, with Rf= 0,590 (SiO2) using 30% EtOAc in hexano. Connection 4Z (652 mg) was obtained from 58% yield, with Rf= 0,482 (SiO2) using 30% EtOAc in hexano.

The connection is ER-809439

To a suspension of compound 3Z (320 mg, 1.0 mmol) in Meon (10 ml) was added Pd(OH)2(50 mg). Filed gaseous N2(balloon pressure) and the reaction mixture was stirred in an atmosphere of H2within 3 hours the Reaction solution was then filtered through a layer of celite and concentrated to obtain compound ER-809439 (185 mg) as a white solid in quantitative yield. Connect the out ER-809439, Rf= (SiO2, 0,292, 100% EtOH).

The connection is ER-809447

Used a procedure similar to that used to obtain compounds ER-809439. Connection ER-809447, Rf= (SiO2, 0,292, 100% EtOH).

The connection is ER-808357

United connection 49 (9.6 mg, 0,031 mmol), N-Deut-butylpiperazine ER-809439 (5.2 mg, 0,028 mmol), HBTU (12.9 mg, 0,034 mmol). Was added DMF (0,28 ml) followed by addition of DIEA (14.9 ml, 0,084 mmol). The solution was stirred at room temperature under nitrogen atmosphere for 20 hours, the Solution was purified directly by RP HPLC with obtaining salt TFU connection ER-808357 (13,6 mg, 82%).

The connection is ER-808367

Salt TFU connection ER-808357 (10.4 mg, 0.018 mmol) was dissolved in 1:2 H2O/EtOH (0,072 ml/0,144 ml) at room temperature. Added LiOH (7.5 g, 0.18 mmol). The suspension was stirred at room temperature for 19 hours, the Solution was purified directly by RP HPLC with obtaining salt TFU connection ER-808367 (10.1 mg, quantitative).

Example 16: the connection is ER-808368

The connection is ER-808358

Used a procedure similar to that used to obtain compounds ER-808357.

Getting connection ER808368

Used a procedure similar to that used to obtain compounds ER-808367.

Example 17: the connection is ER-808662

Getting connection 5Z

To a suspension of D-pipecolinic acid 1Z (1,00 g, 7,74 mmol) in Meon (31 ml) and 3-methyl-2-butanone (15,5 ml) was added Et3N (1.1 ml) and Pd(OH)2(250 mg). Filed gaseous N2(balloon pressure) and the reaction mixture was stirred in an atmosphere of H2throughout the night. The reaction solution is then filtered through a layer of celite and concentrated to obtain the crude white solid. The crude product was subjected to flash chromatography (SiO2), elwira 100% EtOH. Received connection 5Z (377,9 mg, white solid) as a single diastereoisomer with the release of 24.5%. Rf=(SiO2, 0,280, 100% EtOH).

The connection is ER-808656

Used a procedure similar to that used to obtain compounds ER-808357.

The connection is ER-808662

Used a procedure similar to that used to obtain compounds ER-808367.

Connect with ER-809638 on ER-809650 made in accordance with procedures is to obtain ER-808368R - ER-808662 with one change: used N-BOC-L-valine instead of N-BOC-N-methyl-L-valine (46). If necessary, used compounds ER-808998, ER-809439 and 5Z.

Example 18: the connection is ER-808824

Getting connection 6Z

United connection 48 (325,5 mg, 1.38 mmol), L-N-BOC-valine (300,0 mg, 1.38 mmol), HBTU (628,3 mg of 1.66 mmol). Added CH2Cl2(7 ml) followed by addition of DIEA (to 0.72 ml, 4.14 mmol). The solution was stirred at room temperature under nitrogen atmosphere for 1 h the Solution was concentrated in vacuum and the crude product was purified flash chromatography (SiO2), elwira 4% EtOAc in hexano. Received connection 6Z (476,8 mg) as a colourless oil at the exit to 86.7%.

Getting connection 7Z

Connection 6Z (450 mg, 1.13 mmol) was dissolved directly in 4N HCl/dioxane (2.8 ml). The reaction mixture was stirred overnight and then concentrated in vacuum to obtain compound 7Z (374,8 mg) as a white solid in quantitative yield.

