Antiviral compounds

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I, such as below, or its pharmaceutically acceptable salts. What is described is a method for preparing them.

,

wherein: A independently from B means phenyl,

, or ,

and B independently from A means phenyl,

, or ,

and the values Z, Y, D, L1, L2, L3, Z1, Z2 are presented in the patent claim.

EFFECT: compounds are effective for hepatitis C virus (HCV) replication inhibition.

17 cl, 3 tbl, 8 dwg, 177 ex

 

This application claims priority from provisional patent application U.S. No. 61/169449 filed April 15, 2009, and provisional patent application U.S. No. 61/222591, filed July 2, 2009, the contents of which are fully incorporated into the present application by reference.

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to compounds effective in inhibiting replication of hepatitis C virus ("HCV"). The present invention also relates to compositions containing these compounds, and to methods of using these compounds for treatment of HCV infection.

BACKGROUND of INVENTION

HCV is a RNA virus belonging to the genus Hepacivirus of the family Flaviviridae. HCV contains virions that contain remotemachine RNA genome encoding all known virus-specific proteins in a single uninterrupted open reading frame. The open reading frame includes approximately 9500 nucleotides encoding one big polyprotein, consisting of about 3000 amino acids. Polyprotein includes protein core, membrane proteins E1 and E2, membrane-bound protein p7 and nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B.

HCV infection is associated with progressive liver disease, including cirrhosis and hepatocellular carcinoma. Chronic hepatitis C can is treated with peginterferon-Alfa in combination with ribavirin. Remain significant limitations in terms of effectiveness and acceptability of this tool, since many users suffer side effects, and excretion of the virus from the body is often inadequate. There is therefore a need for new drugs to treat HCV infection.

SUMMARY of INVENTION

The present invention includes compounds of formulas I, IA, IBand Icand their pharmaceutically acceptable salts. These compounds and salts are capable of inhibiting the replication of HCV, and therefore they can be used for treatment of HCV infection.

The present invention also includes compositions containing the compounds or salts of the present invention. The composition can also include other therapeutic agents, such as inhibitors of HCV helicase, inhibitors of HCV polymerase inhibitors, HCV protease inhibitors, HCV NS5A, CD81 inhibitors, inhibitors of cyclophilin or inhibitors of the site of penetration into the ribosome (IRES).

The present invention also includes methods of using compounds or salts according to the present invention for inhibiting replication of HCV. The methods include contacting cells infected with the HCV virus, with the compound or salt of the present invention, implementation, thus inhibiting replication of HCV virus in cells

In addition, the present invention includes methods of using compounds or salts of the present invention or compositions comprising such compounds or salts, for the treatment of HCV infection. The methods include introducing the compound or salt of the present invention or pharmaceutical compositions comprising such compound or salt, the needy in this patient, thus reducing the level of HCV virus in the blood or tissue of the patient.

The present invention also includes the use of compounds or salts of the present invention to obtain drugs for treatment of HCV infection.

In addition, the present invention includes methods of producing compounds or salts of the present invention.

Other features, objectives and advantages of the present invention evident from the detailed description presented below. However, it should be understood that the detailed description, although it is preferred variants of the embodiment of the present invention, are presented for illustrative purposes only and not for limitation. Various changes and modifications without leaving the scope of the present invention should be obvious to experts in this field on the basis of a detailed description of the invention.

DETAILED description of the INVENTION

The present image is eenie includes connection, having the formula I, and their pharmaceutically acceptable salt,

,

where:

A and B each independently represents a C3-C10carbocycle or 3-10-membered heterocycle, and are each independently optionally substituted by one or more substituents RA;

D represents C3-C10carbocycle or 3-10-membered heterocycle, and optionally substituted by one or more substituents RA; or D is a RD;

X represents C(RCor N;

L1and L2each independently selected from the communication; or (C1-C6alkylene, C2-C6Alcanena or C2-C6akinlana, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano;

L3is a bond or-LS-K-LS'-, where K is selected from-O-, -S-, -N(RB)-, -C(O)-, -S(O)2-, -S(O)-, -OS(O)-, -OS(O)2-, -S(O)2O-, -S(O)O-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(RB)-, -N(RB)C(O)-, -N(RB)C(O)O-, -OC(O)N(RB)-, -N(RB)S(O)-, -N(RB)S(O)2-, -S(O)N(RB)-, -S(O)2N(RB)-, -C(O)N(RB)C(O)-, -N(RB)C(O)N(RB')-, -N(RB)SO2N(RB')- the Li-N(R B)S(O)N(RB')-;

Y is selected from-T'-C(R1R2)N(R5)-T-RD, -T'-C(R3R4)C(R6R7)-T-RD, -LK-T-RDor-LK-E;

R1and R2each independently represent Rcand R5is an RB; or R1is an Rcand R2and R5taken together with the atoms to which they are attached, form a 3-8-membered heterocyclic ring, which is optionally substituted by one or more substituents RA;

R3, R4, R6and R7each independently represent Rc; or R3and R6each independently represent Rcand R4and R7taken together with the atoms to which they are attached, form a 3-8-membered carbocyclic or heterocyclic ring, which is optionally substituted by one or more substituents RA;

Z is selected from-T'-C(R8R9)N(R12)-T-RD, -T'-C(R10R11)C(R13R14)-T-RD, -LK-T-RDor-LK-E;

R8and R9each independently represent Rcand R12is an RB; or R8is an Rcand R9and R12taken together with the atoms to which they are attached, form a 3-8-membered heterocyclic ring, to the which are optionally substituted by one or more substituents R A;

R10, R11, R13and R14each independently represent Rc; or R10and R13each independently represent Rcand R11and R14taken together with the atoms to which they are attached, form a 3-8-membered carbocyclic or heterocyclic ring, which is optionally substituted by one or more substituents RA;

LKindependently selected in each case, of the communication; -N(RB)C(O)-LS-; -C(O)N(RB)-LS-; or (C1-C6alkylene, C2-C6Alcanena, C2-C6akinlana, C3-C10carbocycle or 3-10-membered heterocycle, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano;

E is independently selected in each case, C3-C10carbocycle or 3-10-membered heterocycle and is, independently, optionally substituted in each case by one or more substituents RA;

T and T' each independently in each instance selected from-LS-, -LS-M-LS'-, -Ls-M-Ls'-M'-Ls"-, where M and M' each independently in each instance selected from-O, -S-, -N(RB)-, -C(O)-, -S(O)2-, -S(O)-, -OS(O)-, -OS(O)2-, -S(O)2O-, -S(O)O-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(RB)-, -N(RB)C(O)-, -N(RB)C(O)O-, -OC(O)N(RB)-, -N(RB)S(O)-, -N(RB)S(O)2-, -S(O)N(RB)-, -S(O)2N(RB)-, -C(O)N(RB)C(O)-, -N(RB)C(O)N(RB')-, N(RB)SO2N(RB')-, -N(RB)S(O)N(RB')- C3-C10carbocycle or 3-10-membered heterocycle, and where the specified C3-C10carbocycle and 3-10-membered heterocycle, each independently, optionally substituted in each case by one or more substituents RA;

RAindependently selected in each case from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, -LAor-LS-REwhere two adjacent groups RAtaken together with the atoms to which they are attached and any atoms located between the atoms to which they are attached, optionally form a C3-C10carbocycle or 3-10-membered heterocycle;

RBand RB'each independently in each instance selected from hydrogen or RF;

RCindependently selected in each instance from hydrogen, halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, or RF;

RDeach independently selected in each instance from hydrogen or R :

REindependently selected in each case from-O-RS, -S-RS, -C(O)RS, -OC(O)RS, -C(O)ORS, -N(RSRS'), -S(O)RS, -SO2RS, -C(O)N(RSRS'), -N(RS)C(O)RS',-N(RS)C(O)N(RS'RS"), -N(RS)SO2RS', -SO2N(RSRS'), -N(RS)SO2N(RS'RS"), -N(RS)S(O)N(RS'RS"), -OS(O)-RS, -OS(O)2-RS, -S(O)2ORS, -S(O)ORS, -OC(O)ORS, -N(RS)C(O)ORS', -OC(O)N(RSRS'), -N(RS)S(O)-RS', -S(O)N(RSRS'), -C(O)N(RS)C(O)-RS', C3-C10carbocycle or 3-10-membered heterocyclyl where the specified C3-C10carbocyclic and 3-10-membered heterocyclyl, each independently, optionally substituted in each case by one or more substituents selected from halogen, RT, -O-RB, -S-RB, -N(RBRB'), -OC(O)RB, -C(O)ORB, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano;

RFindependently selected in each case, from C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil, C3-C6carbocycle, C3-C6carbocyclic1-C6of alkyl, 3-6-membered heterocyclyl or (3 - or 6-membered heterocyclyl)1-C6of alkyl, each of which, independently, optionally Zam is converted in each case by one or more substituents, selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano;

LAindependently selected in each case, from C1-C6of alkyl, C2-C6alkenyl or C2-C6the quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, RT, -O-Rs, -S-Rs, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano;

LS, LS'and LS"each independently selected in each case from the Association; or (C1-C6skilene, C2-C6Alcanena or C2-C6akinlana, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano;

RS, RS'and RS"each independently selected in each instance from hydrogen or RT;

RTindependently selected in each case, from C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil, C3-C6carbocycle, C3-C6carbocyclic1-C6of alkyl, 3-6-membered heterocyclyl Il is (3 - or 6-membered heterocyclyl) 1-C6of alkyl, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, RF, -O-RB, -S-RB, -N(RBRB'), -OC(O)RB, -C(O)ORB, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano.

A and B are preferably independently selected from C5-C6carbocycle, 5-6-membered heterocycle or an 8-10 membered bicyclo, such as

where Z1independently selected in each case from O, S, NH or CH2, Z2independently selected in each case from N or CH, Z3independently selected in each case from N or CH, Z4independently selected in each case from O, S, NH or CH2and W1, W2, W3, W4, W5and W6each independently selected in each case from CH or N. A and B, each independently, optionally substituted by one or more substituents RA.

More preferably, A is selected from C5-C6carbocycle, 5-6-membered heterocycleand optionally substituted by one or more substituents RA; B is selected from C5-C6carbocycle, 5-6-membered heterocycle,orand optionally substituted by one or more substituents RAwhere Z1Z 2, Z3, Z4, W1, W2, W3, W4, W5, W6have the meanings given above. Preferably, Z3represents N, and Z4represents NH. For example, A can be selected from a phenyl (for example,and optionally substituted by one or more substituents RA; and may be selected from phenyl (for example,

and optionally substituted by one or more substituents RA.

D is preferably selected from C5-C6carbocycle, 5-6-membered heterocycle or an 8-10 membered bicyclo and optionally substituted by one or more substituents RA. D can also be preferably selected from C1-C6of alkyl, C2-C6alkenyl or C2-C6the quinil and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. More preferably, D represents C5-C6carbocycle, 5-6-membered heterocycle, or 6-10-membered Bicycle and substituted by one or more substituents RMwhere RMrepresents halogen, nitro, oxo, phosphonooxy, phosphono, thioxo, cyano or-LS-RE. So the e preferably D represents phenyl and optionally substituted by one or more substituents RA. More preferably, D represents phenyl and substituted by one or more substituents RMwhere RMshall have the meaning given above. Most preferably, D representswhere RMshall have the meaning given above, and each RNindependently selected from RDand preferably represents hydrogen.

Preferably, RMrepresents halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, cyano; or (C1-C6alkyl, C2-C6alkenyl or C2-C6quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or a 3-6-membered heterocycle, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil,1-C6halogenoalkane, 2-C6halogenoalkane or C2-C6halogenoalkane. More preferably, RMrepresents halogen, hydroxy, mercapto, amino, carboxy; or (C1-C6alkyl, C2-C6alkenyl or C2-C6quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Most preferably, RMrepresents a C1-C6alkyl, which is optionally substituted by one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.

X preferably represents n

L1and L2preferably constitute represent, independently, With1-C6alkylen, and L3preferably selected from communication With1-C6alkylene or-C(O)-. L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. More preferably, L1and L2represent -(CH2is each independently optionally substituted by one or more substituents selected from the of alogena, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano; and L3is a bond or-C(O)-.

Y is preferably selected from-LS-C(R1R2)N(R5)-T-RD, -LS-C(R3R4)C(R6R7)-T-RD, -G-C(R1R2)N(R5)-T-RD-G-C(R3R4)C(R6R7)-T-RD, -N(RB)C(O)C(R1R2)N(R5)-T-RD-N(RB)C(O)C(R3R4)C(R6R7)-T-RD, -C(O)N(RB)C(R1R2)N(R5)-T-RD-C(O)N(RB)C(R3R4)C(R6R7)-T-RD, -N(RB)C(O)-LS-E or-C(O)N(RB)-LS-E. G represents C5-C6carbocycle or 5-6-membered heterocycle, such aswhere RDshall have the meaning given above. E preferably represents an 8-12-membered Bicycle (for example, 8-10-membered Bicycle, such aswhere U is independently selected in each case from -(CH2)- or -(NH)-; where V and Z20each independently selected from C1-C4alkylene, C2-C4Alcanena or C2-C4akinlana, where at least one carbon atom, independently, optionally substituted atom O, S or N and optionally substituted by one or more substituents R . More preferably, R1is an Rcand R2and R5taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring, or 6-10-membered Bicycle (for example,or 6-8-membered Bicycle; preferably,

which is optionally substituted by one or more substituents RA(such as, but not limited to, hydroxy, halogen (e.g. fluorine), C1-C6alkyl (e.g. methyl) or (C2-C6alkenyl (e.g., allyl)); and R3and R6each independently represent Rcand R4and R7taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring, or 6-10-membered Bicycle (for example,or 6-8-membered Bicycle), which is optionally substituted by one or more substituents RA(such as, but not limited to, hydroxy, halogen (e.g. fluorine), C1-C6alkyl (e.g. methyl) or C2-C6alkenyl (e.g., allyl)). Non-limiting examples of preferred values for Y include

,where T and RDhave the meanings mentioned above and later in this application.

Y also m which may be selected from M-C(R 1R2)N(R5)-C(O)-LY'-M'-RD, -M-C(R1R2)N(R5)-Ly'-M'-RD, -Ls-C(R1R2)N(R5)-C(O)-LY'-M'-RD, -Ls-C(R1R2)N(R5)-LY'-M'-RD, -M-C(R3R4)C(R6R7)-C(O)-LY'-M'-RD, -M-C(R3R4)C(R6R7)-LY'-M'-RD, -LS-C(R3R4)C(R6R7)-C(O)-LY'-M'-RDor-LS-C(R3R4)C(R6R7)-LY'-M'-RDwhere M preferably represents a bond, -C(O)N(RB)- or-N(RB)C(O)-, M' preferably represents a bond, -C(O)N(RB)-, -N(RB)C(O)-, -N(RB)C(O)O -, - N(RB)C(O)N(RB')-, -N(RB)S(O) -, or-N(RB)S(O)2-, and LY'is an LS'and preferably LY'represents a C1-C6alkylene, which is optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. More preferably, R1is an Rcand R2and R5taken together with the atoms to which they are attached, form a 5-6-membered heterocycle, or 6-10-membered Bicycle (for example,or 6-8-membered Bicycle), which is optional is entrusted substituted by one or more substituents R A; and R3and R6each independently represent Rcand R4and R7taken together with the atoms to which they are attached, form a 5-6-membered carbocycle/a heterocycle, or 6-10-membered Bicycle (for example,or 6-8-membered Bicycle), which is optionally substituted by one or more substituents RA.

Also preferably, Y is selected from-N(RB)CO-C(R1R2)N(R5)-C(O)-LY'-N(RB)C(O)O-RD, -N(RB)CO-C(R1R2)N(R5)-C(O)-LY'-N(RB)C(O)-RD, -N(RB)CO-C(R1R2)N(R5)-C(O)-LY'-N(RB)S(O)2-RD, -N(RB)CO-C(R1R2)N(R5)-C(O)-LY'-N(RBRB')-RD, -N(RB)CO-C(R1R2)N(R5)-C(O)LY'-O-RD, -N(RB)CO-C(R1R2)N(R5)-C(O)-LY'-RD, -N(RB)CO-C(R1R2)N(R5)-RD, -LS-C(R1R2)N(R5)-C(O)-LY'-N(RB)C(O)O-RD, -LS-C(R1R2)N(R5)-C(O)-LY'-N(RB)C(O)-RD, -LS-C(R1R2)N(R5)-C(O)-LY'-N(RB)S(O)2-RD, -LS-C(R1R2)N(R5)-C(O)-LY'-N(RBRB')-RD, -LS-C(R1R2)N(R5)-C(O)-LY'-O-RD, -LS-C(R1R2)N(R5)-C(O)-LY'-RD, -LS-C(R1 R2)N(R5)-RD, -N(RB)CO-C(R3R4)C(R6R7)-C(O)-LY'-N(RB)C(O)O-RD, -N(RB)CO-C(R3R4)C(R6R7)-C(O)-LY'-N(RB)C(O)-RD, -N(RB)CO-C(R3R4)C(R6R7)-C(O)-LY'-N(RB)S(O)2-RD, -N(RB)CO-C(R3R4)C(R6R7)-C(O)-LY'-N(RBRB')-RD, -N(RB)CO-C(R3R4)C(R6R7)-C(O)-LY'-O-RD, -N(RB)CO-C(R3R4)C(R6R7)-C(O)-LY'-RD, -N(RB)CO-C(R3R4)C(R6R7)-RD, -LS-C(R3R4)C(R6R7)-C(O)-LY'-N(RB)C(O)O-RD, -LS-C(R3R4)C(R6R7)-C(O)-LY'-N(RB)C(O)-RD, -LS-C(R3R4)C(R6R7)-C(O)-LY'-N(RB)S(O)2-RD, -LS-C(R3R4)C(R6R7)-C(O)-LY'-N(RBRB')-RD, -LS-C(R3R4)C(R6R7)-C(O)-LY'-O-RD, -LS-C(R3R4)C(R6R7)-C(O)-LY'-RDor-LS-C(R3R4)C(R6R7)-RDwhere LY'is an LS'and preferably LY'represents a C1-C6alkylene, which is optionally substituted by one or more substituents selected from halogen, R T, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. R1can represent Rcand R2and R5taken together with the atoms to which they are attached, may form a 5-6-membered heterocycle, or 6-10-membered Bicycle (for example,or 6-8-membered Bicycle), which is optionally substituted by one or more substituents RA; and R3and R6can represent, each independently, Rcand R4and R7taken together with the atoms to which they are attached, may form a 5-6-membered carbocycle/a heterocycle, or 6-10-membered Bicycle (for example,or 6-8-membered Bicycle), which is optionally substituted by one or more substituents RA.