The connection is ER-808815

Used a procedure similar to that used to obtain compounds ER-808357.

The connection is ER-808824

what the objects of study were the procedure, similar to the procedure used to obtain compounds ER-808367.

Example 19: Biological tests:

In some embodiments of compounds of the present invention were tested for activity in vitro and in vivo. Methods of screening consisted of a standard analyses of inhibiting the growth of cells in vitro using a set of lines cancerous human cells, analysis of the reversibility of mitotic block U937 (access number in ADS CRL 1593), analysis of stability in mouse serum, MDR analysis and analysis of cytotoxicity. In some other embodiments of compounds of the invention were evaluated in the analyses of inhibiting the growth of tumor xenografts in vivo.

Activity in vitro was determined in the analysis of inhibition of cell growth of MDA-MB-435 and active compounds (IC50<20 nm) was evaluated in tests of reversibility, MDR and stability in mouse serum. In addition, the active compounds were tested in the analysis of cytotoxicity IMR-90 and additional analyses of the inhibition of cell growth in the set of lines cancerous human cells and solid and solid tumors.

Analysis of inhibition of cell growth: Cultured human cancer cells (including cancer of the breast, prostate, colon, lung, leukemia, lymphoma, and others) were sown in 96-well plates and were grown at the village is a constant state of alert presence of the test compounds for 72 or 96 hours Line of human cells used in this assay inhibition of cell growth include, but are not limited to, the following cell line solid tumors and cell line solid tumors: cancer cells, colon cancer DLD-1 (the access number in ADS CCL-221), cancer cells of the prostate gland DU 145 (access number in ADS HTB-81), non-small cell lung cancer N, cells of colon cancer HCT-15 (access number in ADS CCL-225), cells erythroleukemia HEL cells, promyelocytic leukemia HL-60 (the number of access to the CCL ADS-240), leukemia K (access number in ADS CCL-243), melanoma LOX, breast cancer cells MDA-MB-435 cells, lymphoma U937 (access number in ADS CRL 1593), pancreatic cancer PANC-1 (the access number in ADS CRL-1469), colon cancer HCC-2998 (store cancerous tumors/cell lines of the National cancer Institute-Frederick DCTD), colon cancer HCT 116 (access number in ADS CCL-247), colon cancer HT-29 (the access number in ADS NTV-38), colon cancer LoVo (access number in ADS CCL-229), colon cancer SW-480 (access number in ADS CCL-228), colon cancer SW-620 (the access number in ADS CCL-227) and colon cancer COLO-205 (access number in ADS CCL-222). For single-layer cultures growth was estimated using modifications (Amin et al., Cancer Res., 47: 6040-6045, 1987) analysis of micro cultures on the basis of methylene blue (Finlay et al., Anal. Biochem., 139: 272-277, 1984). Values spectralphotometer ability at 620 and 405 nm was measured on the apparatus for reading tablets Titertek Multiscan MCC/340 and the value of absorbance at 405 nm is subtracted from the absorbance values at 620 nm. For suspension cultures growth was assessed using analysis based on the bromide 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (Mosmann et al., J. Immunol. Methods 65: 55 to 63, 1983), modified as follows. After 4 days of incubation with the test compound subjected to sterilizing filtration bromide 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium was added to each well (final concentration, 0.5 mg/ml) and the plates were incubated at 37°C for 4 h and Then to each well was added the acid-isopropanol (0,1 N HCl in isopropanol, 150 ml) and the resulting crystals formazan was dissolved by gentle mixing. The magnitude of absorbance at 540 nm was measured on the apparatus for reading tablets Titertek Multiscan MCC/340.

Analysis of the reversibility of mitotic block, performed as described(see U.S. patent No. 6214865 issued Littelfield et al., 4/10/01; which is fully incorporated in the description by reference).

Briefly, U937 (access number in ADS CRP 1593) was subjected to various concentrations of compounds within 12 hours of the Compounds were washed and the cells allowed to recover for an additional 10 hours the Cells were collected by centrifugation and fixed overnight in 70% ethanol. Cells were washed in phosphate-buffered solution (PBS), incubated with ribonuclease (RNase) and were stained with CodeDomProvider. Dinoflagellate flow cytometry was carried out on the apparatus Becton Dickinson FACScan; collection and analysis of data was performed using software Becton Dickinson CELLQuest. Doublet effects were eliminated from the analyses corresponding transmission on the primary chart FL2-W/FL2-A prior analysis of the histogram of DNA content (measured in FL2-A).

The definition of activity in vitro using the MDR analysis.This analysis represents the above-described modification of the standard tests of inhibition of cell growth. Used two lines of cultured cancer cells: MDR-negative cells MES-SA sarcoma of the uterus person (the access number in ADS CRL-1976) and MDR-positive cells in MES-SA/Dx5 sarcoma of the uterus person (the access number in ADS CRL-1977). Cells were planted in 96-well titration microplates at a density of 7500 cells/cell. Cells were incubated in the presence and in the absence of test compounds for 96 h cell Growth was assessed using modifications (Amin et al., Cancer Res., 47: 6040-6045, 1987) microcultural analysis based on methylene blue (Finlay et al., Anal. Biochem., 139: 272-277, 1984). The magnitude of absorbance at 620 and 405 nm was measured on the apparatus for reading tablets Titertek Multiscan MCC/340 and the value of absorbance at 405 nm is subtracted from the values of the spectral POG is ostalnoe ability at 620 nm. Calculate the ratio of the concentration of the compound inhibiting cell growth by 50%, and used to assess the sensitivity of the compounds to MDR (resistant to multiple drugs, or facing the flow of drugs mediated by P-glycoprotein). In some cases, used another pair of cell lines: MDR-negative cells of mouse leukemia P388/S and MDR-positive cells of mouse leukemia P388/VMDRC.04. Cells were planted in 96-well tetrofosmin microplates at a density of 4000 cells/cell. Cells were incubated in the presence and in the absence of the test compounds for 72 h cell Growth was assessed using analysis based on the bromide 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (Mosmann et al., J. Immunol. Methods 65: 55 to 63, 1983), modified as follows. After 3 days of incubation with the test compounds subjected to sterilizing filtration bromide 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium was added to each well (final concentration 0.5 mg/ml) and the plates were incubated at 37°C for 4 h In each cell were then added to the acid-isopropanol (0,1 N HCl in isopropanol, 150 ml) and the resulting crystals formazan was dissolved by gentle mixing. The magnitude of absorbance at 540 nm was measured on the apparatus for reading tablets Titertek Multiscan MCC/40.

The resistance to decomposition of the esterase was determined in the analysis of stability in mouse serum. The enzymatic activity of mouse serum can lead to inactivation of the compounds in vivo despite promising activity in vitro. The above-described modification of the standard tests of inhibition of cell growth was used to determine the stability of the test compounds to the decomposition of the esterase. Used cell line carcinoma human breast MDA-MB-435 or cell line carcinoma of the prostate man DU 145. Cells were planted in 96-well tetrofosmin microplates at a density of 7500 cells/cell. Before adding test compounds to the cells in the analysis of inhibition of cell growth test compounds were incubated in 100% mouse serum or normal growth medium for 6 h at 37°C. After that, the test compounds were added in 96-well tetrofosmin microplates containing cells. Cells were incubated in the presence and in the absence of test compounds for 96 h cell Growth was assessed using modifications (Amin et al., Cancer Res., 47: 6040-6045, 1987) analysis of micro cultures on the basis of methylene blue (Finlay et al., Anal. Biochem., 139:272-277, 1984). The magnitude of absorbance at 620 and 405 nm was measured on the apparatus for reading tablets Titrtek Multiscan MCC/340. Evaluated the ability of test compounds to inhibit cell growth after contact of the compounds with mouse serum esterases.

Analysis of cytotoxicity. To determine the toxicity of compounds with respect to the normal non-dividing cells used resting normal human fibroblasts IMR-90 (the access number in ADS CCL-186). Cells IMR-90 were sown in 96-well tetrapody microplate format and were grown to confluence (within 72 hours). After 72 hours of growth, cells were washed and the medium was replaced with normal medium containing 10% fetal bovine serum, a serum containing a low concentration of serum (0.1 per cent). Cells were brought to a standstill by incubation in growth medium containing 0.1% serum for 72 h Cells were incubated with test compounds for 24 h, the Levels of ATP in the cells was measured using a set of ViaLightHS (LumiTech Ltd). Cytotoxic compound carbonylcyanide used in the analysis as a positive control for cytotoxicity.