Most preferably, Y is selected from-N(RB")CO-C(R1R2)N(R5)-C(O)-LY-N(RB")C(O)-LS-REor-C(R1R2)N(R5)-C(O)-LY-N(RB")C(O)-Ls-REwhere LYrepresents a C1-C6alkylene, optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano; and RB", each independently represents RB. RBand R1each preferably represents a hydrogen or C1-C6alkyl, and R2and R5taken together with the atoms to which they are attached, preferably form a 5-6-membered heterocycle, or 6-10-membered Bicycle (for example,or 6-8-membered Bicycle), which is optionally substituted by one or more substituents RA(for example, hydroxy, halogen (e.g. fluorine), C1-C6alkyl (e.g. methyl) or C2-C6alkenyl (e.g., allyl)). Preferably, LYrepresents a C1-C6alkylene substituted by one or more substituents RTsuch as C3-C6carbocycle or a 3-6-membered heterocycle, which is optionally substituted by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil,1-C6halogenoalkane, C2-C6halogenoalkane or C2-C6halogenoalkane.

Z is preferably selected from-LS-C(R8R9)N(R12)-T-RD, -LS-C(R10R11)C(R13R14)-T-RD, -G-C(R8R9)N(R12)-T-RD, -G-C(R10 R11)C(R13R14)-T-RD, -N(RB)C(O)C(R8R9)N(R12)-T-RD, -N(RB)C(O)C(R10R11)C(R13R14)-T-RD, -C(O)N(RB)C(R8R9)N(R12)-T-RD, -C(O)N(RB)C(R10R11)C(R13R14)-T-RD, -N(RB)C(O)-LS-E or-C(O)N(RB)-LS-E. G represents C5-C6carbocycle or 5-6-membered heterocycle, such aswhere RDshall have the meaning given above. E preferably represents an 8-12-membered Bicycle (for example, 8-10-membered Bicycle, such aswhere U is independently selected in each case from -(CH2)- or -(NH)-; where V and Z20each independently selected from C1-C4alkylene, C2-C4Alcanena or C2-C4akinlana, where at least one carbon atom, independently, optionally substituted atom O, S or N, and optionally substituted by one or more substituents RA. More preferably, R8is an Rcand R9and R12taken together with the atoms to which they are attached, form a 5-6-membered heterocycle, or 6-10-membered Bicycle (for example,or 6-8-membered Bicycle; preferably,which is optionally substituted one or neskolkotysyachnaya R A(such as, but not limited to, hydroxy, halogen (e.g. fluorine), C1-C6alkyl (e.g. methyl) or C2-C6alkenyl (e.g., allyl)); and R10and R13each independently represent Rcand R11and R14taken together with the atoms to which they are attached, form a 5-6-membered carbocycle/a heterocycle, or 6-10-membered Bicycle (for example,or 6-8-membered Bicycle), which is optionally substituted by one or more substituents RA(such as, but not limited to, hydroxy, halogen (e.g. fluorine), C1-C6alkyl (e.g. methyl) or C2-C6alkenyl (e.g., allyl)). Non-limiting examples of preferred substituents Z includewhere T and RDhave the meanings given above and hereinafter in this application.

Z may also be selected from-M-C(R8R9)N(R12)-C(O)-LY'-M'-RD, -M-C(R8R9)N(R12)-LY'-M'-RD, -LS-C(R8R9)N(R12)-C(O)-LY'-M'-RD, -LS-C(R8R9)N(R12)-LY'-M'-RD, -M-C(R10R11)C(R13R14)-C(O)-LY'-M'-RD, -M-C(R10R11)C(R13R14)-LY'-M'-RD, -LS-C(R10R11)C(R13R14)-C(O)-LY '-M'-RDor-LS-C(R10R11)C(R13R14)-LY'-M'-RDwhere M preferably represents a bond, -C(O)N(RB)- or-N(RB)C(O)-, M' preferably represents a bond, -C(O)N(RB)-, -N(RB)C(O)-, -N(RB)C(O)O -, - N(RB)C(O)N(RB')-, -N(RB)S(O) -, or-N(RB)S(O)2-, and LY'is an LS'and preferably LY'represents a C1-C6alkylene, which is optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. More preferably, R8is an Rcand R9and R12taken together with the atoms to which they are attached, form a 5-6-membered heterocycle, or 6-10-membered Bicycle (for example,or 6-8-membered Bicycle), which is optionally substituted by one or more substituents RA; and R10and R13each independently represent Rcand R11and R14taken together with the atoms to which they are attached, form a 5-6-membered carbocycle/a heterocycle, or 6-10-membered Bicycle (for example,or 6-8-membered Bicycle), which is optionally substituted by one or more mixing what italiani R A.

Also preferably, Z is selected from-N(RB)CO-C(R8R9)N(R12)-C(O)-LY'-N(RB)C(O)O-RD, -N(RB)CO-C(R8R9)N(R12)-C(O)-LY'-N(RB)C(O)-RD, -N(RB)CO-C(R8R9)N(R12)-C(O)-LY'-N(RB)S(O)2-RD, -N(RB)CO-C(R8R9)N(R12)-C(O)-LY'-N(RBRB')-RD, -N(RB)CO-C(R8R9)N(R12)-C(O)-LY'-O-RD, -N(RB)CO-C(R8R9)N(R12)-C(O)-LY'-RD, -N(RB)CO-C(R8R9)N(R12)-RD, -LS-C(R8R9)N(R12)-C(O)-LY'-N(RB)C(O)O-RD, -LS-C(R8R9)N(R12)-C(O)-LY'-N(RB)C(O)-RD, -LS-C(R8R9)N(R12)-C(O)-LY'-N(RB)S(O)2-RD, -LS-C(R8R9)N(R12)-C(O)-LY'-N(RBRB')-RD, -LS-C(R8R9)N(R12)-C(O)-LY'-O-RD, -LS-C(R8R9)N(R12)-C(O)-LY'-RD, -LS-C(R8R9)N(R12)-RD, -N(RB)CO-C(R10R11)C(R13R14)-C(O)-LY'-N(RB)C(O)O-RD, -N(RB)CO-C(R10R11)C(R13R14)-C(O)-LY'-N(RB)C(O)-RD, -N(RB)CO-C(R10R11)C(R13R14)-C(O)-LY'-N(RB)S(O)2-RD, -N(R8)CO-C(R10R11)C(R13R )-C(O)-LY'-N(RBRB')-RD, -N(RB)CO-C(R10R11)C(R13R14)-C(O)-LY'-O-RD, -N(RB)CO-C(R10R11)C(R13R14)-C(O)-LY'-RD, -N(RB)CO-C(R10R11)C(R13R14)-RD, -LS-C(R10R11)C(R13R14)-C(O)-LY'-N(RB)C(O)O-RD, -LS-C(R10R11)C(R13R14)-C(O)-LY'-N(RB)C(O)-RD, -LS-C(R10R11)C(R13R14)-C(O)-LY'-N(RB)S(O)2-RD, -Ls-C(R10R11)C(R13R14)-C(O)-LY'-N(RBRB')-RD, -LS-C(R10R11)C(R13R14)-C(O)-LY'-O-RD, -LS-C(R10R11)C(R13R14)-C(O)-LY'-RDor-LS-C(R10R11)C(R13R14)-RDwhere LY'is an LS'and preferably LY'represents a C1-C6alkylene, which is optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. R8can represent Rcand R9and R12taken together with the atoms to which they are attached, may form a 5-6-membered heterocycle, or 6-10-membered ring b is a cycle (for example, or 6-8-membered Bicycle), which is optionally substituted by one or more substituents RA; and R10and R13can represent, each independently, Rcand R11and R14taken together with the atoms to which they are attached, may form a 5-6-membered carbocycle/a heterocycle, or 6-10-membered Bicycle (for example,or 6-8-membered Bicycle), which is optionally substituted by one or more substituents RA.

Most preferably, Z is selected from-N(RB")CO-C(R8R9)N(R12)-C(O)-LY-N(RB")C(O)-LS-REor-C(R8R9)N(R12)-C(O)-LY-N(RB")C(O)-LS-REwhere LYrepresents a C1-C6alkylene, optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano; and RB"each independently represents RB. RBand R8each preferably represents a hydrogen or C1-C6alkyl, and R9and R12taken together with the atoms to which they are attached, preferably form a 5-6-membered heterocycle, or 6-10-membered Bicycle (for example,or 6-8 membered shall icicle), which is optionally substituted by one or more substituents RA(such as, but not limited to, hydroxy, halogen (e.g. fluorine), C1-C6alkyl (e.g. methyl) or C2-C6alkenyl (e.g., allyl)). Preferably, LYrepresents a C1-C6alkylene substituted by one or more substituents RTsuch as3-C6carbocycle or a 3-6-membered heterocycle, which is optionally substituted by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil,1-C6halogenoalkane, C2-C6halogenoalkane or C2-C6halogenoalkane.

T can be, without limitation, independently selected in each case from-C(O)-LS'-, -C(O)O-LS'-, -C(O)-LS'-N(RB)C(O)-LS"-, -C(O)-LS'-N(RB)C(O)O-LS"-, -N(RB)C(O)-LS'-N(RB)C(O)-LS"-, -N(RBB)C(O)-LS'-N(RB)C(O)O-LS"- or-N(RB)C(O)-LS'-N(RB)-LS"-. Preferably, T is independently selected in each case from-C(O)-LS'-M'-LS"- or-N(RB)C(O)-LS'-M'-LS"-. More preferably, T is independently selected in each case from-C(O)-LS'-N(RB)C()-L S"- or-C(O)-LS'-N(RB)C(O)O-LS"-.

T may also represent, for example, -LS-M-LS'-M'-LS"-, where LSis a bond; M is C(O); LS'represents a C1-C6alkylene (for example,where LS'optionally substituted with RT; optional substituent RTis a Deputy, such as, but not limited to, -C1-C6alkyl, -C2-C6alkenyl, -C1-C6alkyl-OH, -C1-C6alkyl-O-C1-C6alkyl, 3-6-membered heterocycle (e.g., tetrahydrofuranyl) or C3-C6carbocyclic (for example, phenyl, cyclohexyl); M' represents-NHC(O)-, -N(Et)C(O) -, or-N(Me)C(O)-; and LS"that is the link. RDpreferably represents hydrogen, -C1-C6alkyl (e.g. methyl), -O-C1-C6alkyl (e.g., methoxy, tert-butoxy), methoxymethyl or-N(C1-C6alkyl)2(for example, -NMe2).

T-RDmay represent, without limitation,

where the stereochemistry at the carbon atom in the group T-RDcan be either (R) or (S).

T may also represent, without limitation, -LS-M-LS'-, where LSrepresents a bond; represents C(O); LS'represents a C1-C6alkylene (for example,,where LS'optionally substituted by a group RT; optional substituent RTis a Deputy, such as, but not limited to, -C1-C6alkyl, -C1-C6alkyl-OH, -C1-C6alkyl-O-C1-C6alkyl or C3-C6carbocyclic (for example, phenyl, cyclohexyl). RDfor example, represents-OH; -OC(O)Me,- NH(C1-C6alkyl) (for example, -NHMe, -NHEt); -N(C1-C6alkyl)2(for example, -NMe2, -NEt2); 3-10-membered heterocyclyl (for example, pyrrolidinyl, imidazolidinyl, hexahydropyridine, morpholinyl, piperidinyl), optionally substituted by one or more groups of halogen, exography; C3-C10carbonyl (for example, cyclopentyl), optionally substituted by a group-OH; -C1-C6alkyl (e.g. isopropyl, 3-pentyl), optionally substituted by a group-OH; or otherTwhere RTrepresents a 3-6-membered heterocyclyl (for example, thiazolyl, pyrimidinyl). T-RDincludes, but is not limited to:

where the stereochemistry at the carbon atom in the group T-RDcan be either (R) or (S).

For the formula I, as well as for formulas IAI Band Icdescribed below, including any and each variant of the embodiment of the present invention, described below, RApreferably represents halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, cyano; or (C1-C6alkyl, C2-C6alkenyl or C2-C6quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; or (C3-C6carbocycle or a 3-6-membered heterocycle, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil,1-C6halogenoalkane, C2-C6halogenoalkane or C2-C6halogenoalkane; or-LA-O-RS, -LA-S-RS, -LA-C(O)RS, -LA-OC(O)RS, -LA-C(O)ORS, -LA-N(RSRS'), -LA-S(O)RS, -LA-SO2RS, -LA-C(O)N(RSRS'), -LA-N(RS)C(O)RS', -LA-N(RS)C(O)N(RS'RS") -L A-N(RS)SO2RS', -LA-SO2N(RSRS'), -LA-N(RS)SO2N(RS'RS"), -LA-N(RS)S(O)N(RS'Rs"), -LA-OS(O)-RS, -LA-OS(O)2-RS, -LA-S(O)2ORS, -LA-S(O)ORS, -LA-OC(O)ORs, -LA-N(RS)C(O)ORS', -LA-OC(O)N(RSRS'), -LA-N(RS)S(O)-RS', -LA-S(O)N(RSRS'or-LA-C(O)N(RS)C(O)-RS'where LAis a relationship With1-C6alkylene, C2-C6alkanine or C2-C6akinyan.

More preferably, RArepresents halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, cyano; or (C1-C6alkyl, C2-C6alkenyl or C2-C6quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; or (C3-C6carbocycle or a 3-6-membered heterocycle, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1C 6of alkyl, C2-C6alkenyl, C2-C6the quinil,1-C6halogenoalkane, C2-C6halogenoalkane or C2-C6halogenoalkane.

Most preferably, RArepresents halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, cyano; or (C1-C6alkyl, C2-C6alkenyl or C2-C6quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano.

LS, LS'and LS"preferably, each independently, in each case selected from the communication; or (C1-C6alkylene, C2-C6Alcanena or C2-C6albinyana.

A and B may be the same or different from each other. Also, L1and L2or Y and Z, or Y-A - Z-B-or-A-L1- I-B-L2- may be the same or different from each other. In some cases, Y-A-L1is identical to Z-B-L2-. In other cases, Y-A-L1- differs from Z-B-L2-.

For each of the compounds of formula I, LKcan also be independently selected in each instance of communication; -LS'-N(RB)C(O)-LS-; -LS'-C(O)N(RB)-LS-; or (C1-C6and what of kilen, C2-C6Alcanena, C2-C6akinlana, C3-C10carbocycle or 3-10-membered heterocycle, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano, where LSand LS'have the meanings given above.

In one variant of embodiment A, B, and D, each independently, represent phenyl, and are each independently optionally substituted by one or more substituents RA. L1and L2each independently represent a1-C6alkylen, L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. Preferably, L1and L2represent -(CH2is each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, ofono, oxo, thioxo, formyl or cyano; and L3is a bond or-C(O)-. Y represents-LS-C(R1R2)N(R5)-T-RD, -LS-C(R3R4)C(R6R7)-T-RD, -N(RB)C(O)C(R1R2)N(R5)-T-RDor-N(RB)C(O)C(R3R4)C(R6R7)-T-RDand Z represents-LS-C(R8R9)N(R12)-T-RD, -LS-C(R10R11)C(R13R14)-T-RD, -N(RB)C(O)C(R8R9)N(R12)-T-RDor-N(RB)C(O)C(R10R11)C(R13R14)-T-RD. R1is an Rcand R2and R5taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring, which is optionally substituted by one or more substituents RA; R3and R6each independently represent Rcand R4and R7taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring, which is optionally substituted by one or more substituents RA. R8is an Rcand R9and R12taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring, which is optionally substituted by one or more of the Deputy is mi R A; and R10and R13each independently represent Rcand R11and R14taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring, which is optionally substituted by one or more substituents RA. T is preferably independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"- or-C(O)-LS'-N(RB)C(O)O-LS"-, where LS'preferably represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. T can also be, without limitation, selected from-C(O)-LS'-LS"-, -C(O)-LS'-O-LS"-, -C(O)-LS'-N(RB)-LS"- or-C(O)-LS'-N(RB)S(O)2-LS"-. In some cases, at least one of Y and Z represents independentlywhere RDand RThave the meanings defined above, and non-limiting examples of RDinclude 5 - or 6-membered heterocycles (e.g., pyridinyl), and non-limiting examples of RTinclude1-C6alkyl, optionally substituted in each case one or more is likemy substituents, selected from halogen, RF, -O-RB, -S-RB, -N(RBRB'), -OC(O)RB, -C(O)ORB, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano.

In another variant embodiment A representsand optionally substituted by one or more substituents RA; B representsand optionally substituted by one or more substituents RA; and D represents C5-C6carbocycle or 5-6-membered heterocycle (e.g., phenyl), and optionally substituted by one or more substituents RA. Z1independently selected in each case from O, S, NH or CH2; and Z2independently selected in each case from N or CH. L1and L2each independently represent a1-C6alkylen, L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. Preferably, L1and L2represent -(CH2is each independently optionally substituted by one or more substituents selected from Galaga is a, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano; and L3is a bond or-C(O)-. Y represents-LS-C(R1R2)N(R5)-T-RD-LS-C(R3R4)C(R6R7)-T-RD, -N(RB)C(O)C(R1R2)N(R5)-T-RDor-N(RB)C(O)C(R3R4)C(R6R7)-T-RDand Z represents-LS-C(R8R9)N(R12)-T-RD, -LS-C(R10R11)C(R13R14)-T-RD, -N(RB)C(O)C(R8R9)N(R12)-T-RDor-N(RB)C(O)C(R10R11)C(R13R14)-T-RD. R1is an Rcand R2and R5taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring, which is optionally substituted by one or more substituents RA; R3and R6each independently represent Rcand R4and R7taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring, which is optionally substituted by one or more substituents RA. R8is an Rcand R9and R12taken together with the atoms to which they are attached, form a is a 5-6-membered heterocyclic ring, which is optionally substituted by one or more substituents RA; and R10and R13each independently represent Rcand R11and R14taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring, which is optionally substituted by one or more substituents RA. T is preferably independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"- or-C(O)-LS'-N(RB)C(O)O-LS"-, where LS'preferably represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. T can also be, without limitation, selected from-C(O)-LS'-LS"-, -C(O)-LS'-O-LS"-, -C(O)-LS'-N(RB)-LS"- or-C(O)-LS'-N(RB)S(O)2-LS"-. In some cases, at least one of Y and Z is a or Y and Z are independentlywhere RDand RThave the meanings defined above, and non-limiting examples of RDinclude 5 - or 6-membered heterocycles (e.g., pyridinyl), and non-limiting examples R Tinclude1-C6alkyl, optionally substituted in each case by one or more substituents selected from halogen, RF, -O-RB, -S-RB, -N(RBRB'), -OC(O)RB, -C(O)ORB, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano.