Determination of antitumor activity in mice in vivo.Studies of tumor xenografts in vivo studies were performed in mice with impaired immunity (hairless). Mice (female Nude mice Ncr) implanted subcutaneous xenografts of human tumors (including breast cancer MDA-MB-45, Tolstoy is Eski COLO-205, HCT-15, HCT-116, HCC-2998, HT-29, SW-620, DLD-1, LoVo, melanoma LOX, lung cancer N, pancreatic cancer PANC-1). After the xenografts reached the average size of 75-200 mm3or 400-600 mm3animals were weighed and randomly divided into groups of 8-10 on the first day of the introduction of the connection. Compounds were injected intravenously or intraperitoneally. Measurement of tumor mass and body held 2 times/week.

1. The compound having the structure (Ic)

and its pharmaceutically acceptable salts, esters, or salts of such esters;

where X2represents-C(=O);

R2represents hydrogen, C1-6alkyl, which is possibly substituted by a halogen atom, a C2-6quinil, C1-6alkyls6-10aryl, C3-6cycloalkyl,1-6alkyls3-6cycloalkyl or-C(=O)Rcwhere Rcindependently represents a C1-6alkyl or orDwhere RDrepresents a C1-6alkyl;

R3represents hydrogen;

R5, R6and R7independently represents hydrogen or C1-6alkyl, C3-6cycloalkyl,1-6alkyls6-10aryl, which may substituted by benzoyl, R is a-CH(R8a)C(R9a)=C(R10a)-, where R8arepresents a C1-6alkyl,

R9apredstavljaet a hydrogen

R10arepresents a C1-6alkyl,

or R represents-C(R8b)C(R9b)N(R10b)C(R11b)-,

where R8brepresents a C1-6alkyl,

R9brepresents hydrogen,

R10brepresents a C1-6alkyl,

R11brepresents hydrogen,

or R10band R11btogether with the atoms to which they are attached, form a saturated4-6a heterocycle containing up to 2 heteroatoms selected from nitrogen, oxygen, or sulfur;

Q represents ORQ'or NRQ'RQwhere each of RQ'and RQindependently represents hydrogen, C1-6alkyl, which is substituted by-C(O)OC1-6alkyl group, -S(O)OS3-6cycloalkyl group, -COOH, C1-6alkenylphenol group, a hydroxy-group, cyano, C1-6alkylthiol; C2-6quinil,1-6alkyls6-10aryl, C3-8cycloalkyl, C1-6alkyls3-6cycloalkyl,6-10aryl, C1-6alkylglycerol, heteroaryl where heteroaryl represents a 5-6 membered ring that contains up to 2 heteroatoms selected from nitrogen, oxygen, or sulfur, or

RQ'and RQtaken together with the nitrogen atom to which they are attached, form a saturated4-6a heterocycle, the soda is containing up to 2 heteroatoms, selected from nitrogen, oxygen or sulfur, and which may substituted bentilee group, benzhydryl group1-6alkyl group, a hydroxy-group, With1-6alkoxygroup, C1-6alkyl group, amino, mono - or dialkylamino group, the acyl carbamoyl,1-6allylcarbamate, carboxypropyl, a halogen atom, a C6-10aryl group, where

each of G, J, L and M independently represents CHRiv, CRivRv, O, S, NRivRvwhere each occurring Rivand Rvindependently absent or represents hydrogen or C1-6alkyl, C6-10aryl, or

Rivand Rvtaken together form an alicyclic group containing 3-6 atoms

each N and G, G and J, J and L, L, and m, M and CR3and CR3and N independently associated single or a double bond, to the extent permitted by valence, and each g, j, l and m independently equal 0, 1, 2, 3, 4, 5 or 6, where the sum of g, j, l and m is 3-6.

2. The compound according to claim 1, where R is a fragment-CH(R8a)C(R9a)=C(R10a)- and the compound has the following structure:

where each R8a, R9aand R10ahave the meanings indicated in claim 1; and where R7can form C1-6alkyl, C3-6cycloalkyl,1-6alkyls6-10aryl.