In another variant embodiment A represents a phenyl,optionally substituted by one or more substituents RA; Represents phenyl,and optionally substituted by one or more substituents RA; and D represents C5-C6carbocycle or 5-6-membered heterocycle (e.g., phenyl), and optionally substituted by one or more substituents RA. Z1independently selected in each case from O, S, NH or CH2; and Z2independently selected in each case from N or CH. L1and L2each independently represent a1-C6alkylen, L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. Preferably, L1and L 2represent -(CH2is each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano; and L3is a bond or-C(O)-. Y represents-LS-C(R1R2)N(R5)-T-RD-LS-C(R3R4)C(R6R7)-T-RD, -N(RB)C(O)C(R1R2)N(R5)-T-RDor-N(RB)C(O)C(R3R4)C(R6R7)-T-RDand Z represents-LS-C(R8R9)N(R12)-T-RD, -LS-C(R10R11)C(R13R14)-T-RD, -N(RB)C(O)C(R8R9)N(R12)-T-RDor-N(RB)C(O)C(R10R11)C(R13R14)-T-RD. R1is an Rcand R2and R5taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring, which is optionally substituted by one or more substituents RA; R3and R6each independently represent Rcand R4and R7taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring, which is optionally substituted by one or more C is Mascitelli R A. R8is an Rcand R9and R12taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring, which is optionally substituted by one or more substituents RA; and R10and R13each independently represent Rcand R11and R14taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring, which is optionally substituted by one or more substituents RA. T is preferably independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"- or-C(O)-LS'-N(RB)C(O)O-LS"-, where LS'preferably represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. T can also be, without limitation, selected from-C(O)-LS'-LS"-, -C(O)-LS'-O-LS"-, -C(O)-LS'-N(RB)-LS"- or-C(O)-LS'-N(RB)S(O)2-LS"-. In some cases, at least one of Y and Z represents, or Y and Z are independentlywhere pogranicze the surrounding examples R Dinclude 5 - or 6-membered heterocycles (e.g., pyridinyl), and non-limiting examples of RTinclude1-C6alkyl, optionally substituted in each case by one or more substituents selected from halogen, RF, -O-RB, -S-RB, -N(RBRB'), -OC(O)RB, -C(O)ORB, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano.

In another variant embodiment A represents aand optionally substituted by one or more substituents RA; and B representsand optionally substituted by one or more substituents RA; and D represents C5-C6carbocycle or 5-6-membered heterocycle (e.g., phenyl), and optionally substituted by one or more substituents RA. L1and L2each independently represent a1-C6alkylen, L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. Preferably, L1and L2represent -(CH2 is each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano; and L3is a bond or-C(O)-. Y represents-LS-C(R1R2)N(R5)-T-RD-LS-C(R3R4)C(R6R7)-T-RD, -N(RB)C(O)C(R1R2)N(R5)-T-RDor-N(RB)C(O)C(R3R4)C(R6R7)-T-RDand Z represents-LS-C(R8R9)N(R12)-T-RD, -LS-C(R10R11)C(R13R14)-T-RD, -N(RB)C(O)C(R8R9)N(R12)-T-RDor-N(RB)C(O)C(R10R11)C(R13R14)-T-RD. R1is an Rcand R2and R5taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring, which is optionally substituted by one or more substituents RA; R3and R6each independently represent Rcand R4and R7taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring, which is optionally substituted by one or more substituents RA. R8PR is dstanley a Rc and R9and R12taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring, which is optionally substituted by one or more substituents RA; and R10and R13each independently represent Rcand R11and R14taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring, which is optionally substituted by one or more substituents RA. T is preferably independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"- or-C(O)-LS'-N(RB)C(O)O-LS"-, where LS'preferably represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. T can also be, without limitation, selected from-C(O)-LS'-LS"-, -C(O)-LS'-O-LS"-, -C(O)-LS'-N(RB)-LS"- or-C(O)-LS'-N(RB)S(O)2-LS"-. In some cases, at least one of Y and Z represents, or Y and Z are independentlywhere non-limiting examples of RDinclude 5 - or 6-members of the nye heterocycles (for example, pyridinyl), and non-limiting examples of RTinclude1-C6alkyl, optionally substituted in each case by one or more substituents selected from halogen, RF, -O-RB, -S-RB, -N(RBRB'), -OC(O)RB, -C(O)ORB, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano.

In one variant of embodiment A, B, and D, each independently, represent phenyl, and are each independently optionally substituted by one or more substituents RA. L1and L2each independently represent a1-C6alkylen, L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. Preferably, L1and L2represent -(CH2is each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano; and L3is a bond or-C(O)-. Y represents-G-C(R1R2/sub> )N(R5)-T-RDor-G-C(R3R4)C(R6R7)-T-RDand Z represents-G-C(R8R9)N(R12)-T-RDor-G-C(R10R11)C(R13R14)-T-RD. G represents a C5-C6carbocycle or 5-6-membered heterocycle, such asR1is an Rcand R2and R5taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring, which is optionally substituted by one or more substituents RA; R3and R6each independently represent Rcand R4and R7taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring, which is optionally substituted by one or more substituents RA. R8is an Rcand R9and R12taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring, which is optionally substituted by one or more substituents RA; and R10and R13each independently represent Rcand R11and R14taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring, which is optionally substituted on the him or more substituents R A. RDshall have the meaning given above. T is preferably independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"- or-C(O)-LS'-N(RB)C(O)O-LS"-, where LS'preferably represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. T can also be, without limitation, selected from-C(O)-LS'-LS"-, -C(O)-LS'-O-LS"-, -C(O)-LS'-N(RB)-LS"- or-C(O)-LS'-N(RB)S(O)2-LS"-. In some cases, at least one of Y and Z represents, or Y and Z are independentlywhere RDshall have the meaning given above and preferably represents hydrogen, RD'is an RDand non-limiting examples of RD'include 5 - or 6-membered heterocycles (e.g., pyridinyl), and non-limiting examples of RTinclude1-C6alkyl, optionally substituted in each case by one or more substituents selected from halogen, RF, -O-RB, -S-RB, -N(RBRB'), -OC(O)RB, -C(O)ORB, nitro, phosphonate, FOS is it, oxo, thioxo, formyl or cyano.

In another variant embodiment A representsand optionally substituted by one or more substituents RA; B representsand optionally substituted by one or more substituents RA; and D represents C5-C6carbocycle or 5-6-membered heterocycle (e.g., phenyl), and optionally substituted by one or more substituents RA. Z1independently selected in each case from O, S, NH or CH2; and Z2independently selected in each case from N or CH. L1and L2each independently represent a1-C6alkylen, L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. Preferably, L1and L2represent -(CH2is each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, CTI is about, the formyl or cyano; and L3is a bond or-C(O)-. Y represents-G-C(R1R2)N(R5)-T-RDor-G-C(R3R4)C(R6R7)-T-RDand Z represents-G-C(R8R9)N(R12)-T-RDor-G-C(R10R11)C(R13R14)-T-RD. G represents a C5-C6carbocycle or 5-6-membered heterocycle, such asR1is an Rcand R2and R5taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring, which is optionally substituted by one or more substituents RA; R3and R6each independently represent Rcand R4and R7taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring, which is optionally substituted by one or more substituents RA. R8is an Rcand R9and R12taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring, which is optionally substituted by one or more substituents RA; and R10and R13each independently represent Rcand R11and R14taken together with the atoms to which they recognize the ENES, form a 5-6-membered carbocyclic or heterocyclic ring, which is optionally substituted by one or more substituents RA. RDshall have the meaning given above. T is preferably independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"- or-C(O)-LS'-N(RB)C(O)O-LS"-, where LS'preferably represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. T can also be, without limitation, selected from-C(O)-LS'-LS"-, -C(O)-LS'-O-LS"-, -C(O)-LS'-N(RB)-LS"- or-C(O)-LS'-N(RB)S(O)2-LS"-. In some cases, at least one of Y and Z represents, or Y and Z are independentlywhere RDshall have the meaning given above and preferably represents hydrogen, RD'is an RDand non-limiting examples of RD'include 5 - or 6-membered heterocycles (e.g., pyridinyl), and non-limiting examples of RTinclude1-C6alkyl, optionally substituted in each case one or more C is Mascitelli, selected from halogen, RF, -O-RB, -S-RB, -N(RBRB'), -OC(O)RB, -C(O)ORB, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano.

In another variant embodiment A represents a phenyl,and optionally substituted by one or more substituents RA; B represents phenyl,and optionally substituted by one or more substituents RA; and D represents C5-C6carbocycle or 5-6-membered heterocycle (e.g., phenyl), and optionally substituted by one or more substituents RA. Z1independently selected in each case from O, S, NH or CH2; and Z2independently selected in each case from N or CH. L1and L2each independently represent a1-C6alkylen, L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. Preferably, L1and L2represent -(CH2is each independently optionally substituted by one or more for what estately, selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano; and L3is a bond or-C(O)-. Y represents-G-C(R1R2)N(R5)-T-RDor-G-C(R3R4)C(R6R7)-T-RDand Z represents-G-C(R8R9)N(R12)-T-RDor-G-C(R10R11)C(R13R14)-T-RD. G represents a C5-C6carbocycle or 5-6-membered heterocycle, such asR1is an RCor R2and R5taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring, which is optionally substituted by one or more substituents RA; R3and R6each independently represent Rcand R4and R7taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring, which is optionally substituted by one or more substituents RA. R8is an Rcand R9and R12taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring, which is optionally substituted by one or more substituents RA ; and R10and R13each independently represent Rcand R11and R14taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring, which is optionally substituted by one or more substituents RA. RDshall have the meaning given above. T is preferably independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"- or-C(O)-LS'-N(RB)C(O)O-LS"-, where LS'preferably represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. T can also be, without limitation, selected from-C(O)-LS'-LS"-, -C(O)-LS'-O-LS"-, -C(O)-LS'-N(RB)-LS"- or-C(O)-LS'-N(RB)S(O)2-LS"-. In some cases, at least one of Y and Z represents, or Y and Z are independentlywhere RDshall have the meaning given above and preferably represents hydrogen, RD'is an RDand non-limiting examples of RD'include 5 - or 6-membered heterocycles (for example the EP, pyridinyl), and non-limiting examples of RTinclude1-C6alkyl, optionally substituted in each case by one or more substituents selected from halogen, RF, -O-RB, -S-RB, -N(RBRB'), -OC(O)RB, -C(O)ORB, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano.

In another variant embodiment A representsand optionally substituted by one or more substituents RA; and B representsand optionally substituted by one or more substituents RA; and D represents C5-C6carbocycle or 5-6-membered heterocycle (e.g., phenyl), and optionally substituted by one or more substituents RA. L1and L2each independently represent a1-C6alkylen, L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. Preferably, L1and L2represent -(CH2is each independently optionally substituted one is m or more substituents, selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano; and L3is a bond or-C(O)-. Y represents-G-C(R1R2)N(R5)-T-RDor-G-C(R3R4)C(R6R7)-T-RDand Z represents-G-C(R8R9)N(R12)-T-RDor-G-C(R10R11)C(R13R14)-T-RD. G represents a C5-C6carbocycle or 5-6-membered heterocycle, such asR1is an RCand R2and R5taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring, which is optionally substituted by one or more substituents RA; R3and R6each independently represent Rcand R4and R7taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring, which is optionally substituted by one or more substituents RA. R8is an Rcand R9and R12taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring, which is optionally substituted by one or more substituents RAand R 10and R13each independently represent Rcand R11and R14taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring, which is optionally substituted by one or more substituents RA. RDshall have the meaning given above. T is preferably independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"- or-C(O)-LS'-N(RB)C(O)O-LS"-, where LS'preferably represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. T can also be, without limitation, selected from-C(O)-LS'-LS"-, -C(O)-LS'-O-LS"-, -C(O)-LS'-N(RB)-LS"- or-C(O)-LS'-N(RB)S(O)2-LS"-. In some cases, at least one of Y and Z represents, or Y and Z are independentlywhere RDshall have the meaning given above and preferably represents hydrogen, RD'is an RDand non-limiting examples of RD'include 5 - or 6-membered heterocycles (e.g., pyridi the Il), and non-limiting examples of RTinclude1-C6alkyl, optionally substituted in each case by one or more substituents selected from halogen, RF, -O-RB, -S-RB, -N(RBRB'), -OC(O)RB, -C(O)ORB, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano.

In one embodiment, embodiments A and B, each independently, represent a 5 - or 6-membered carbocycle or heterocycle (for example, phenyl, such asand, each independently, optionally substituted by one or more substituents RA. X preferably represents a n D preferably represents C5-C6carbocycle or 5-6-membered heterocycle (e.g., phenyl), and optionally substituted by one or more substituents RA. L1and L2each independently represent a1-C6alkylen, and L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. Preferably, L1and L2each independently represent a1-C6 alkylene (for example, -CH2-), and L3that is the link. Y represents-N(RB)C(O)C(R1R2)N(R5)-T-RDor-N(RB)C(O)C(R3R4)C(R6R7)-T-RDand Z represents-N(RB)C(O)C(R8R9)N(R12)-T-RDor-N(RB)C(O)C(R10R11)C(R13R14)-T-RD. R1is an Rcand R2and R5taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring (for example,,which is optionally substituted by one or more substituents RA; R3and R6each independently represent Rcand R4and R7taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring (for example,,which is optionally substituted by one or more substituents RA. R8is an Rcand R9and R12taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring (for example,,which is optionally substituted by one or more substituents RA; and R10and R13each independently represent Rc, R 11and R14taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring (for example,,which is optionally substituted by one or more substituents RA. T is preferably independently selected in each case from-C(O)-LY'-N(RB)C(O)-LS"- or-C(O)-LY'-N(RB)C(O)O-LS"-. LY'each independently represents an LS'and, preferably, each independently represents a C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. T can also be, without limitation, selected from-C(O)-LY'-LS"-, -C(O)-LY'-O-LS"-, -C(O)-LY'-N(RB)-LS"- or-C(O)-LY'-N(RB)S(O)2-LS"-. In some cases, at least one of Y and Z represents, or Y and Z are independentlywhere non-limiting examples of RDincludes (1) -O-C1-C6alkyl, -O-C2-C6alkenyl, -O-C2-C6quinil,1-C6alkyl, C2-C6alkenyl or C2-C6quinil, each of Kotor is x, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C3-C6carbocycle or a 3-6-membered heterocycle; or (2)3-C6carbocycle or a 3-6-membered heterocycle, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil,1-C6halogenoalkane, C2-C6halogenoalkane or C2-C6halogenoalkane; and non-limiting examples of LY'include1-C6alkylene, optionally substituted with halogen, hydroxy, mercapto, amino, carboxy, phosphonate, -O-C1-C6by alkyl, -O-C2-C6alkenyl, -O-C2-C6the quinil or a 3-6-membered carbocycle or heterocycle specified 3-6-membered carbocycle or a heterocycle optionally substituted by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1-C6of alkyl, C2-C6alkenyl, C2-C6Ala the Nile, With1-C6halogenoalkane, C2-C6halogenoalkane or C2-C6halogenoalkane.

In another variant embodiment A representsand optionally substituted by one or more substituents RA; B representsand optionally substituted by one or more substituents RA. Z1independently selected in each case from O, S, NH or CH2; and Z2independently selected in each case from N or CH. X represents a 5 - or 6-membered carbocycle or a heterocycle, or 6-10-membered Bicycle and optionally substituted by one or more substituents RA. X preferably represents a n D preferably represents C5-C6carbocycle or 5-6-membered heterocycle (e.g., phenyl), and optionally substituted by one or more substituents RA. L1and L2each independently represents a C1-C6alkylen, and L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. Prepact the tion, L1and L2each independently represent a1-C6alkylene (for example, -CH2-), and L3that is the link. Y represents-LS-C(R1R2)N(R5)-T-RDor-LS-C(R3R4)C(R6R7)-T-RDand Z represents-LS-C(R8R9)N(R12)-T-RDor-LS-C(R10R11)C(R13R14)-T-RD. R1is an Rcand R2and R5taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring (for example,,which is optionally substituted by one or more substituents RA; R3and R6each independently represent Rcand R4and R7taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring (for example,,which is optionally substituted by one or more substituents RA. R8is an Rcand R9and R12taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring (for example,,which is optionally substituted by one or more substituents RA; and R10and R13 each independently represent Rcand R11and R14taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring (for example,,which is optionally substituted by one or more substituents RA. T is preferably independently selected in each case from-C(O)-LY'-N(RB)C(O)-LS"- or-C(O)-LY'-N(RB)C(O)O-LS"-. LY'each independently represents an LS'and, preferably, is an independently1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. T can also be, without limitation, selected from-C(O)-LY'-LS"-, -C(O)-LY'-O-LS"-, -C(O)-LY'-N(RB)-LS"- or-C(O)-LY'-N(RB)S(O)2-LS"-. In some cases, at least one of Y and Z represents, or both Y and Z are independentlywhere non-limiting examples of RDincludes (1) -O-C1-C6alkyl, -O-C2-C6alkenyl, -O-C2-C6quinil,1-C6alkyl, C2-C6al is enyl or C 2-C6quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C3-C6carbocycle or a 3-6-membered heterocycle; or (2) C3-C6carbocycle or a 3-6-membered heterocycle, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil,1-C6halogenoalkane, C2-C6halogenoalkane or C2-C6halogenoalkane; and non-limiting examples of LY'include1-C6alkylene, optionally substituted with halogen, hydroxy, mercapto, amino, carboxy, phosphonate, -O-C1-C6by alkyl, -O-C2-C6alkenyl, -O-C2-C6the quinil or a 3-6-membered carbocycle or heterocycle specified 3-6-membered carbocycle or a heterocycle optionally substituted by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1-C6of alkyl, C2 -C6alkenyl, C2-C6the quinil,1-C6halogenoalkane, C2-C6halogenoalkane or C2-C6halogenoalkane.