3. The connection p is 2, has the following stereochemistry:

4. The compound according to claim 2, where each R5and R9arepresent hydrogen, each of R6, R7, R8aand R10aindependently represents a C1-6alkyl or C3-6cycloalkyl.

5. The compound according to claim 1, where Q is an optionally substituted, nitrogen-containing cyclic portion; and the compound has the following structure:

where each occurring a, b, D and E independently represents CHRi, CRiRii, O, S, NRiRiiwhere each occurring Riand Riiindependently absent or represents hydrogen, -C(=O)Riiior benzyl group, benzhydryl group, C1-6alkyl group, a C6-10aryl group; or where any two adjacent groups Ri, Riior Riiitaken together, form With the6-10aryl part, where each occurring Riiirepresents a C1-6alkyl group, a C6-10aryl part;

each N and A, a and b, and D, D and E and E and N are independently associated with single or double bond, as valency; and each a, b, d and e are independently equal 0, 1, 2, 3, 4, 5, 6 or 7, where the sum of a, b, d and e is equal to 4-7.

6. The compound according to claim 5, having the following stereochemistry:

7. The compound according to claim 5, where each R5and R9arepresents hydrogen, and each R6, R7, R8aand R10Arepresents independently C1-6alkyl.

8. The compound according to claim 3, where R6represents tert-butyl; each of R7and R10arepresents methyl and R8arepresents isopropyl.

9. The compound according to claim 5, where each a, b, d and e is 1; each b and D represents CH2; and each of a and E independently represents CH2, CHRi, CHORi, CHNRiRiiCH(C=O)RiCH(C=O)ORior CH(C=O)NRiRiiwhere each occurring Riand Riiindependently represents hydrogen, C1-6alkyl.

10. The compound according to claim 1, where R represents

-C(R8b)C(R9b)N(R10b)C(R11b)-; and the compound has the following structure:

where each R9band R11brepresent hydrogen, and

R8band R10brepresent1-6alkyl;

each NR7and CR8b, CR8band CR9b, CR9band CR10b, CR10band CR11bindependently associated with single or double bond, as valency.

11. The connection of claim 10, having the following stereochemistry:

12. The connection p is paragraph 10, where each R5, R9band R11brepresents hydrogen, and each R6, R7, R8band R10brepresents independently1-6alkyl.

13. The connection section 12, where R6represents tert-butyl, R7represents methyl, R8brepresents isopropyl and R10brepresents methyl.

14. The connection of claim 10, where R10band R11btaken together, form a saturated4-6a heterocycle; and the compound has the following structure:

where p=1 or 2; q=0.

15. The connection 14 having the following stereochemistry:

16. The connection 14, where each of R5and R9brepresents hydrogen, and each R6, R7and R8brepresents independently1-6alkyl.

17. Connection P16, where R6represents tert-butyl, R7represents methyl, R8brepresents isopropyl.

18. The connection 14, where p=1 and q=0.

19. The compound according to claim 1, where j=0; each of 1 and m is 1; R3represents hydrogen; G is a CRG1; M represents CRM1RM2so that part

has the following structure:

the de g=1, 2, 3, or 4;

L represents CRL1RL2, S, O or NRL3where each occurring RL1, RL2and RL3represents independently hydrogen, C1-6alkyl or C6-10aryl;

each found RG1, RM1and RM2represents independently hydrogen, C1-6alkyl or C6-10aryl; and

where any two adjacent groups RL1, RL2, RL3, RG1RM1or RM2taken together, form an alicyclic part containing 3-6 atoms.

20. The connection according to claim 19, where R2represents hydrogen, lower alkyl; RG1represents hydrogen, lower alkyl or phenyl; and each of RM1and RM2represents independently hydrogen, lower alkyl, phenyl.

21. The compound according to claim 1, where each G, J and M represents CH2; each of j, l and m are equal to 1; so that the part

has the following structure:

where each RL1and RL2represents independently hydrogen, C1-6alkyl or C6-10aryl.

22. Connection item 21, where R2represents hydrogen, lower alkyl or acyl; each RL1and RL2represents independently hydrogen, C1-6alkyl or C6-10aryl.