In another variant embodiment of A and B, each independently, represent a 5 - or 6-membered carbocycle or heterocycle (for example, A and B, each independently, represent phenyl, such asand, each independently, optionally substituted by one or more substituents RA. X preferably represents a n D preferably represents C5-C6carbocycle or 5-6-membered heterocycle (e.g., phenyl), and optionally substituted by one or more substituents RA. L1and L2each independently represent a1-C6alkylen, and L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. Preferably, L1and L2each independently represents a C1-C6alkylene (for example, -CH2-), and L3that is the link. Y represents-G-C(R1R2)N(R 5)-T-RDor-G-C(R3R4)C(R6R7)-T-RDand Z represents-G-C(R8R9)N(R12)-T-RDor-G-C(R10R11)C(R13R14)-T-RD. G represents a C5-C6carbocycle or 5-6-membered heterocycle, such asand optionally substituted by one or more substituents RA. R1is an Rcand R2and R5taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring (for example,,which is optionally substituted by one or more substituents RA; R3and R6each independently represent Rcand R4and R7taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring (for example,,which is optionally substituted by one or more substituents RA. R8is an Rcand R9and R12taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring (for example,,which is optionally substituted by one or more substituents RA; and R10and R13each independently presented Aut a R cand R11and R14taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring (for example,,which is optionally substituted by one or more substituents RA. T is preferably independently selected in each case from-C(O)-LY'-N(RB)C(O)-LS"- or-C(O)-LY'-N(RB)C(O)O-LS"-. LY'each independently represents an LS'and, preferably, each independently represents a C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. T can also be, without limitation, selected from-C(O)-Ly'-LS"-, -C(O)-LY'-O-LS"-, -C(O)-LY'-N(RB)-LS"- or-C(O)-LY'-N(RB)S(O)2-LS"-. In some cases, at least one of Y and Z represents, or Y and Z both represent independentlywhere non-limiting examples of RDincludes (1) -O-C1-C6alkyl, -O-C2-C6alkenyl, -O-C2-C6quinil,1-C6alkyl, C2-C6alkenyl or C2-C6quinil, it is gdy of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C3-C6carbocycle or a 3-6-membered heterocycle; or (2)3-C6carbocycle or a 3-6-membered heterocycle, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil,1-C6halogenoalkane, C2-C6halogenoalkane or C2-C<5halogenoalkane; and non-limiting examples of LY'include1-C6alkylene, optionally substituted with halogen, hydroxy, mercapto, amino, carboxy, phosphonate, -O-C1-C6by alkyl, -O-C2-C6alkenyl, -O-C2-C6the quinil or a 3-6-membered carbocycle or heterocycle specified 3-6-membered carbocycle or a heterocycle optionally substituted by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1-C6of alkyl, C2-C6alkenyl, C2-C6is lkine, With1-C6halogenoalkane, C2-C6halogenoalkane or C2-C6halogenoalkane.

In another variant embodiment of A and B, each independently, represent a 5 - or 6-membered carbocycle or heterocycle (for example, A and B, each independently, represent phenyl, such asand, each independently, optionally substituted by one or more substituents RA. X preferably represents a n D preferably represents C5-C6carbocycle or 5-6-membered heterocycle (e.g., phenyl), and optionally substituted by one or more substituents RA. L1and L2each independently represent a1-C6alkylen, and L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. Preferably, L1and L2each independently represent a1-C6alkylene (for example, -CH2-), and L3that is the link. Y represents-N(RB)C(O)C(R1R2)N(R5)-T-RDor-N(RB)C(O)CR 3R4)C(R6R7)-T-RDand Z represents-G-C(R8R9)N(R12)-T-RDor-G-C(R10R11)C(R13R14)-T-RD; or Y is-G-C(R1R2)N(R5)-T-RDor-G-C(R3R4)C(R6R7)-T-RDand Z represents-N(RB)C(O)C(R8R9)N(R12)-T-RDor-N(RB)C(O)C(R10R11)C(R13R14)-T-RD. R1is an Rcand R2and R5taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring (for example,,which is optionally substituted by one or more substituents RA; R3and R6each independently represent Rcand R4and R7taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring (for example,,which is optionally substituted by one or more substituents RA. R8is an Rcand R9and R12taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring (for example,,which is optionally substituted by one or more substituents RA; and R10 and R13each independently represent Rcand R11and R14taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring (for example,,which is optionally substituted by one or more substituents RA. G represents a C5-C6carbocycle or 5-6-membered heterocycle, such asand optionally substituted by one or more substituents RA. T is preferably independently selected in each case from-C(O)-LY'-N(RB)C(O)-LS"- or-C(O)-LY'-N(RB)C(O)O-LS"-. LY'each independently represents an Ls'and, preferably, each independently represents a C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. T can also be, without limitation, selected from-C(O)-LY'-LS"-, -C(O)-LY'-O-LS"-, -C(O)-LY'-N(RB)-LS"- or-C(O)-LY'-N(RB)S(O)2-LS"-. In some cases, Y is a,as described above, and Z represents suboid src="https://img.russianpatents.com/1194/11944751-s.jpg" height="27" width="96" /> ,as explained above. In other cases, Y is a,as described above, and Z represents,as explained above.

In another variant embodiment of the present invention A represents a 5 - or 6-membered carbocycle or heterocycle (for example, phenyl, such asand is a(for example,or Rather it represents a(for example,and represents a 5 - or 6-membered carbocycle or heterocycle (for example, phenyl, such asA and B, each independently, optionally substituted by one or more substituents RA. Z1independently selected in each case from O, S, NH or CH2; and Z2independently selected in each case from N or CH. X preferably represents a n D preferably represents C5-C6carbocycle or 5-6-membered heterocycle (e.g., phenyl), and optionally substituted by one or more substituents RA. L1and L2each independently represent a1-C6alkylen, and L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optional is entrusted substituted by one or more substituents, selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. Preferably, L1and L2each independently represent a1-C6alkylene (for example, -CH2-), and L3that is the link. When A represents a 5 - or 6-membered carbocycle or heterocycle (for example, phenyl, such asY represents-N(RB)C(O)C(R1R2)N(R5)-T-RD, -N(RB)C(O)C(R3R4)C(R6R7)-T-RD, -G-C(R1R2)N(R5)-T-RDor-G-C(R3R4)C(R6R7)-T-RDand Z represents-LS-C(R8R9)N(R12)-T-RDor-LS-C(R10R11)C(R13R14)-T-RD. When B represents a 5 - or 6-membered carbocycle or heterocycle (for example, phenyl, such asY represents-LS-C(R1R2)N(R5)-T-RDor-LS-C(R3R4)C(R6R7)-T-RDand Z represents-N(RB)C(O)C(R8R9)N(R12)-T-RD, -N(RB)C(O)C(R10R11)C(R13R14)-T-RD, -G-C(R8R9)N(R12)-T-RDor-G-C(R10R11)C(R13R14)-T-RD. R1is an Rc2and R5taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring (for example,,which is optionally substituted by one or more substituents RA; R3and R6each independently represent Rcand R4and R7taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring (for example,,which is optionally substituted by one or more substituents RA. R8is an Rcand R9and R12taken together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring (for example,,which is optionally substituted by one or more substituents RA; and R10and R13each independently represent Rcand R11and R14taken together with the atoms to which they are attached, form a 5-6-membered carbocyclic or heterocyclic ring (for example,,which is optionally substituted by one or more substituents RA. G represents a C5-C6carbocycle or 5-6-membered heterocycle, such asand long is correctly substituted by one or more substituents R A. T is preferably independently selected in each case from-C(O)-LY'-N(RB)C(O)-Ls"- or-C(O)-LY'-N(RB)C(O)O-LS"-. LY'each independently represents an LS'and, preferably, each independently represents a C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. T can also be, without limitation, selected from-C(O)-LY'-Ls"-, -C(O)-LY'-O-LS"-, -C(O)-LY'-N(RB)-LS"- or-C(O)-LY'-N(RB)S(O)2-LS"-. In some cases, when A represents a 5 - or 6-membered carbocycle or heterocycle (for example, phenyl, such asY represents,as described above, and Z represents,as explained above. In other cases, when B represents a 5 - or 6-membered carbocycle or heterocycle (for example, phenyl, such asY represents,as described above, and Z represents,as explained above.

In another aspect of the present invention which engages the compounds of formula I Aand their pharmaceutically acceptable salts.

,

where:

RNBeach independently selected from RB;

Rc'each independently selected from Rc;

RD'each independently selected from RD;

R2and R5taken together with the atoms to which they are attached, form a 3-8-membered heterocyclic ring, which is optionally substituted by one or more substituents RA;

R9and R12taken together with the atoms to which they are attached, form a 3-8-membered heterocyclic ring, which is optionally substituted by one or more substituents RA;

A, B, D, L1, L2, L3, T, RA, RB, Rcand RDhave the values described above for formula I.

In this aspect, A and B, preferably, independently selected from C5-C6carbocycle, 5-6-membered heterocycle or an 8-10 membered bicyclo, such aswhere Z1independently selected in each case from O, S, NH or CH2, Z2independently selected in each case from N or CH, Z3independently selected in each case from N or CH, Z4independently selected in each case from O, S, NH or CH2and W1, W2, W3, W4, W5and W6each independently in each instance selected from CH or N. A and B, each is th independently optionally substituted by one or more substituents RA.

More preferably, A is selected from C5-C6carbocycle, 5-6-membered heterocycle,and optionally substituted by one or more substituents RA; B is selected from C5-C6carbocycle, 5-6-membered heterocycle,and optionally substituted by one or more substituents RAwhere Z1, Z2, Z3, Z4, W1, W2, W3, W4, W5, W6have the meanings given above. Preferably, Z3represents N, and Z4represents NH. For example, A can be selected from a phenyl (for example,and optionally substituted by one or more substituents RA; and may be selected from phenyland optionally substituted by one or more substituents RA.

Most preferably, A and B are independently selected from C5-C6carbocycle or 5-6-membered heterocycle, and are each independently optionally substituted by one or more substituents RA. Preferably, at least one of A and B represents a phenyl (for example,and it is certainly substituted by one or more substituents R A. For example, both A and B, each independently can be a phenyl (for example,and, each independently, optionally substituted by one or more substituents RA.

D is preferably selected from C5-C6carbocycle, 5-6-membered heterocycle or an 8-10 membered bicyclo and optionally substituted by one or more substituents RA. D can also be preferably selected from C1-C6of alkyl, C2-C6alkenyl or C2-C6the quinil and optionally substituted by one or more substituents selected from halogen, RT, -O-Rs, -S-Rs, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. More preferably, D represents C5-C6carbocycle, 5-6-membered heterocycle, or 6-10-membered Bicycle and substituted by one or more substituents RMwhere RMrepresents halogen, nitro, oxo, phosphonooxy, phosphono, thioxo, cyano or-LS-RE. Also preferably, D represents phenyl and optionally substituted by one or more substituents RA. More preferably, D represents phenyl and substituted by one or more substituents RMwhere RMshall have the meaning given above. Most preferred is entrusted, D representswhere RMshall have the meaning given above, and each RNindependently selected from RDand preferably represents hydrogen.

Preferably, RMrepresents halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, cyano; or (C1-C6alkyl, C2-C6alkenyl or C2-C6quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or a 3-6-membered heterocycle, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil,1-C6halogenoalkane, C2-C6halogenoalkane or C2-C6halogenoalkane. More preferably, RMrepresents halogen, hydroxy, mercapto, amino, carboxy; or (C1-C6alkyl, C2-C6alkenyl or C2-C6quinil, each of which, regardless what about, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Most preferably, RMrepresents a C1-C6alkyl, which is optionally substituted by one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.

L1and L2preferably independently represent a1-C6alkylen, and L3preferably selected from communication With1-C6alkylene or-C(O)-. L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-Rs, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano. More preferably, L1and L2represent -(CH2is each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; and L3is a bond or-C(O)-.

R2and R5taken together with the atoms to which they are attached, preferably form a 5-6-membered heterocyclic ring (for example, or 6-8-membered Bicycle (for example,which is optionally substituted by one or more substituents RA.

R9and R12taken together with the atoms to which they are attached, preferably form a 5-6-membered heterocyclic ring (for example,or 6-8-membered Bicycle (for example,which is optionally substituted by one or more substituents RA.

-T-RD'may be, without limitation, independently selected in each case from-C(O)-LS'-RD', -C(O)O-LS'-RD', -C(O)-LS'-N(RB)C(O)-LS"-RD', -C(O)-LS'-N(RB)C(O)O-LS"-RD', -N(RB)C(O)-LS'-N(RB)C(O)-LS"-RD', -N(RB)C(O)-LS'-N(RB)C(O)O-LS"-RD'or-N(RB)C(O)-LS'-N(RB)-LS"-RD'. Preferably, -T-RD'is independently selected in each case from-C(O)-Ls'-M'-Ls"-RD'or-N(RB)C(O)-LS'-M'-LS"-RD'. More preferably, -T-RD'is independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"-RD'or-C(O)-LS'-N(RB)C(O)O-LS"-RD'.

-T-RD'can also be, without limitation, independently selected in each case from-C(O)-LY'-RD', -C(O)O-LY'-RD', -C(O)-LY'-N(RB)C(O)-LS "-RD', -C(O)-LY'-N(RB)C(O)O-LS"-RD', -N(RB)C(O)-LY'-N(RB)C(O)-LS"-RD', -N(RB)C(O)-LY'-N(RB)C(O)O-LS"-RD'or-N(RB)C(O)-LY'-N(RB)-LS"-RD'where LY'each independently represents an LS'and preferably each independently represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. Preferably, -T-RD'is independently selected in each case from-C(O)-LY'-M'-LS"-RD'or-N(RB)C(O)-LY'-M'-LS"-RD'. More preferably, -T-RD'is independently selected in each case from-C(O)-LY'-N(RB)C(O)-LS"-RD'or-C(O)-LY'-N(RB)C(O)O-LS"-RD'. Most preferably, -T-RD'is independently selected in each case from-C(O)-LY'-N(RB)C(O)-RD'or-C(O)-LY'-N(RB)C(O)O-RD'where LY'preferably each independently represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-Rs, -S-RS, -N(R SRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano.

RNBand Rc'are preferably hydrogen, and RD'are preferably independently selected in each case from the LAor 5 - or 6-membered carbocycle or heterocycle, which is optionally substituted by one or more substituents selected from halogen, RT, -O-RB, -S-RB, -N(RBRB'), -OC(O)RB, -C(O)ORB, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. More preferably, RD'is independently selected in each case from C1-C6of alkyl, C2-C6alkenyl or C2-C6the quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C3-C6carbocycle or a 3-6-membered heterocycle; or (C3-C6carbocycle or a 3-6-membered heterocycle, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1-C6of alkyl, C2-C6alkenyl, C2-C6quinil is, With1-C6halogenoalkane, C2-C6halogenoalkane or C2-C6halogenoalkane.

For each of the compounds of formula IALKcan also be independently selected in each instance of communication; -LS'-N(RB)C(O)-LS-; -LS'-C(O)N(RB)-LS-; or (C1-C6alkylene, C2-C6Alcanena, C2-C6akinlana, C3-C10carbocycle or 3-10-membered heterocycle, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano, where LSand LS'have the meanings given above.

RApreferably represents halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, cyano; or (C1-C6alkyl, C2-C6alkenyl or C2-C6quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or a 3-6-membered heterocycle, each of which, independently, not necessarily for what Eden in each case by one or more substituents, selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil,1-C6halogenoalkane, C2-C6halogenoalkane or2-C6halogenoalkane; or-LA-O-RS, -LA-S-RS, -LA-C(O)RS, -LA-OC(O)RS, -LA-C(O)ORS, -LA-N(RSRS'), -LA-S(O)RS, -LA-SO2RS, -LA-C(O)N(RSRS'), -LA-N(RS)C(O)RS', -LA-N(RS)C(O)N(RS'RS"), -LA-N(RS)SO2RS', -LA-SO2N(RSRS'), -LA-N(RS)SO2N(RS'RS"), -LA-N(RS)S(O)N(RS'RS"), -LA-OS(O)-RS, -LA-OS(O)2-RS, -LA-S(O)2ORS, -LA-S(O)ORS, -LA-OC(O)ORS, -LA-N(RS)C(O)ORS', -LA-OC(O)N(RSRS'), -LA-N(RS)S(O)-RS', -LA-S(O)N(RSRS'or-LA-C(O)N(RS)C(O)-RS'where LAis a relationship With1-C6alkylene, C2-C6alkanine or C2-C6akinyan.

More preferably, RArepresents halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, cyano;or (C 1-C6alkyl, C2-C6alkenyl or C2-C6quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or a 3-6-membered heterocycle, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil,1-C6halogenoalkane, C2-C6halogenoalkane or C2-C6halogenoalkane.

Most preferably, RArepresents halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, cyano; or (C1-C6alkyl, C2-C6alkenyl or C2-C6quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano.

LS, LS'and LS"preferably, each independently, in each case, ibrani of communication; or1-C6alkylene, C2-C6Alcanena or C2-C6albinyana.

A and B may be the same or different from each other. Also, L1and L2may be the same or different from each other.

In one variant embodiment of this aspect, A, B, and D, each independently, represent phenyl, and are each independently optionally substituted by one or more substituents RA. L1and L2each independently represent a1-C6alkylen, L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano. Preferably, L1and L2represent -(CH2is each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; and L3is a bond or-C(O)-. -T-RD'are preferably independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"-RD'Il is-C(O)-L S'-N(RB)C(O)O-LS"-RD'where LS'preferably represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. -T-RD'can also be, without limitation, selected from-C(O)-LS'-LS"-RD', -C(O)-LS'-O-LS"-RD', -C(O)-LS'-N(RB)-LS"-RD'or-C(O)-LS'-N(RB)S(O)2-LS"-RD'.

In another variant embodiment of this aspect A is aand optionally substituted by one or more substituents RA; B representsand optionally substituted by one or more substituents RA; and D represents C5-C6carbocycle or 5-6-membered heterocycle (e.g., phenyl), and optionally substituted by one or more substituents RA. Z1independently selected in each case from O, S, NH or CH2; and Z2independently selected in each case from N or CH. L1and L2each independently represent a1-C6alkylen, L3is a relationship With1-C6alkylene or-C(O)-, and L1 , L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano. Preferably, L1and L2represent -(CH2is each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; and L3is a bond or-C(O)-. -T-RD'are preferably independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"-RD'or-C(O)-LS'-N(RB)C(O)O-LS"-RD'where LS'preferably represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. T can also be, without limitation, selected from-C(O)-LS'-LS"-RD', -C(O)-LS'-O-LS"-RD', -C(O)-LS'-N(RB)-LS"-RD'or-C(O)-LS'-N(RB)S(O)2-LS"-RD'.

In od the Ohm variant embodiment of this aspect, A represents phenyl,and optionally substituted by one or more substituents RA; B represents phenyl,and optionally substituted by one or more substituents RA; and D represents C5-C6carbocycle or 5-6-membered heterocycle (e.g., phenyl), and optionally substituted by one or more substituents RA. Z1independently selected in each case from O, S, NH or CH2; and Z2independently selected in each case from N or CH. L1and L2each independently represent a1-C6alkylen, L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano. Preferably, L1and L2represent -(CH2is each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; and L3that is the link the Li-C(O)-. -T-RD'are preferably independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"-RD'or-C(O)-LS'-N(RB)C(O)O-LS"-RD'where LS'preferably represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. -T-RD'can also be, without limitation, selected from-C(O)-LS'-LS"-RD', -C(O)-LS'-O-LS"-RD', -C(O)-LS'-N(RB)-LS"-RD'or-C(O)-LS'-N(RB)S(O)2-LS"-RD'.

In another variant embodiment of this aspect A is aand optionally substituted by one or more substituents RA; and B representsand optionally substituted by one or more substituents RA; and D represents C5-C6carbocycle or 5-6-membered heterocycle (e.g., phenyl), and optionally substituted by one or more substituents RA. L1and L2each independently represent a1-C6alkylen, L3is a relationship With1-C6alkylene or-C(O)-, and L 1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano. Preferably, L1and L2represent -(CH2is each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; and L3is a bond or-C(O)-. -T-RD'are preferably independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"-RD'or-C(O)-LS'-N(RB)C(O)O-LS"-RD'where LS'preferably represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. -T-RD'can also be, without limitation, selected from-C(O)-LS'-LS"-RD', -C(O)-LS'-O-LS"-RD', -C(O)-LS'-N(RB)-LS"-RD'or-C(O)-LS'-N(RB)S(O)2-LS"-RD '.

In the following variant embodiment of this aspect A, B, and D, each independently, represent a5-C6carbocycle, 5-6-membered heterocycle (e.g., A, B, and D, each independently, represent phenyl), and each independently optionally substituted by one or more substituents RA. L1and L2each independently represent a1-C6alkylen, and L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. Preferably, L1and L2each independently represent a1-C6alkylene (for example, -CH2-), and L3that is the link. -T-RD'is independently selected in each case from-C(O)-LY'-N(RB)C(O)-LS"-RD'or-C(O)-LY'-N(RB)C(O)O-LS"-RD'where LY'represents a C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, CTI is about, the formyl or cyano, and LS"preferably represents a bond. -T-RD'can also be, without limitation, selected from-C(O)-LY'-LS"-RD', -C(O)-LY'-O-LS"-RD', -C(O)-LY'-N(RB)-LS"-RD'or-C(O)-LY'-N(RB)S(O)2-LS"-RD'.

In another aspect of the present invention includes compounds of formula IBand their pharmaceutically acceptable salts:

,

where:

RC'each independently selected from Rc;

RD'each independently selected from RD;

R2and R5taken together with the atoms to which they are attached, form a 3-8-membered heterocyclic ring, which is optionally substituted by one or more substituents RA;

R9and R12taken together with the atoms to which they are attached, form a 3-8-membered heterocyclic ring, which is optionally substituted by one or more substituents RA;

A, B, D, L1, L2, L3, T, RA, RCand RDhave the values described above for formula I.

In this aspect A and B are preferably independently selected from C5-C6carbocycle, 5-6-membered heterocycle or an 8-10 membered bicyclo, such aswhere Z1independently selected in each case and the O S, NH or CH2, Z2independently selected in each case from N or CH, Z3independently selected in each case from N or CH, Z4independently selected in each case from O, S, NH or CH2and W1, W2, W3, W4, W5and W6each independently in each instance selected from CH or N. A and B, each independently, optionally substituted by one or more substituents RA.

More preferably, A is selected from C5-C6carbocycle, 5-6-membered heterocycle,and optionally substituted by one or more substituents RA; B is selected from C5-C6carbocycle, 5-6-membered heterocycle,and optionally substituted by one or more substituents RAwhere Z1, Z2, Z3, Z4, W1, W2, W3, W4, W5, W6have the meanings given above. Preferably, Z3represents N, and Z4represents NH. For example, A can be selected from a phenyl (for example,and optionally substituted by one or more substituents RA; and may be selected from phenyland optionally substituted by one or more substituents RA./p>

Most preferably, A is selected fromand optionally substituted by one or more substituents RA; B is selected fromand optionally substituted by one or more substituents RAwhere Z1, Z2, Z3, Z4, W1, W2, W3, W4, W5, W6have the meanings given above. Preferably, Z3represents N, and Z4represents NH. For example, A can be selected fromand optionally substituted by one or more substituents RA; and B can be selected fromand optionally substituted by one or more substituents RA.

Also preferably, A representsand B representsA' and B' are independently selected from C5-C6carbocycle or 5-6-membered heterocycle, and A and B are independently optionally substituted by one or more substituents RA.

D is preferably selected from C5-C6carbocycle, 5-6-membered heterocycle or an 8-10 membered bicyclo and optionally substituted by one or more substituents RA. D can also be preferably selected from the 1-C6of alkyl, C2-C6alkenyl or C2-C6the quinil and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. More preferably, D represents C5-C6carbocycle, 5-6-membered heterocycle, or 6-10-membered Bicycle and substituted by one or more substituents RMwhere RMrepresents halogen, nitro, oxo, phosphonooxy, phosphono, thioxo, cyano or-LS-RE. Also preferably, D represents phenyl and optionally substituted by one or more substituents RA. More preferably, D represents phenyl and substituted by one or more substituents RMwhere RMshall have the meaning given above. Most preferably, D representswhere RMshall have the meaning given above, and each RNindependently selected from RDand preferably represents hydrogen.

Preferably, RMrepresents halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, cyano; or (C1-C6alkyl, C2-C6alkenyl or C2-C6quinil, each of to the which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; or (C3-C6carbocycle or a 3-6-membered heterocycle, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil,1-C6halogenoalkane, C2-C6halogenoalkane or C2-C6halogenoalkane. More preferably, RMrepresents halogen, hydroxy, mercapto, amino, carboxy; or (C1-C6alkyl, C2-C6alkenyl or C2-C6quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Most preferably, RMrepresents a C1-C6alkyl, which is optionally substituted by one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.

L1and L2preferably independently represent a1 -C6alkylen, and L3preferably selected from communication With1-C6alkylene or-C(O)-. L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano. More preferably, L1and L2represent -(CH2is each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; and L3is a bond or-C(O)-.

R2and R5taken together with the atoms to which they are attached, preferably form a 5-6-membered heterocyclic ring (for example,or 6-8-membered Bicycle (for example,which is optionally substituted by one or more substituents RA.

R9and R12taken together with the atoms to which they are attached, preferably form a 5-6-membered heterocyclic ring (for example,or 6-8-membered Bicycle (for example,which optional is entrusted substituted by one or more substituents R A.

-T-RD'may be, without limitation, independently selected in each case from-C(O)-LS'-RD', -C(O)O-LS'-RD', -C(O)-LS'-N(RB)C(O)-LS"-RD', -C(O)-LS'-N(RB)C(O)O-LS"-RD', -N(RB)C(O)-LS'-N(RB)C(O)-LS"-RD', -N(RB)C(O)-LS'-N(RB)C(O)O-LS"-RD'or-N(RB)C(O)-LS'-N(RB)-LS"-RD'. Preferably, -T-RD'is independently selected in each case from-C(O)-LS'-M'-LS"-RD'or-N(RB)C(O)-LS'-M'-LS"-RD'. More preferably, -T-RD'is independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"-RD'or-C(O)-LS'-N(RB)C(O)O-LS"-RD'.

-T-RD'can also be, without limitation, independently selected in each case from-C(O)-LY'-RD', -C(O)O-LY'-RD', -C(O)-LY'-N(RB)C(O)-LS"-RD', -C(O)-LY'-N(RB)C(O)O-LS"-RD', -N(RB)C(O)-LY'-N(RB)C(O)-LS"-RD', -N(RB)C(O)-LY'-N(RB)C(O)O-LS"-RD'or-N(RB)C(O)-LY'-N(RB)-LS"-RD'where LY'each independently represents an LS'and preferably, each independently, represents a C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more deputies who, selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. Preferably, -T-RD'is independently selected in each case from-C(O)-LY'-M'-LS"-RD'or-N(RB)C(O)-LY'-M'-LS"-RD'. More preferably, -T-RD'is independently selected in each case from-C(O)-LY'-N(RB)C(O)-LS"-RD'or-C(O)-LY'-N(RB)C(O)O-LS"-RD'. Most preferably, -T-RD'is independently selected in each case from-C(O)-LY'-N(RB)C(O)-RD'or-C(O)-LY'-N(RB)C(O)O-RD'where LY'preferably represents, each independently, With1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano.

Rc'preferably represents hydrogen, and RD'are preferably independently selected in each case from the LAor 5 - or 6-membered carbocycle or heterocycle, which is optionally substituted by one or more substituents selected from halogen, RT, -O-RB, -S-RB, -N(RBRB'), -OC(O)RB, -C(O)ORBthat bat is about, phosphonooxy, phosphono, oxo, thioxo, formyl or cyano. More preferably, RD'is independently selected in each case from C1-C6of alkyl, C2-C6alkenyl or C2-C6the quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C3-C6carbocycle or a 3-6-membered heterocycle; or (C3-C6carbocycle or a 3-6-membered heterocycle, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil,1-C6halogenoalkane, C2-C6halogenoalkane or C2-C6halogenoalkane.

For each of the compounds of formula IBLkcan also be independently selected in each case, of the communication; -LS'-N(RB)C(O)-LS-; -LS'-C(O)N(RB)-LS-; or (C1-C6alkylene, C2-C6Alcanena, C2-C6akinlana, C3-C10carbocycle or 3-10-membered heterocycle, each of which, independently, not battelino substituted in each case by one or more substituents, selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano, where LSand LS'have the meanings given above.

RApreferably represents halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, cyano; or (C1-C6alkyl, C2-C6alkenyl or C2-C6quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; or (C3-C6carbocycle or a 3-6-membered heterocycle, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil,1-C6halogenoalkane, C2-C6halogenoalkane or C2-C6halogenoalkane; or-LA-O-Rs, -LA-S-RS, -LA-C(O)RS, -LA-OC(O)RS, -LA-C(O)ORS, -LA-N(RSRS'), -LA-S(O)RS, -LA-SO2R , -LA-C(O)N(RSRS'), -LA-N(RS)C(O)RS', -LA-N(RS)C(O)N(RS'RS"), -LA-N(RS)SO2RS', -LA-SO2N(RSRS'), -LA-N(RS)SO2N(RS'RS"), -LA-N(RS)S(O)N(RS'RS"), -LA-OS(O)-RS, -LA-OS(O)2-RS, -LA-S(O)2ORS, -LA-S(O)ORS, -LA-OC(O)ORS, -LA-N(RS)C(O)ORS', -LA-OC(O)N(RSRS'), -LA-N(RS)S(O)-RS', -LA-S(O)N(RSRS'or-LA-C(O)N(RS)C(O)-RS'where LAis a relationship With1-C6alkylene, C2-C6alkanine or C2-C6akinyan.

More preferably, RArepresents halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, cyano; or (C1-C6alkyl, C2-C6alkenyl or C2-C6quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or a 3-6-membered heterocycle, each of which, independently, optionally substituted in each case by one or more substituents selected is passed from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil,1-C6halogenoalkane, C2-C6halogenoalkane or C2-C6halogenoalkane.

Most preferably, RArepresents halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, cyano; or (C1-C6alkyl, C2-C6alkenyl or C2-C6quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano.

LS, LS'and LS"preferably, each independently, in each case selected from the communication; or (C1-C6alkylene, C2-C6Alcanena or C2-C6albinyana.

A and B may be the same or different from each other. Also, L1and L2may be the same or different from each other.

In one variant embodiment of this aspect, A, B, and D, each independently, represent phenyl, and are each independently optionally substituted by one or more substituents RA. L1and L2each independently predstavljaetsja 1-C6alkylen, L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano. Preferably, L1and L2represent -(CH2is each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; and L3is a bond or-C(O)-. -T-RD'are preferably independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"-RD'or-C(O)-LS'-N(RB)C(O)O-LS"-RD'where LS'preferably represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. -T-RD'can also be, without limitation, selected from-C(O)-LS'-LS"-RD', -C(O)-LS'-O-LS"-RD ', -C(O)-LS'-N(RB)-LS"-RD'or-C(O)-LS'-N(RB)S(O)2-LS"-RD'.

In another variant embodiment of this aspect And is aand optionally substituted by one or more substituents RA; Is aand optionally substituted by one or more substituents RA; and D represents C5-C6carbocycle or 5-6-membered heterocycle (e.g., phenyl), and optionally substituted by one or more substituents RA. Z1independently selected in each case from O, S, NH or CH2; and Z2independently selected in each case from N or CH. L1and L2each independently represent a1-C6alkylen, L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano. Preferably, L1and L2represent -(CH2is each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N( SRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; and L3is a bond or-C(O)-. -T-RD'are preferably independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"-RD'or-C(O)-LS'-N(RB)C(O)O-LS"-RD'where LS'preferably represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. -T-RD'can also be, without limitation, selected from-C(O)-LS'-LS"-RD', -C(O)-LS'-O-LS"-RD', -C(O)-LS'-N(RB)-LS"-RD'or-C(O)-LS'-N(RB)S(O)2-LS"-RD'. -T-RD'may also be independently selected in each case from-C(O)-LY'-N(RB)C(O)-LS"-RD'or-C(O)-LY'-N(RB)C(O)O-LS"-RD'where LY'represents a C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano, and LS"predpochtitelno is a link. -T-RD'can also be, without limitation, selected from-C(O)-LY'-LS"-RD', -C(O)-LY'-O-LS"-RD', -C(O)-LY'-N(RB)-LS"-RD'or-C(O)-LY'-N(RB)S(O)2-LS"-RD'.

In another variant embodiment of this aspect, A is phenyl,and optionally substituted by one or more substituents RA; B represents phenyl,and optionally substituted by one or more substituents RA; and D represents C5-C6carbocycle or 5-6-membered heterocycle (e.g., phenyl), and optionally substituted by one or more substituents RA. Z1independently selected in each case from O, S, NH or CH2; and Z2independently selected in each case from N or CH. L1and L2each independently represent a1-C6alkylen, L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano. Preferably, L1and L2represent -(CH2and each is th independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; and L3is a bond or-C(O)-. -T-RD'are preferably independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"-RD'or-C(O)-LS'-N(RB)C(O)O-LS"-RD'where LS'preferably represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. -T-RD'can also be, without limitation, selected from-C(O)-LS'-LS"-RD', -C(O)-LS'-O-LS"-RD', -C(O)-LS'-N(RB)-LS"-RD'or-C(O)-LS'-N(RB)S(O)2-LS"-RD'.

In another variant embodiment of this aspect, A is aand optionally substituted by one or more substituents RA; and B representsand optionally substituted by one or more substituents RA; and D represents C5-C6carbocyclic 5-6-membered heterocycle (e.g., phenyl and optionally substituted by one or more substituents RA. L1and L2each independently represent a1-C6alkylen, L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano. Preferably, L1and L2represent -(CH2is each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; and L3is a bond or-C(O)-. -T-RD'are preferably independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"-RD'or-C(O)-LS'-N(RB)C(O)O-LS"-RD'where LS'preferably represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, t is CSR the formyl or cyano. -T-RD'can also be, without limitation, selected from-C(O)-LS'-LS"-RD', -C(O)-LS'-O-LS"-RD', -C(O)-LS'-N(RB)-LS"-RD'or-C(O)-LS'-N(RB)S(O)2-LS"-RD'.

In another aspect of the present invention also includes compounds of formula ICand their pharmaceutically acceptable salts.

,

where:

RNBis an RB;

Rc'each independently selected from Rc;

RD'each independently selected from RD;

R2and R5taken together with the atoms to which they are attached, form a 3-8-membered heterocyclic ring, which is optionally substituted by one or more substituents RA;

R9and R12taken together with the atoms to which they are attached, form a 3-8-membered heterocyclic ring, which is optionally substituted by one or more substituents RA;

A, B, D, L1, L2, L3, T, RA, RB, Rcand RDhave the meanings given above in formula I.

In this aspect, A and B, preferably, independently selected from C5-C6carbocycle, 5-6-membered heterocycle or an 8-10 membered bicyclo, such aswhere Z1independently selected in each case the C O S, NH or CH2, Z2independently selected in each case from N or CH, Z3independently selected in each case from N or CH, Z4independently selected in each case from O, S, NH or CH2and W1, W2, W3, W4, W5and W6each independently in each instance selected from CH or N. A and B, each independently, optionally substituted by one or more substituents RA.

More preferably, A is selected from C5-C6carbocycle, 5-6-membered heterocycle,and optionally substituted by one or more substituents RA; Selected from C5-C6carbocycle, 5-6-membered heterocycle,and optionally substituted by one or more substituents RAwhere Z1, Z2, Z3, Z4, W1, W2, W3, W4, W5, W6have the meanings given above. Preferably, Z3represents N, and Z4represents NH. For example, A can be selected from a phenyl (for example,and optionally substituted by one or more substituents RA; and may be selected from phenyl (for example,and optionally substituted by one or more substituents RA.

Most preferably, A not only is em a C 5-C6carbocycle or 5-6-membered heterocycle, and optionally substituted by one or more substituents RA; and B preferably represents an 8-10-membered Bicycle (such asand optionally substituted by one or more substituents RA. Z1represents O, S, NH or CH2; Z2represents N or CH; Z3represents N or CH; Z4represents O, S, NH or CH2; and W1, W2, W3, W4, W5and W6each independently selected from CH or N.

Most preferably, A is a phenyl (for example,and optionally substituted by one or more substituents RA; and B representsand optionally substituted by one or more substituents RAwhere Z1, Z2, Z3, Z4, W1, W2, W3, W4, W5, W6have the meanings given above. Preferably, Z3represents N, and Z4represents NH. For example, can be a

and optionally substituted by one or more substituents RA.

Also preferably, A represents a C5-C6carbonyl(for example, phenyl or 5-6-membered heterocycle, and B representsB' is selected from C5-C6carbocycle or 5-6-membered heterocycle, and A and B are, independently, optionally substituted by one or more substituents RA.

D is preferably selected from C5-C6carbocycle, 5-6-membered heterocycle or an 8-10 membered bicyclo and optionally substituted by one or more substituents RA. D can also be preferably selected from C1-C6of alkyl, C2-C6alkenyl or C2-C6the quinil and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. More preferably, D represents C5-C6carbocycle, 5-6-membered heterocycle, or 6-10-membered Bicycle and substituted by one or more substituents RMwhere RMrepresents halogen, nitro, oxo, phosphonooxy, phosphono, thioxo, cyano or-LS-RE. Also preferably, D represents phenyl and optionally substituted by one or more substituents RA. More preferably, D represents phenyl and substituted by one or more substituents RMwhere RMhas a value which, defined above. Most preferably, D representswhere RMshall have the meaning given above, and each RNindependently selected from RDand preferably represents hydrogen.

Preferably, RMrepresents halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, cyano; or (C1-C6alkyl, C2-C6alkenyl or C2-C6quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or a 3-6-membered heterocycle, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil,1-C6halogenoalkane, C2-C6halogenoalkane or C2-C6halogenoalkane. More preferably, RMrepresents halogen, hydroxy, mercapto, amino, carboxy; or (C1-C6alkyl, C2-C6alkenyl or 2-C6quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Most preferably, RMrepresents a C1-C6alkyl, which is optionally substituted by one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.