23. Connection item 21, where R pre which represents a-CH(R 8a)C(R9a)=C(R10a)-; R2represents methyl, R5represents hydrogen, R6represents tert-butyl, R7represents methyl, R8arepresents isopropyl and Q represents ORQ'or NRQ'RQwhere each RQ'and RQindependently represent hydrogen, C1-6alkyl, which may substituted by cyano, C1-6alkylthiol; C6-10aryl, heteroaryl where heteroaryl is a 5-6-membered ring which contains up to 2 heteroatoms selected from nitrogen, oxygen, or sulfur, or

RQ'and RQtaken together with the nitrogen atom to which they are attached, form a saturated4-6a heterocycle containing up to 2 heteroatoms selected from nitrogen, oxygen or sulfur.

24. The compound of claim 10 or 15, where Q is a ORQ'or NRQ'RQwhere each RQ'and RQindependently represents hydrogen, C1-6alkyl, which may substituted by cyano, C1-6alkylthiol; C1-6alkyls6-10aryl, C6-10aryl, C1-6alkylglycerol, heteroaryl where heteroaryl is a 5-6-membered ring which contains up to 2 heteroatoms selected from nitrogen, oxygen, or sulfur, or

RQ'and RQtaken together with the nitrogen atom, to the which they are attached, form a saturated4-6a heterocycle containing up to 2 heteroatoms selected from nitrogen, oxygen or sulfur.

25. The compound according to claim 1, where X2represents C(=O); each g, j, l and m is equal to 1, each occurring G, J, L and M independently represents CHRiv, CRivRvwhere each Rivand Rvindependently represents hydrogen or C1-6alkyl, C6-10aryl;

R2represents hydrogen or C1-6alkyl, possibly substituted with halogen, C1-6alkyls6-10aryl;

R3represents hydrogen;

R5, R6and R7each independently represents hydrogen or C1-6alkyl or C3-6cycloalkyl;

R represents a-CH(R8a)C(R9a)=C(R10a)-, where R8arepresents a C1-6alkyl;

R9arepresents hydrogen, and

R10arepresents a C1-6alkyl; and

Q represents ORQ'where RQ'represents hydrogen or C1-6alkyl.

26. Connection A.25, where R2represents C1-6alkyl, C3-6cycloalkyl.

27. Connection A.25, where R3and R9aeach represents hydrogen and R6, R7, R8a, R10aeach independently represents a C1-6alkyl or C3-6cycloalkyl.

6represents tert-butyl, R7and R10aeach represents methyl and R8arepresents isopropyl.

29. Connection A.25, where R2represents hydrogen or C1-6alkyl, possibly substituted with halogen, C1-6alkyls6-10aryl; RL1and RL2each independently represents hydrogen, C1-6alkyl or C6-10aryl.

30. Connection A.25, where R2is methyl, R5is hydrogen, R6represents tert-butyl, R7is methyl, R8arepresents isopropyl and part of the

has the following structure:

where each RL1and RL2represents independently hydrogen or C1-6alkyl.

31. Connection A.25, where R8arepresents methyl, ethyl, propyl, isopropyl, or sec-butyl.

32. Connection A.25, where R5represents hydrogen.

33. Connection A.25, where R6represents tert-butyl or isopropyl.

34. Connection A.25, where R7represents hydrogen, methyl or ethyl.

35. Connection A.25, where R10arepresents methyl.

36. Connection A.25, where R2is methyl or isopropyl, R5is hydrogen, R6represents tert-butyl, R7presented AET methyl, R8arepresents isopropyl, and part of the

has the following structure:

R1vrepresents independently hydrogen or C1-6alkyl.

37. The compound and pharmaceutically acceptable salts him A.25 having the structure

or has the structure:

where Q represents HE or OEt;

or having the structure

or having the structure

or having the structure

or having the structure

or having the structure

or having the structure

38. Connection A.25 having the structure

and pharmaceutically acceptable salts.