L1and L2preferably independently represent a1-C6alkylen, and L3preferably selected from communication With1-C6alkylene or-C(O)-. L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano. More preferably, L1and L2represent -(CH2is each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; and L3is a bond or-C(O)-.

R2and R5taken together with the atoms to which they are attached, preferably the image of the t 5-6-membered heterocyclic ring (for example, or 6-8-membered Bicycle (for example,which is optionally substituted by one or more substituents RA.

R9and R12taken together with the atoms to which they are attached, preferably form a 5-6-membered heterocyclic ring (for example,or 6-8-membered Bicycle (for example,which is optionally substituted by one or more substituents RA.

-T-RD'may be, without limitation, independently selected in each case from-C(O)-LS'-RD', -C(O)O-LS'-RD', -C(O)-LS'-N(RB)C(O)-LS"-RD', -C(O)-LS'-N(RB)C(O)O-LS"-RD', -N(RB)C(O)-LS'-N(RB)C(O)-LS"-RD', -N(RB)C(O)-LS'-N(RB)C(O)O-LS"-RD'or-N(RB)C(O)-LS'-N(RB)-LS"-RD'. Preferably, -T-RD'is independently selected in each case from-C(O)-LS'-M'-LS"-RD'or-N(RB)C(O)-LS'-M'-LS"-RD'. More preferably, -T-RD'is independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"-RD'or-C(O)-LS'-N(RB)C(O)O-LS"-RD'.

-T-RD'can also be, without limitation, independently selected in each case from-C(O)-LY'-RD', -C(O)O-LY'-RD', -C(O)-L Y'-N(RB)C(O)-LS"-RD', -C(O)-LY'-N(RB)C(O)O-LS"-RD', -N(RB)C(O)-LY'-N(RB)C(O)-LS"-RD', -N(RB)C(O)-LY'-N(RB)C(O)O-LS"-RD'or-N(RB)C(O)-LY'-N(RB)-LS"-RD'where LY'each independently represents an LS'and preferably, each independently, represents a C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. Preferably, -T-RD'is independently selected in each case from-C(O)-LY'-M'-LS"-RD'or-N(RB)C(O)-LY'-M'-LS"-RD'. More preferably, -T-RD'is independently selected in each case from-C(O)-LY'-N(RB)C(O)-LS"-RD'or-C(O)-LY'-N(RB)C(O)O-LS"-RD'. Most preferably, -T-RD'is independently selected in each case from-C(O)-LY'-N(RB)C(O)-RD'or-C(O)-LY'-N(RB)C(O)O-RD'where LY'preferably each independently represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-R S, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano.

RNBand Rc'preferably represent hydrogen, and RD'are preferably independently selected in each case from the LAor 5 - or 6-membered carbocycle or heterocycle, which is optionally substituted by one or more substituents selected from halogen, RT, -O-RB, -S-RB, -N(RBRB'), -OC(O)RB, -C(O)ORB, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. More preferably, RD'is independently selected in each case from C1-C6of alkyl, C2-C6alkenyl or C2-C6the quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C3-C6carbocycle or a 3-6-membered heterocycle; or (C3-C6carbocycle or a 3-6-membered heterocycle, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1-C6of alkyl, C2-C6alkenyl, C -C6the quinil,1-C6halogenoalkane, C2-C6halogenoalkane or2-C6halogenoalkane.

For each of the compounds of formula IcLKcan also be independently selected in each instance of communication; -LS'-N(RB)C(O)-LS-; -LS'-C(O)N(RB)-LS-; or (C1-C6alkylene, C2-C6Alcanena,2-C6akinlana, C3-C10carbocycle or 3-10-membered heterocycle, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano, where LSand LS'have the meanings given above.

RApreferably represents halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, cyano; or (C1-C6alkyl, C2-C6alkenyl or C2-C6quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or a 3-6-membered heterocycle, each of which, regardless what about, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil,1-C6halogenoalkane, C2-C6halogenoalkane or C2-C6halogenoalkane; or-LA-O-RS, -LA-S-RS, -LA-C(O)RS, -LA-OC(O)RS, -LA-C(O)ORS, -LA-N(RSRS'), -LA-S(O)RS, -LA-SO2RS, -LA-C(O)N(RSRS'), -LA-N(RS)C(O)RS', -LA-N(RS)C(O)N(RS'RS"), -LA-N(RS)SO2RS', -LA-SO2N(RSRS'), -LA-N(RS)SO2N(RS'RS"), -LA-N(RS)S(O)N(RS'RS"), -LA-OS(O)-RS, -LA-OS(O)2-RS, -LA-S(O)2ORS, -LA-S(O)ORS, -LA-OC(O)ORS, -LA-N(RS)C(O)ORS', -LA-OC(O)N(RSRS'), -LA-N(RS)S(O)-RS', -LA-S(O)N(RSRS'or-LA-C(O)N(RS)C(O)-RS'where LAis a relationship With1-C6alkylene, C2-C6alkanine or C2-C6akinyan.

More preferably, RArepresents halogen, hydro is si, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, cyano; or (C1-C6alkyl, C2-C6alkenyl or C2-C6quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or a 3-6-membered heterocycle, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl, cyano, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil,1-C6halogenoalkane, C2-C6halogenoalkane or C2-C6halogenoalkane.

Most preferably, RArepresents halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, cyano; or (C1-C6alkyl, C2-C6alkenyl or C2-C6quinil, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano.

L S, LS'and LS"preferably, each independently, in each case selected from the communication; or (C1-C6alkylene, C2-C6Alcanena or C2-C6albinyana.

A and B may be the same or different from each other. Also, L1and L2may be the same or different from each other.

In one variant embodiment of this aspect, A, B, and D, each independently, represent phenyl, and are each independently optionally substituted by one or more substituents RA. L1and L2each independently represent a1-C6alkylen, L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano. Preferably, L1and L2represent -(CH2is each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; and L3is a bond or-C(O)-. -T-RD'before occhialino independently selected in each case from-C(O)-L S'-N(RB)C(O)-LS"-RD'or-C(O)-LS'-N(RB)C(O)O-LS"-RD'where LS'preferably represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. -T-RD'can also be, without limitation, selected from-C(O)-LS'-LS"-RD', -C(O)-LS'-O-LS"-RD', -C(O)-LS'-N(RB)-LS"-RD'or-C(O)-LS'-N(RB)S(O)2-LS"-RD'.

In another variant embodiment of this aspect, A is aand optionally substituted by one or more substituents RA; Is aand optionally substituted by one or more substituents RA; and D represents C5-C6carbocycle or 5-6-membered heterocycle (e.g., phenyl), and optionally substituted by one or more substituents RA. Z1independently selected in each case from O, S, NH or CH2; and Z2independently selected in each case from N or CH. L1and L2each independently represent a1-C6alkylen, L3is the Wallpaper link, With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano. Preferably, L1and L2represent -(CH2is each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; and L3is a bond or-C(O)-. -T-RD'are preferably independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"-RD'or-C(O)-LS'-N(RB)C(O)O-LS"-RD'where LS'preferably represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. -T-RD'can also be, without limitation, selected from-C(O)-LS'-LS"-RD', -C(O)-LS'-O-LS"-RD', -C(O)-LS'-N(RB)-LS"-RD'or-C(O)-LS '-N(RB)S(O)2-LS"-RD'.

In another variant embodiment of this aspect, A is phenyl,and optionally substituted by one or more substituents RA; B represents phenyl,and optionally substituted by one or more substituents RA; and D represents C5-C6carbocycle or 5-6-membered heterocycle (e.g., phenyl), and optionally substituted by one or more substituents RA. Z1independently selected in each case from O, S, NH or CH2; and Z2independently selected in each case from N or CH. L1and L2each independently represent a1-C6alkylen, L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano. Preferably, L1and L2represent -(CH2is each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)OR , nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; and L3is a bond or-C(O)-. -T-RD'are preferably independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"-RD'or-C(O)-LS'-N(RB)C(O)O-LS"-RD'where LS'preferably represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. -T-RD'can also be, without limitation, selected from-C(O)-LS'-LS"-RD', -C(O)-LS'-O-LS"-RD', -C(O)-LS'-N(RB)-LS"-RD'or-C(O)-LS'-N(RB)S(O)2-LS"-RD'.

In another variant embodiment of this aspect, A is aand optionally substituted by one or more substituents RA; and B representsandoptionally substituted by one or more substituents RA; and D represents C5-C6carbocycle or 5-6-membered heterocycle (e.g., phenyl), and optionally substituted by one or more substituents RA. L1and L2, each independently, before which represent 1-C6alkylen, L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano. Preferably, L1and L2represent -(CH2is each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano; and L3is a bond or-C(O)-. -T-RD'are preferably independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"-RD'or-C(O)-LS'-N(RB)C(O)O-LS"-RD'where LS'preferably represents C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. -T-RD'can also be, without limitation, selected from-C(O)-LS'-LS"-RD', -C(O)-LS'-O-LS"-RD ', -C(O)-LS'-N(RB)-LS”-RD'or-C(O)-LS'-N(RB)S(O)2-LS"-RD'.

In the following variant embodiment of this aspect, A is phenyl and optionally substituted by one or more substituents RA; and B representsand optionally substituted by one or more substituents RAwhere Z1represents O, S, NH or CH2; and Z2represents N or CH. D represents C5-C6carbocycle or 5-6-membered heterocycle (e.g., phenyl), and optionally substituted by one or more substituents RA. L1and L2each independently represent a1-C6alkylen, and L3is a relationship With1-C6alkylene or-C(O)-, and L1, L2and L3each independently optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano. Preferably, L1and L2each independently represent a1-C6alkylene (for example, -CH2-), and L3that is the link. -T-RD'is independently selected in each case from-C(O)-LY'-N(RB)C(O)-LS"-RD'or-C(O)-LY '-N(RB)C(O)O-LS"-RD'where LY'represents a C1-C6alkylene (for example, -CH2-) and optionally substituted by one or more substituents selected from halogen, RT, -O-RS, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, phosphonate, phosphono, oxo, thioxo, formyl or cyano, and LS"preferably represents a bond. -T-RD'can also be, without limitation, selected from-C(O)-LY'-LS"-RD', -C(O)-LY'-O-LS"-RD', -C(O)-LY'-N(RB)-LS"-RD'or-C(O)-LY'-N(RB)S(O)2-LS"-RD'.

The present invention also includes compounds of formulas I, IA, IBand Icdescribed in this application (including each embodiment described in this application), or their salts, except for the case when D is a C3-C10carbocycle or 3-10-membered heterocycle, which is substituted with J and optionally substituted by one or more substituents RAwhere J represents a C3-C10carbocycle or 3-10-membered heterocycle, and optionally substituted by one or more substituents RAor J represents-SF5. Preferably, D represents C5-C6carbocycle, 5-6-membered heterocycle, or 6-10-membered Bicycle and not necessarily amesen one or more substituents R Aand J represents C3-C6carbocycle or a 3-6-membered heterocycle, and optionally substituted by one or more substituents RA. More preferably, D represents C5-C6carbocycle or 5-6-membered heterocycle, and optionally substituted by one or more substituents RAand J represents C3-C6carbocycle or a 3-6-membered heterocycle, and optionally substituted by one or more substituents RA. Most preferably, D represents phenyl, substituted Deputy J, and optionally substituted by one or more substituents RAwhere J represents a C3-C6carbocycle or a 3-6-membered heterocycle, and optionally substituted by one or more substituents RA. Preferred groups RAhave the meanings given above. In one variant of embodiment D is awhere each RNindependently selected from RDand preferably represents hydrogen, and J has the meaning given above and preferably represents a C3-C6carbocycle or a 3-6-membered heterocycle, optionally substituted by one or more substituents RA. In another variant embodiment of the present invention,D represents and J represents C3-C6carbocycle or a 3-6-membered heterocycle, and optionally substituted by one or more substituents RA.

The present invention also includes compounds of formulas I, IA, IBand Icdescribed in this application (including each embodiment described in this application), or their salts, except when:

R1and R2each independently represent Rcand R5is an RB; or R1is an Rcand R2and R5taken together with the atoms to which they are attached, form a 3-10-membered heterocyclic ring, which is optionally substituted by one or more substituents RA; and

R3, R4, R6and R7each independently represent Rc; or R3and R6each independently represent Rcand R4and R7taken together with the atoms to which they are attached, form a 3-10-membered carbocyclic or heterocyclic ring, which is optionally substituted by one or more substituents RA.

Compounds of the present invention can be used in the form of salts. Depending on the specific compound, the salt of the compounds may have advantages due to one or more physical and the mental properties of such salts, such as the best pharmaceutical stability under certain conditions, or a desirable solubility in water or oil. In some cases, the salt of the compound may be useful for isolation or purification of compounds.

When salt is intended for introduction to the patient, the salt is preferably a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include, but are not limited to, an acid additive salt, basic additive salts and alkali metal salts.

Pharmaceutically acceptable acid salt additive can be obtained from inorganic or organic acids. Examples of suitable inorganic acids include, but are not limited to, hydrochloric, Hydrobromic, yodiewonderdog, nitric, carbonic, sulfuric and phosphoric acid. Examples of suitable organic acids include, but are not limited to, organic acids are aliphatic, cycloaliphatic, aromatic, analiticheskogo, heterocyclyl, carboxylic and sulfonic classes. Specific examples of suitable salts of organic acids include acetate, triptorelin, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, salt of tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, salt of Anthranilic the acid, mesilate, stearate, salicylate, para-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, aconsultant, bansilalpet, Pantothenate, toluensulfonate, 2-hydroxyethanesulfonic, sulfanilate, cyclohexylsulfamate, salt alienboy acid, b-hydroxybutyric acid, galactarate, galacturonic, adipate, alginate, bisulfate, butyrate, comfort, camphorsulfonate, cyclopentanepropionate, dodecyl sulphate, glucoheptonate, glycyrrhizinate, hemisulfate, heptanoate, hexanoate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, thiocyanate, toilet, undecanoate.

Pharmaceutically acceptable basic additive salts include, but are not limited to, metal salts and organic salts. Non-limiting examples of suitable metal salts include salts of alkali metals (group Ia), salts of alkaline earth metals (group IIa) and other pharmaceutically acceptable metal salts. Such salts can be obtained, without limitation, aluminum, calcium, lithium, magnesium, potassium, sodium or zinc. Non-limiting examples of suitable organic salts can be derived from tertiary amines and Quaternary amine, such as tromethamine, diethylamine, N,N'-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine) and procaine. The basics what's nitrogen-containing groups can be stereoselectivity agents, such as alkylhalogenide (for example, methyl, ethyl, propyl, butyl, decyl, lauryl, myristyl and stearyl chlorides/bromides/iodides), diallylsulfide (e.g., dimethyl, diethyl, dibutil and diamyl sulfates), aralkylated (for example, benzyl and phenethyl bromides), and others.

Compounds or salts of the present invention can exist in the form of a solvate, such as formed with water (i.e., hydrates) or organic solvents (e.g. methanol, ethanol or acetonitrile with education, respectively, methanolate, ethanolate or acetonitrile).

Compounds or salts of the present invention can also be used in the form of prodrugs. Some prodrugs are aliphatic or aromatic esters formed from acid groups contained in the compounds of the present invention. Others are aliphatic or aromatic esters of hydroxyl or amino group of the compounds of the present invention. Phosphate prodrugs formed by hydroxyl groups, are preferred prodrugs.

Compounds of the present invention may include asimmetricheskii substituted carbon atoms, known as chiral centers. These compounds can exist, without limitation, in the form of single stereoisomers (e.g. the R, individual enantiomers or a single diastereoisomer), mixtures of stereoisomers (for example, a mixture of enantiomers or diastereomers) or racemic mixtures. The connections defined in this application as a separate stereoisomers, mean compounds that are present in the form, which essentially contains no other stereoisomers (for example, essentially contains no other enantiomers or diastereomers). "Essentially does not contain" means that at least 80% of the compounds in the composition described is a stereoisomer; preferably, at least 90% of the compound in the composition is opisywany stereoisomer; and more preferably, at least, 95%, 96%, 97%, 98% or 99% of compound in the composition described is a stereoisomer. When the stereochemistry of the chiral carbon is not specifically listed in the chemical structure of the compounds, it is assumed that the chemical structure covers compounds containing any stereoisomer of a chiral center.

Individual stereoisomers of compounds of the present invention can be obtained using various methods known from the prior art. These methods include, but are not limited to, stereospecific synthesis, chromatographic separation of the diastereomers, the chromatographic separation of enantiomers, the transformation of the W enantiomers in an enantiomeric mixture to diastereomers and subsequent chromatographic separation of the diastereomers and recovering the individual enantiomers and enzymatic separation.

Stereospecific synthesis usually involves the use of a suitable optically pure (enantiomerically pure) or substantially optically pure substances and reactions of synthesis, which do not cause racemization or inversion of stereochemistry at the chiral centers. Mixtures of stereoisomers of compounds, including racemic mixtures, obtained in reactions of synthesis, can be divided, for example, chromatographic methods, as is well known to specialists in this area with average skills. Chromatographic separation of enantiomers can be accomplished by use of chiral resins for chromatography, many of which are commercially available. In a non-limiting example, the racemate is placed in the solution and loaded into a column containing a chiral stationary phase. Enantiomers can then be shared by using HPLC.

The separation of enantiomers can be accomplished by conversion of the enantiomers in the mixture of diastereoisomers by the interaction with chiral auxiliaries. The resulting diastereomers can be divided column chromatography or crystallization/recrystallization. This method is useful when the compounds to be separated contain carboxyl, amino or hydroxyl group which will form a salt or covalent bond with chiral VSP the service agent. Non-limiting examples of suitable chiral auxiliary substances include pure chiral amino acids, organic carboxylic acids or organosulfate acid. After separation of the diastereomers by chromatography, can be restored individual enantiomers. Often chiral auxiliary substance can be extracted and used again.

Enzymes such as esterase, phosphatase or lipase may be useful to separate the derivatives of the enantiomers in an enantiomeric mixture. For example, the ester derivative of the carboxy group in the compounds subject to separation, can be treated with enzyme selectively hydrolyzes only one of the enantiomers in the mixture. Obtained enantiomerically pure acid can then be separated from the non-hydrolyzed ether complex.

Alternatively, the salts of the enantiomers in the mixture can be obtained using any suitable method known from the prior art, including processing carboxylic acid with a suitable optically pure base, such as alkaloids or penicillin, followed by precipitation or crystallization/recrystallization enantiomerically pure salts. Methods suitable for decomposition into components/separating a mixture of stereoisomers including a racemic mixture can be found in ENANTIOMERS, RACEMATES, AND RESOLUTIONS (Jacques et a., 1981, John Wiley and Sons, New York, NY).