39. Connection A.25 and pharmaceutically acceptable salts, its structural formula Ic is selected from the group consisting of

40. The compound according to claim 1 and pharmaceutically acceptable salts, its structural formula Ic is selected from the group consisting of

41. The compound having structural formula (Id)

where R1and R2independently represent hydrogen or lower alkyl;

each R3and R4represents independently methyl, ethyl, propyl, butyl, pentyl, tert-butyl, isopropyl, -CH(CH3)CH2CH3, - CH(CH3)CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)cyclobutyl, -CH(Et)2, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl;

R5is the Wallpaper hydrogen;

R6represents methyl, ethyl, propyl, butyl, pentyl, tert-butyl, isopropyl, -CH(CH3)CH2CH3, -CH2CH(CH3)2;

R7represents lower alkyl;

R represents a-CH(R8a)C(R9a)=C(R10a)-, where

R8arepresents lower alkyl;

R9arepresents hydrogen;

R10arepresents lower alkyl;

X2represents the C=O;

Q represents ORQ'where RQ'represents independently hydrogen

or lower alkyl,

or its pharmaceutically acceptable salt.

42. Connection paragraph 41 and pharmaceutically acceptable salts, its structural formula Id, selected from the group consisting of

43. The pharmaceutical composition inhibiting the growth of cancer cells, comprising an effective amount of a compound according to any one of claims 1 or 41, pharmaceutically acceptable carrier or diluent.

44. The pharmaceutical composition according to item 43, in which the compound is in amount effective to inhibit the growth of cancer cells in vitro.

45. The pharmaceutical composition according to item 43, where the compound is present in amount effective to cause regression of tumors in vivo.

46. The pharmaceutical composition according to item 43 intended for the treatment of cancer.

47. The pharmaceutical composition according to item 46, where the cancer is a solid tumor.

48. The pharmaceutical composition according to item 46, where cancer is not a solid tumor.

49. The pharmaceutical composition according to item 46, intended for the treatment of cancer of the prostate, breast, colon, bladder, cervix, skin, testes, kidney, ovarian, stomach, brain, liver, pagelog is offered by the cancer or esophagus, lymphoma, leukemia or multiple myeloma.

50. The pharmaceutical composition according to item 46, intended for the treatment of cancer of the prostate, esophagus, stomach, colon, pancreas or brain.

51. The pharmaceutical composition according PP-50, optionally containing an additional therapeutic agent intended for the treatment of glioblastoma, retinoblastoma, cancer of the rectum, leukemia, lymphoma, lung cancer, melanoma, multiple myeloma, nehodgkinski lymphoma and gastric cancer.

52. The compound according to any one of claims 1 to 48, where the connection is a

or

and its pharmaceutically acceptable salts.

53. The stent having a generally tubular structure, to prevent and reduce the frequency of restenosis, and the surface of the structure is covered (or is adapted to release otherwise) composition comprising a compound having the structure according to claim 1 or 41.

54. The stent having a generally tubular structure, for expanding the lumen of the conduit body, the surface structure is covered (or is adapted to release otherwise) composition comprising a compound having the structure according to claim 1 or 41.

55. The stent according to item 54, where the lumen of the channel of the body extends to the mouth is anemia obstruction of the bile ducts, gastrointestinal tract, esophagus, trachea/bronchi, urethra and/or vessels, preferably where the lumen of the conduit body is expanded to eliminate the obstruction of blood vessels.



 

Same patents:

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to method for production of tripeptides of general formula I: A-Pro-GlY-Pro-OX, wherein A is H, Bzl, t-Bu. Synthesis is carried out by liquid phase method by condensation of C-terminal proline derivatives of general formula H-Pro-OX1, wherein X1 is Bzl, t-Bu with protected dipeptide of general formula Y-Pro-Gly-OH, wherein Y is Z, Boc, and obtained protected tripeptide of general formula Y-Pro-Gly-Pro-X1 is treated with deprotecting reagents and optionally obtained product is acetylated and optionally hydrochlorides are obtained.

EFFECT: improved method for tripeptide production.

2 cl, 7 ex

The invention relates to new derivatives of acetic acid, hydrate, solvate and pharmaceutically acceptable salts, which can find application in the pharmaceutical industry

FIELD: biochemistry.

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

EFFECT: new synthetic intermediates for LHRH antagonists.

7 cl, 8 ex

FIELD: biotechnology, medicine, oncology.

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

EFFECT: valuable medicinal properties of peptide and pharmaceutical composition.

20 cl, 48 tbl

FIELD: synthesis of biologically active compounds.

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

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

36 cl, 121 ex

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

FIELD: medicine; pharmacology.

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

EFFECT: high haemostatic activity.

8 ex

FIELD: organic chemistry, biochemistry.

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

EFFECT: valuable biochemical property of compounds.

8 cl, 7 tbl

FIELD: medicine, biochemistry.

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

EFFECT: valuable medicinal properties of inhibitors.

6 cl, 2 tbl, 472 ex

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

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

The invention relates to medicine, namely to methods of producing biologically active substances that have immunoregulatory properties, and may find application in medicine, veterinary medicine and experimental biochemistry

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to compounds of general formula: , wherein R1 represents phenyl-С16-alkyl group or 1-naphthyl-С16-alkyl group; R2 biologically labile ether forming group in the form of pharmaceutically acceptable metal salt, which is selected from lithium, calcium, magnesium, and zinc slats; and also to a method for preparing above-defined compounds and to pharmaceutical composition containing salts according to this invention. These compounds are used in treatment cardiac diseases or hypertension, in improvement of gastrointestinal blood circulation, and in treatment and prevention of cardiac disturbances induced by adriamicyn and analogous antitumor agents.

EFFECT: increased assortment of pharmaceutically active compounds of benzazepin series.

15 cl, 2 tbl, 5 ex

Peptide compounds // 2281955

FIELD: chemistry of peptides, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): wherein R1 represents benzofuranyl substituted with halogen atom or styryl substituted with halogen atom; R2 represents substituted hydroxyl substituted with mercapto-group or substituted sulfonyl, or its pharmaceutically acceptable salts. Compound of the formula (I) and its pharmaceutically acceptable salts possess the strong inhibitory effect on production of nitrogen oxide (NO) and can be useful in prophylaxis and/or treatment of NO-mediated diseases in humans and animals.

EFFECT: valuable medicinal and biochemical properties of compounds.

The invention relates to a group of compounds of General formula (I) high degree of purification

The invention relates to a derivative of D-Proline General formula

< / BR>
or

< / BR>
where R is SH, benzyl or phenyl, optionally substituted by a hydroxy-group or a lower alkoxygroup, or a group of the formula

< / BR>
R1is hydrogen or halogen; X represents -(CH2)n-; -CH(R2)(CH2)n-; -CH2O(CH2)n-; CH2NH-; benzyl, -C(R2)=CH-; CH2CH (OH)- or thiazol-2,5-diyl; Y represents-S -; (CH2)n; -O-; -NH-; -N (R2)-; -CH=CH-; -NHC(O)NH-; -N(R2)C(O)N(R2)-; -N[CH2WITH6H3(OCH3)2]-; -N(CH2WITH6H5)-; -N(CH2WITH6H5)C(O)N(CH2WITH6H5)-; -N(alkoxyalkyl)-; -N(cyclooctylmethyl)-; 2,6-pyridyl; 2,5-furanyl; 2,5-thienyl; 1,2-cyclohexyl; 1,3-cyclohexyl; 1,4-cyclohexyl; 1,2-naphthyl; 1,4-naphthyl; 1,5-naphthyl; 1,6-naphthyl or diphenylene; 1,2-phenylene; 1,3-phenylene or 1,4-phenylene, where phenylenebis group optionally substituted by 1-4 substituents selected from the group comprising halogen, lower alkyl, lower alkoxygroup, the hydroxy-group, carboxypropyl, -COO-lower thiazolyl, 2-oxo[1,2,3,5] oxadiazolyl, 5-thioxo[1,2,4]oxadiazolyl and 5-tert-butylsulfonyl[1,2,4] oxadiazolyl; X' represents -(CH2)n-; (CH2)nCH(R2)-; -(CH2)nOCH2-; -NHCH2-; benzyl, -CH= C(R2)-; -CH(OH)CH2or thiazol-2,5-diyl; R2denotes lower alkyl, lower alkoxygroup or benzyl and n = 0-3, their pharmaceutically acceptable salts, mono - and diesters, except (R)-1-[(R)- and (R)-1-[(S)-3-mercapto-2-methylpropionyl] pyrrolidin-2-carboxylic acid; medicinal product with amyloidoses activity, and the method of obtaining these derivatives

The invention relates to new derivatives of dipeptides with pharmacological activity, and the way they are received, and may find application in medicine
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