The compound of the present invention may contain one or more unsaturated carbon-carbon double bonds. All isomers on double bond, such as CIS(Z) and TRANS(E) isomers, and mixtures thereof covered by the volume of disclosed compounds, unless otherwise noted. In addition, when the connection exists in various tautomeric forms, the specified connection is not limited to any one specific tautomerism, but it is expected that covers all tautomeric forms.

Some compounds of the present invention may exist in different stable conformational forms which may be separated. Torsional asymmetry as a result of limited spins around the asymmetric simple communication, for example, because of the spatial strain or deformation of the ring, makes possible the separation of the various conformers. The present invention covers each conformational isomer of these compounds and mixtures thereof.

Some compounds of the present invention can also exist in zwitterionic form, and the present invention covers every zwitterion form of these compounds and mixtures thereof.

Compounds of the present invention in General terms described in this application using standard nomenclature. As for ukazannoj the connection, containing asymmetric center (centers), it should be clear that all stereoisomers of the compounds and their mixtures are encompassed by the present invention, unless otherwise indicated. Non-limiting examples of stereoisomers include enantiomers, diastereomers, CIS-TRANS isomers. When the specified connection exists in various tautomeric forms, it is assumed that the connection encompasses all tautomeric forms. Some compounds described in this application using a General formula that includes variables (e.g., A, B, D, X, L1, L2, L3, Y, Z, T, RAor RB). Unless otherwise specified, each variable within such a formula is defined independently of any other variable, and any variable that appears more than once in a formula is defined independently in each case her presence. If the fragments are described as "independent" is selected from the group, each fragment is selected independently of the other. Each fragment can therefore be identical to or different from another fragment or group.

The number of carbon atoms in the hydrocarbon group may be indicated by the prefix "Cx-Cy",where x is the minimum and y is the maximum number of carbon atoms in such a group. So, for example, "C1-C6alkyl" refers to alkyl Deputy containing from 1 to 6 and the Ohm carbon. As another example, C3-C6cycloalkyl means a saturated hydrocarbon ring containing from 3 to 6 carbon ring atoms. The prefix used for multicomponent Deputy, applies only to the first component, which directly follows the prefix. To illustrate, the term "carbocyclic" contains two components: carbocyclic and alkyl. Thus, for example, C3-C6carbocyclic1-C6alkyl refers to C3-C6carbocyclic attached to the original molecular fragment through With1-C6alkyl group.

Unless otherwise stated, when the connecting element connects two other elements in the specified chemical structure, the leftmost specified component connecting element is connected with the left element in the described structure, and the rightmost specified component connecting element is connected with the right element in the described structure. For illustration, when the chemical structure is an LS-M-LS'- and M means-N(RB)S(O)-, then the chemical structure is an Ls-N(RB)S(O)-Ls'-.

When linking element in this structure is a relation, then the element to the left of a connecting element associated with the element to the right of the binding is found element via a covalent bond. For example, when the chemical structure is specified as-LS-M-LS'- and M is selected as meaning the connection, then the chemical structure will be a-LS-LS'-. When two or more adjacent binding elements in this structure are due, then the element to the left of these connecting elements associated with the element to the right of these connecting elements through a covalent bond. For example, when the chemical structure is specified as-LS-M-LS'-M'-LS"and M and LS'is selected as means of communication, then the chemical structure will be a-LS-M'-LS"-. Also, when the chemical structure is specified as-LS-M-LS'-M'-LS"- M, LS'and M' are due, then the chemical structure will be a-LS-LS"-.

When a chemical formula is used to describe the group, dashed line (line) specifies the group that contains the free valence (valence).

When a group is described as being "optionally substituted", this group may be either substituted or unsubstituted. When a group is described as being optionally substituted by a group a certain number of non-hydrogen radicals, such group may be either unsubstituted or substituted non-hydrogen glad the Kalami in the amount up to the specified or until the maximum number of substitutable positions in this group, which is less. Thus, for example, when a group is described as a heterocycle, optionally substituted non-hydrogen radicals in the amount of up to three, then any heterocycle less than three substituted provisions will be optional substituted only so many non-hydrogen radicals, how many of superseded provisions in the heterocycle. For illustration, tetrazolyl (which contains only one substitutable position) is optionally substituted non-hydrogen radical in the number down to one. To further illustrate, when the nitrogen of the amino group is described as optionally substituted non-hydrogen radicals in the amount of up to two, then the nitrogen of the primary amine is optionally substituted non-hydrogen radicals in the amount of up to two, whereas the nitrogen of the secondary amine is optionally substituted by only one non-hydrogen radical.

The term "alkenyl" means linear or branched hydrocarbon chain containing one or more double bonds. Each carbon-carbon double bond may be either CIS or TRANS geometry in alkenylphenol group, relative to the groups substituted on the carbon atoms of a double bond. Non-limiting examples alkenyl groups include ethynyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl and 3-butenyl.

The term "alkanine" refers to a divalent unsaturated hydrocarbon chain that may be linear or branched and contains at least one carbon-carbon double bond. Non-limiting examples alkenylamine groups include-C(H)=C(H)-, -C(H)=C(H)-CH2-, -C(H)=C(H)-CH2-CH2-, -CH2-C(H)=C(H)-CH2-, -C(H)=C(H)-CH(CH3)- and-CH2-C(H)=C(H)-CH(CH2CH3)-.

The term "alkyl" means a linear or branched saturated hydrocarbon chain. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl and hexyl.

The term "alkylene" means a divalent saturated hydrocarbon chain that may be linear or branched. Representative examples of alkylene include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2- and-CH2CH(CH3)CH2-.

The term "quinil" means a linear or branched uglevodorodno chain containing one or more triple bonds. Non-limiting examples of quinil include ethinyl, 1-PROPYNYL, 2-PROPYNYL, 3-PROPYNYL, decenyl, 1-butenyl, 2-butenyl and 3-butenyl.

The term "akinyan" refers to a divalent unsaturated hydrocarbon group, which may be the linear or branched and contains at least one carbon-carbon triple bond. Representative alkenylamine groups include, as an example, -C≡C-, -C≡C-CH2-, -C≡C-CH2-CH2-, -CH2-C≡C-CH2-, -C≡C-CH(CH3)- and-CH2-C≡C-CH(CH2CH3)-.

The term "carbocycle" or "carbocyclic" or "carbocyclic" refers to a saturated (e.g., "cycloalkyl"), partially saturated (e.g., "cycloalkenyl" or "cycloalkenyl") or completely unsaturated (e.g., "aryl") ring system containing zero heteroatoms in the number of ring atoms. "Ring atoms" or "the ring members are atoms linked together to form a ring or rings. Carbocyclic may represent, without limitation, one ring, two condensed rings or associated bridge connection or Spiro rings. Substituted carbocyclic may have either CIS or TRANS geometry. Representative examples carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl, cyclohexadienyl, substituted, decahydro-naphthalenyl, octahydro-indenyl, cyclohexenyl, phenyl, naphthyl, indanyl, 1,2,3,4-tetrahydro-naphthyl, indenyl, isoindolyl, decaline and nobinary. Carbonilla group can be attached to the original molecular fragment through any substitutable carbon is alzieu atom. When carbonilla group is a divalent group linking the two other elements in the specified chemical structure (for example, A in the formula (I), carbonilla group can be attached to these two other elements through any two substitutable ring atom.

The term "carbocyclic" refers to carbonitrile group attached to the original molecular fragment through alkylenes group. For example, C3-C6carbocyclic1-C6alkyl refers to C3-C6carbonitrile group attached to the original molecular fragment through With1-C6alkylen.

The term "cycloalkenyl" refers to non-aromatic, partially unsaturated carbocycles group containing zero heteroatoms as ring members. Representative examples cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl and octahydronaphthalene.

The term "cycloalkyl" refers to a saturated carbocycles group containing zero heteroatoms as ring members. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decaline and nobinary.

The prefix "halogen" indicates that the Deputy is attached to this paragraph shall epics, substituted by one or more independently selected halogen radicals. For example, "C1-C6halogenated" means1-C6alkyl substituent in which one or more hydrogen atoms replaced with independently selected halogen radicals. Non-limiting examples With1-C6halogenoalkane include chloromethyl, 1-bromacil, vermeil, deformity, trifluoromethyl and 1,1,1-triptorelin. It should be clear that, when the Deputy substituted by more than one halogen radical, these halogen radicals can be the same or different from each other (unless specified otherwise).

The term "heterocycle" or "heterocycle" or "heterocyclyl" refers to a saturated (e.g., "heteroseksualci"), partially unsaturated (e.g., "geteroseksualen" or "heteroseksualnymi") or completely unsaturated (e.g., "heteroaryl") ring system, where at least one of the ring atoms is a heteroatom (i.e., nitrogen, oxygen or sulfur), with the remaining ring atoms independently selected from the group including carbon, nitrogen, oxygen and sulfur. The heterocycle may represent, without limitation, one ring, two condensed rings or associated bridge connection or Spiro rings. Heterocyclyl group can be linked to the original molecular fragment che is without any substitutable atom (atoms) of carbon or nitrogen in the group. When heterocycly group is a divalent group linking the two other elements in the specified chemical structure (for example, A in the formula (I), heterocycly group can be attached to the other two elements through any two substitutable ring atom.

Heterocyclyl may represent, without limitation, monocycle, which contains one ring. Non-limiting examples of monociclo include furanyl, dihydrofurane, tetrahydrofuranyl, pyrrolyl, isopropyl, pyrrolidyl, pyrrolidinyl, imidazolyl, isoimidazole, imidazolines, imidazolidinyl, pyrazolyl, pyrazolyl, pyrazolidine, triazole, tetrazole, ditolyl, oxacillin, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, thiazolyl, isothiazolines, diazolidinyl, isothiazolinones, thiadiazolyl, oxadiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl (also known as "assimil"), 1,2,5-oxadiazolyl (also known as "furutani") and 1,3,4-oxadiazolyl), oxadiazolyl (including 1,2,3,4-oxadiazolyl and 1,2,3,5-oxadiazolyl), doxazosin (including 1,2,3-doxazosin, 1,2,4-doxazosin, 1,3,2-doxazosin and 1,3,4-doxazosin), oxathiolane, pyranyl (including 1,2-pyranyl and 1,4-pyranyl), dihydropyran, pyridinyl, piperidinyl, diazines (including pyridazinyl (also known as "1,2-diazines"), pyrimidinyl (also known as "1,3-diazine is") and pyrazinyl (also known as "1,4-diazines")), piperazinil, triazinyl (including s-triazinyl (also known as "1,3,5-triazinyl"), as triazinyl (also known as 1,2,4-triazinyl) and v-triazinyl (also known as "1,2,3-triazinyl), oxazinyl (including 1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl (also known as "Pantokrator"), 1,2,6-oxazinyl and 1,4-oxazinyl), isoxazolyl (including o-isoxazolyl and para-isoxazolyl), oxazolidinyl, isoxazolidine, oxathiazine (including 1,2,5-oxathiazine or 1,2,6-oxathiazine), oxadiazolyl (including 1,4,2-oxadiazine and 1,3,5,2-oxadiazolyl), morpholinyl, azepine, oxepin, tiepins and diazepines.

Heterocyclyl also may represent, without limitation, bicikl containing two condensed rings, such as, for example, naphthyridines (including [1,8] naphthyridine and [1,6] naphthyridine), thiazolidinediones, thienopyrimidines, pyrimidopyrimidine, pyridopyrimidines, pyrazolopyrimidines, indolizinyl, pyridinyl, pirenopolis, 4H-hemolysins, purinol, pyridopyrimidines (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, and pyrido[4,3-b]-pyridinyl), pyridopyrimidines and pteridinyl. Other non-limiting examples of heterocyclic compounds with condensed rings include benzo-condensed heterocyclyl, such as indolyl, isoindolyl, indolizinyl (also known as "pseudohistory"), isoindolyl (also known as "respiratory") benzathine (including chinoline (also known as "1-benzathine") and ethenolysis (also known as "2-benzazolyl")), benzimidazolyl, phthalazine, honokalani, benzodiazines (including cinnolines (also known as "1,2-benzodiazines") and hintline (also known as "1,3-benzodiazepin")), benzopyranyl (including chromanol" and "Isopropenyl"), benzothiophene (also known as "thiochroman"), benzoxazolyl, indicazioni (also known as "benzisoxazole"), Anthranilic, benzodioxolyl, benzodioxane, benzoxadiazole, benzofuranyl (also known as "coumaroyl"), isobenzofuranyl, benzothiazyl (also known as "benzothiophenes", "tianeptine and benzothiophenes"), isobenzofuranyl (also known as "isobenzofuranyl", "socionatural and isobenzofuranyl"), benzothiazolyl, benzotriazolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl (including 1,3,2-benzoxazines, 1,4,2-benzoxazine, 2,3,1-benzoxazine and 3,1,4-benzoxazine), benzisoxazole (including 1,2-benzisoxazoles and 1,4-benzisoxazol) and tetrahydroisoquinolines.

Heterocyclyl may include one or more sulfur atoms as ring members; and in some cases the atom (atoms) of sulfur is oxidized to SO or SO2. Heteroatom(atoms) of nitrogen in heterocyclyl may be, or may not be, and stereoselectivity can be, or can be oxidized to N-oxide. In addition, the heteroatom(atoms) of nitrogen may be or may not be N-protected.

in the chemical formula refers to a simple or double bonds.

The term "pharmaceutically acceptable" is used as an adjective, meaning that the defined noun is appropriate for use as a pharmaceutical product or as part of a pharmaceutical product.

The term "therapeutically effective amount" refers to the total amount of each active substance, which is sufficient for the manifestation of favorable effect in a patient, for example, reduction of viral load.

The term "prodrug" refers to derivatives of the compounds of the present invention, which contain chemically or metabolically degradable group and converted, as a result of solvolysis or under physiological conditions, the compounds of the present invention which are pharmaceutically activein vivo. The prodrug compounds can be formed in the usual way by reacting the functional group of compounds (such as amino, hydroxy or carboxy group). Prodrugs are often other benefits, such as solubility, compatibility with tissues or delayed release in the mammalian organism (see, Bungard, H., DESIGN OF PRODRUGS, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known specialist is in this area, such as, for example, esters, obtained by interaction of initial acid compound with a suitable alcohol, or amides obtained by reacting a source of an acid compound with a suitable amine. Examples of prodrugs include, but are not limited to, acetate, formate, benzoate or other acylated derivative of an alcohol or amine functional groups in the compounds of the present invention.

The term "MES" refers to the physical Association of a compound of the present invention with one or more solvent molecules, organic or inorganic. This physical Association often includes hydrogen binding. In some cases, the MES can be selected, for example, when one or more solvent molecules included in the crystal lattice of the crystalline solid. "MES" covers both the solvate in solution phase and insoluble. Examples of the solvate include, but are not limited to, hydrates, ethanolate and methanolate.

The term "N-protective group" or "N-protected" refers to those groups that are able to protect an amino group against undesirable interactions. Commonly used N-protective groups are described in Greene and Wuts, PROTECTING GROUPS IN CHEMICAL SYNTHESIS (3rded., John Wiley & Sons, NY (1999). Non-limiting examples of N-protecting groups in luchot acyl group, such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, TRIFLUOROACETYL, trichloroacetyl, phthalyl, o-nitrophenoxyacetic, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl or 4-nitrobenzoyl; sulfonylurea groups, such as benzazolyl or para-toluensulfonyl; sulfanilimide groups, such as phenylsulfinyl (phenyl-S-) or triphenylmethylchloride (trityl-S-); sulfinyl groups such as para-methylphenylsulfonyl (p-were-S(O)-) or tert-butylsulfonyl (t-Bu-S(O)-); carbamate-forming group, such as benzyloxycarbonyl, para-chlorobenzenesulfonyl, para-methoxybenzeneboronic, para-nitrobenzenesulfonyl, 2-nitrobenzenesulfonyl, para-bromobenzyloxycarbonyl, 3,4-dimethoxyphenylacetone, 3,5-dimethoxybenzoquinone, 2,4-dimethoxybenzoquinone, 4-methoxybenzenesulfonyl, 2-nitro-4,5-dimethoxybenzonitrile, 3,4,5-trimethoxybenzylamine, 1-(para-biphenylyl)-1-methylethanolamine, dimethyl-3,5-dimethoxybenzoquinone, benzylaminocarbonyl, tert-butyloxycarbonyl, diisopropylperoxydicarbonate, isopropoxycarbonyl, etoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloro-ethoxy-carbonyl, phenoxycarbonyl, 4-nitro-phenoxycarbonyl, cyclopentanecarbonyl, adamantanecarbonyl, cyclohexyloxycarbonyl or phenylthiocarbamyl; alkyl who groupings, such as benzyl, para-methoxybenzyl, triphenylmethyl or benzoyloxymethyl; para-methoxyphenyl; and silyl groups such as trimethylsilyl. Preferably, the N-protective groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, tert-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

Compounds of the present invention can be obtained using various methods. As a non-limiting example, the compounds of the present invention can be obtained by combining the compounds of formula II with the compound of the formula III as shown in Scheme I, where Q represents a halogen (e.g. bromine, chlorine or iodine), and A, B, D, L1, L2, L3, Y and Z have the meanings given above. Aminosidine II can be alkylated by reacting with halogenosilanes (for example, halogenmethyl) of the compound III in the presence of a base, such as KOH, t-BuOK, sodium amide, sodium hydride, CsOH, the base Hunya, Na2CO3or NaHCO3, in a suitable organic solvent, such as THF or DMF, or water (if the base is compatible with a water solvent), with or without the addition of surfactants such as sodium dodecylsulfate or tetrabutylammonium. Education symmetric products (for example, the formula F in Scheme I, where B, Z and L2in the ormula I is identical to A, Y and L1respectively) can be done using the same procedure as shown, or shown asymmetrical products can be obtained by successive education monoalkylamines product V with subsequent interaction with the second halogenosilanes (for example, halogenmethyl) of the compound VI in conditions similar to those described above.

Alternatively, Q in compounds III and VI (for example, bromine, chlorine or iodine), you can substitute 4-methylbenzenesulfonate and subject interaction with II or V, respectively, under similar conditions. Monoalkylamines compound V can also be obtained by reacting amine II with an aldehyde IV with the formation of Schiff bases (Imin), which can be restored to products V using a hydride reducing agent such as sodium borohydride or cyanoborohydride sodium (with or without the addition of acid, such as acetic acid) in a solvent such as ethanol, toluene, THF or dichloromethane. Alternatively, the Schiff base formed from II and IV, can be restored to the product of V by hydrogenation in the presence of a suitable catalyst, such as palladium or platinum catalyst or Raney Nickel.

As another non-limiting example, the compounds of the present invention can what the returns through a combination of compounds of formula II with the compound of the formula III, as shown in Scheme II, where R represents an-LS'-M'-LS"- RDand LS', M', LSand RDhave the meanings given above. Aminosidine II can be alkylated by reacting with 4-nitrobenzylamine III in the presence of a base, such as KOH, t-BuOK, sodium amide, sodium hydride, CsOH, the base Hunya, Na2CO3or NaHCO3, in a suitable organic solvent, such as THF or DMF, or water (if the base is compatible with a water solvent), with or without the addition of surfactants such as sodium dodecylsulfate or tetrabutylammonium bromide. Dinitrosobenzene IV can be restored to the diamino product V using a hydride reducing agent such as sodium borohydride (with or without transition metal salt, such as BiCl3, SbCl3, NiCl2, Cu2Cl2or CoCl2), in a solvent such as ethanol or THF. Alternatively, the IV can be restored to the product of V by hydrogenation in the presence of a suitable catalyst, such as palladium or platinum catalyst or Raney Nickel. Diamine V can be subjected to interaction with suitably protected prolinnova acid (shown Boc, although it is possible substituents Cbz, Troc or Fmoc), in the presence of a peptide coupling reagent, such as EDAC/HOBT, PyBOP, HATU is whether DEBPT, in a solvent such as THF, DMF, dichloromethane, or DMSO, with or without an amine base, such as base Hunya, pyridine, 2,6-lutidine or triethylamine, to obtain VI. The removal of the protective group Boc obtaining VII can be accomplished by treatment with acid, such as TFUK, HCl, or formic acid. Compounds of the present invention can be obtained by combining VII with the selected acid using standard peptide coupling reagents and conditions described above. Also, the compounds of formula IAas described above, can be obtained in a similar manner.

As another non-limiting example, the compounds of the present invention can be obtained by the methods shown in Scheme III, where R represents an-LS'-M'-LS"-RDand LS', M', LSand RDhave the meanings given above. The diamine II can be subjected to interaction with a suitable protected prolinnova acid (shown Boc, although it may be Deputy Cbz, Troc or Fmoc) in the presence of a peptide coupling reagent, such as EDAC/HOBT, PyBOP, HATU or DEBPT, in a solvent such as THF, DMF, dichloromethane, or DMSO, with or without an amine base, such as base Hunya, pyridine, 2,6-lutidine or triethylamine, to obtain the III as a mixture of amide n is the FL. Heat III in acetic acid (50-100ºC) gives a benzimidazole compound IV. Alternatively, the IV can be obtained by reacting II with an aldehyde, followed by treatment with an oxidant, such as Cu(OAc)2or MnO2. Cm. Penning et al., BIOORG. MED. CHEM. 16:6965-6975 (2008), which is incorporated into the present application by reference in its entirety. Ester functional group IV can be restored to alcohol V under standard conditions such as treatment sociallyengaged or DIBAL, in a suitable solvent, such as THF or dichloromethane. Alcohol V can be converted to bromoethylene connection VI using conventional conditions, for example, by processing using CBr4and triphenylphosphine or by processing using PBr3. Alternatively, V can be oxidized in a variety of ways to aldehyde VII, for example, using MnO2, PCC, PDC, using the oxidation method Swarna or periodinane dess-Martin. Compound VII can be used to obtain compound IX by reacting with aniline to form Schiff bases (Imin), which can be restored to IX using a hydride reducing agent such as sodium borohydride or cyanoborohydride sodium (with or without the addition of acid, such as acetic acid) in a solvent such as ethanol, toluene, THF or dihl rotan. Alternatively, the Schiff base formed from VII, can be restored to IX products by hydrogenation in the presence of a suitable catalyst, such as palladium or platinum catalyst or Raney Nickel. Compound VI can be subjected to interaction with aniline in the presence of a base, such as KOH, t-BuOK, sodium amide, sodium hydride, CsOH, the base Hunya, Na2CO3or NaHCO3, in a suitable organic solvent, such as THF or DMF, or water (if the base is compatible with a water solvent), with or without the addition of surfactants such as sodium dodecylsulfate or tetrabutylammonium, obtaining a symmetric connection VIII. Alternatively, VIII can also be obtained by reacting IX with VI in the alkylation conditions described above. After removal of the protective group Boc from VIII (carried out by treatment with acid, such as TFUK, HCl, or formic acid), compounds of the present invention can be obtained by combining the obtained diamine with the selected acid using standard peptide coupling reagents and conditions described above. Compound IX can also be subjected to interaction with 4-nitrobenzylamine in the alkylation conditions described above, with the receipt of X. the restoration of the nitro group of compound X with ISOE what Itanium conditions, described above, and combined with a suitable protected prolinnova acid can provide compound XI. After removal of the protective group Boc from compound XI (carried out by treatment with acid, such as TFUK, HCl, or formic acid), compounds of the present invention can be obtained by combining the obtained diamine with the selected acid using standard peptide coupling reagents and conditions described above. Also, the compounds of formula IBcan be obtained in a similar way, where a is aRepresents aA' and B' have the meanings given above, and A and B are, independently, optionally substituted by one or more substituents RA. Similarly, the compounds of formula Iccan be obtained in accordance with Scheme III.

As another non-limiting example, the compounds of the present invention can be obtained by the methods shown in Scheme IV, where R represents an-LS'-M'-LS"-RDand LS', M', LS", RD, R1, R2and R5have the meanings given above. Compound II can be obtained from 4'-iodization using known conditions, such as processing using Br2. Compound II mo is but to expose the interaction with the salt of the amino acids (obtained from a suitably protected amino acids and bases, such as Cs2CO3, KOH, NaOH or Na2CO3in a solvent such as ethanol or THF) in a solvent such as THF, DMF or DMSO, with the receipt of ester III. Ester III can be treated with a source of ammonia, such as NH4OAc, NH4Cl or ammonia gas, and subjected to heating in a solvent such as toluene or xylene, with azeotropic removal of water, to obtain the imidazole IV. Cm. Gordon et al., TET. LETT. 34:1901-1904 (1993) and Moinet et a, BIOORG. MED. CHEM. LETT. 11:991-995 (2001), which are both incorporated into the present application by reference in their entirety. Iodide IV can be converted to ester V by treatment with palladium catalyst (such as Pd(PPh3)4or Pd(dppf)Cl2or Pd(II) catalyst, such Pd(OAc)2or Pd2(dba)3with or without the addition of organophosphorus ligands, such as PPh3or P(t-Bu)3and carbon monoxide in the presence of a base such as triethylamine or base Hunya, in a solvent such as methanol or ethanol, with or without heating. The obtained ester V can be restored to alcohol VI and then oxidized to the aldehyde VII by methods described above. Compound VII can be used to obtain compound VIII by reacting with aniline to form Schiff bases (Imin), which can be restored to connect the drop-VIII using a hydride reducing agent, such as sodium borohydride or cyanoborohydride sodium (with or without the addition of acid, such as acetic acid) in a solvent such as ethanol, toluene, THF or dichloromethane. Alternatively, the Schiff base formed from VII, can be restored to VIII products by hydrogenation in the presence of a suitable catalyst, such as palladium or platinum catalyst or Raney Nickel. Compound VIII can be subjected to interaction with 4-nitrobenzylamine in the alkylation conditions described above to obtain compound IX. The restoration of the nitro group of compound IX using the conditions described above, and the combination with suitably protected prolinnova acid can provide compound XI. After removal of the protective group Boc from XI (carried out by treatment with acid, such as TFUK, HCl, or formic acid), compounds of the present invention can be obtained by combining the obtained diamine with the selected acid using standard peptide coupling reagents and conditions described above. Also, the compounds of formula Iccan be obtained in a similar manner.

As another non-limiting example, the compounds of the present invention of General formula I can be obtained as shown in Scheme I'. The combination of connect four is uly (1) with the compound of the formula (2), as shown in Scheme I, where Q represents a halogen (e.g. bromine, chlorine or iodine), and A, B, D, L1, L2, L3, Y and Z have the meanings given above, gives the compounds of formula (4). Aminosidine (1) can be alkylated by reacting with halogenosilanes (for example, halogenmethyl) of the compound (2) in the presence of a base, such as KOH, t-BuOK, sodium amide, sodium hydride, CsOH, the base Hunya, Na2CO3or NaHCO3, in a suitable organic solvent, such as THF or DMF, or water (if the base is compatible with a water solvent), with or without the addition of surfactants such as sodium dodecylsulfate or tetrabutylammonium. The compounds of formula (4) can be subjected to interaction with (5), where Q represents a halogen (e.g. bromine, chlorine or iodine), using the same conditions as the conditions for interaction (1) with (2), to obtain the compounds of General formula (I) When B, Z and L2in the formula I is identical to A, Y and L1receive , respectively, the symmetric products. Obtaining symmetric products can be done using a single procedure or single-ended products (where one of the B, Z, or L2different from A, Y, or L1respectively) can be obtained by successive education monoalkylamines product (4) with PEFC is blowing the interaction with the second halogenosilanes (for example, halogenmethyl) of the compound (5) under conditions similar to those described above. Alternatively, Q in the compounds (2) and (5) (for example, bromine, chlorine or iodine), you can substitute 4-methylbenzenesulfonate and subjected to interaction with (1) or (4), respectively, under similar conditions. Monoalkylamines compound (4) can also be obtained by reacting amine (1) with the aldehyde (3) with the formation of Schiff bases (Imin), which can be restored to the products (4) using a hydride reducing agent such as sodium borohydride or cyanoborohydride sodium (with or without the addition of acid, such as acetic acid) in a solvent such as ethanol, toluene, THF or dichloromethane. Alternatively, the Schiff base formed from (1) and (3), can be restored to the products (4) by hydrogenation in the presence of a suitable catalyst, such as palladium or platinum catalyst or Raney Nickel.

As another non-limiting example, the compounds of the present invention can be obtained as shown in Scheme II'. The combination of the compounds of formula (6), where RAshall have the meaning given above and n is 0, 1, 2, 3, 4 or 5, with the compound of the formula (7) can give the compounds of formula (8). For example, aminosidine (6) can be alkylated by reacting with 4-nitroben what avramidou (7) in the presence of a base, such as KOH, t-BuOK, sodium amide, sodium hydride, CsOH, the base Hunya, Na2CO3or NaHCO3, in a suitable organic solvent, such as THF or DMF, or water (if the base is compatible with a water solvent), with or without the addition of surfactants such as sodium dodecylsulfate or tetrabutylammonium. Dinitrosobenzene (8) can be restored to diaminopropane (9) using a hydride reducing agent such as sodium borohydride (with or without transition metal salt, such as BiCl3, SbCl3, NiCl2, Cu2Cl2or CoCl2), in a solvent such as ethanol or THF. Alternatively, (8) can be restored to the product (9) by hydrogenation in the presence of a suitable catalyst, such as palladium or platinum catalyst or Raney Nickel. Diamine (9) can be subjected to interaction with suitably protected prolinnova acid (shown Boc, although you can use Deputy Cbz, Troc or Fmoc) in the presence of a peptide coupling reagent, such as EDAC/HOBT, PyBOP, HATU or DEBPT, in a solvent such as THF, DMF, dichloromethane, or DMSO, with or without an amine base, such as base Hunya, pyridine, 2,6-lutidine or triethylamine, to obtain (10). The removal of the protective group Boc obtaining (11) can be carried out is by treatment with acid, such as TFUK, HCl, or formic acid. Compounds of the present invention (12), where R20represents-LS'-M'-LS"-RDand LS', M', LSand RDhave the meanings given above, can be obtained by combining (11) with the selected acid using standard peptide coupling reagents and conditions described above. Also, the compounds of formula IAas described above, can be obtained in a similar manner.

As another non-limiting example, the compounds of the present invention (20) and (24) can be obtained by the methods shown in Scheme III', where R20represents-LS'-M'-LS"-RDand LS', M', LS", RDand RAhave the meanings defined above, and n is 0, 1, 2, 3, 4 or 5. Diamine (13) can be subjected to interaction with suitably protected prolinnova acid (shown Boc, although you can use Deputy Cbz, Troc or Fmoc) in the presence of a peptide coupling reagent, such as EDAC/HOBT, PyBOP, HATU or DEBPT, in a solvent such as THF, DMF, dichloromethane, or DMSO, with or without an amine base, such as base Hunya, pyridine, 2,6-lutidine or triethylamine, to obtain (14) in a mixture of amide products. Heating of the compound (14) in acetic acid (50-100°C) gives Ben the imidazole compound (15). Alternatively, the compound (15) can be obtained by reacting compound (13) with the aldehyde, followed by treatment with an oxidant, such as Cu(OAc)2or MnO2. Cm. Penning et al., BIOORG. MED. CHEM. 16:6965-6975 (2008), which is incorporated into the present application by reference in its entirety. Ester functional group of the compound (15) can be reduced to alcohol (16) under standard conditions such as treatment sociallyengaged or DIBAL, in a suitable solvent, such as THF or dichloromethane. The alcohol (16) can be transformed into bromoethylene connection (17) using conventional conditions, such as processing using CBr4and triphenylphosphine or processing using PBr3. Alternatively, compound (16) can be oxidized in a variety of ways to aldehyde (18), for example, using MnO2, PCC, PDC oxidation method Swarna or periodinane dess-Martin. The compound (18) can be used to obtain the compound (21) by reacting with aniline to form Schiff bases (Imin), which can be restored to (21) using a hydride reducing agent such as sodium borohydride or cyanoborohydride sodium (with or without the addition of acid, such as acetic acid) in a solvent such as ethanol, toluene, THF or dichloromethane. Alternatively, a Schiff base, the way the pot of (18), you can restore to products (21) by hydrogenation in the presence of a suitable catalyst, such as palladium or platinum catalyst or Raney Nickel. The compound (17) can be subjected to interaction with (6) in the presence of a base, such as KOH, t-BuOK, sodium amide, sodium hydride, CsOH, the base Hunya, Na2CO3or NaHCO3, in a suitable organic solvent, such as THF or DMF, or water (if the base is compatible with a water solvent), with or without the addition of surfactants such as sodium dodecylsulfate or tetrabutylammonium, obtaining a symmetric connection (19). Alternatively, the compound (19) can also be obtained by reacting compound (21) with compound (17) in the alkylation conditions described above. After removal of the protective group Boc from (19) (carried out by treatment with acid, such as TFUK, HCl, or formic acid), compounds of the present invention (20) can be obtained by combining the obtained diamine with the selected acid using standard peptide coupling reagents and conditions described above. The compound (21) can also be subjected to interaction with 4-nitrobenzylamine in the alkylation conditions described above to obtain (22). The restoration of the nitro group of the compound (22) with the use of the occupational groups, described above, and the combination with suitably protected prolinnova acid can provide the connection (23). After removal of the protective group Boc from (23) (carried out by treatment with acid, such as TFUK, HCl, or formic acid), compounds of the present invention (24) can be obtained by combining the obtained diamine with the selected acid using standard peptide coupling reagents and conditions described above. Also, the compounds of formula IByou can get a similar way, where a is aRepresents aA' and B' have the meanings given above, and A and B are, independently, optionally substituted by one or more substituents RA. Similarly, the compounds of formula Iccan be obtained in accordance with Scheme III'.

As another non-limiting example, the compounds of the present invention (35) can be obtained by the methods shown in Scheme IV', where R20represents-LS'-M'-LS"-RDand LS', M', LS", RD, R1, R2, R5and RAhave the meanings defined above, and n is 0, 1, 2, 3, 4 or 5. The compound (25) can be obtained from 4'-iodization using known conditions, such as processing the ri using Br 2. The compound (25) can be subjected to interaction with the salt of the amino acids (obtained from a suitably protected amino acids and bases, such as Cs2CO3, KOH, NaOH or Na2CO3in a solvent such as ethanol or THF) in a solvent such as THF, DMF or DMSO, with the receipt of ester (26). Ester (26) can be processed using a source of ammonia, such as NH4OAc, NH4Cl or ammonia gas, and subjected to heating in a solvent such as toluene or xylene, with azeotropic removal of water, obtaining imidazole (27). Cm. Gordon et al., TET. LETT. 34:1901-1904 (1993) and Moinet et al., BIOORG. MED. CHEM. LETT. 11:991-995 (2001), both of which are incorporated into the present application by reference in their entirety. Iodide (27) can be converted to ester (28) by treatment with palladium catalyst (such as Pd(PPh3)4or Pd(dppf)Cl2or Pd(II) catalyst, such Pd(OAc)2or Pd2(dba)3), with or without organophosphorus ligands, such as PPh3or P(t-Bu)3and carbon monoxide in the presence of a base such as triethylamine or base Hunya, in a solvent such as methanol or ethanol, with or without heating. The obtained ester (28) can be restored to the alcohol (29) and then oxidized to the aldehyde (30) by the methods described above. The compound (30) can use is to use to obtain the compound (31) by reacting with aniline to form Schiff bases (Imin), which can be restored to (31) using a hydride reducing agent such as sodium borohydride or cyanoborohydride sodium (with or without the addition of acid, such as acetic acid) in a solvent such as ethanol, toluene, THF or dichloromethane. Alternatively, the Schiff base formed from (30), can be restored to the products (31) by hydrogenation in the presence of a suitable catalyst, such as palladium or platinum catalyst or Raney Nickel. The compound (31) can be subjected to interaction with 4-nitrobenzylamine in the alkylation conditions described above to obtain (32). The restoration of the nitro group of the compound (32) using the conditions described above, and the combination with suitably protected prolinnova acid can provide the connection (34). After removal of the protective group Boc from (34) (carried out by treatment with acid, such as TFUK, HCl, or formic acid), compounds of the present invention (35) can be obtained by combining the obtained diamine with the selected acid using standard peptide coupling reagents and conditions described above. Also, the compounds of formula Iccan be obtained in a similar manner.

If the group described in this application (for example, -NH2or-OH), not compatible with method and synthesis, such group may be protected by a suitable protective group which is stable to the reaction conditions used in the methods. The protective group can be removed at the appropriate time consistent reactions to give the desired intermediate or target compound. Suitable protective groups and methods for the introduction or removal of the protective groups are well known in the prior art, examples of which can be found in Greene and Wuts, above. Optimal reaction conditions and reaction time for each stage can vary depending on the particular used in the reaction substances and substituents present in the reacting substances. Solvents, temperatures and other reaction conditions can easily choose a specialist in this area with average skills on the basis of the present invention.

Other compounds of the present invention can be obtained in a similar way as described in the above schemes, as well as the procedures described in examples presented here, as should be clear to the experts. It should be clear that the above-described variants of the incarnation and of the scheme and the following examples are presented for purposes of illustration and not for limitation. Various changes and modifications within the scope of the present invention on what should be obvious to experts in the field of the present description.

Illustrative of the compounds below were named using either ChemDraw version 9.0 or ACD version 10 (ACD v10). The final compounds and intermediate compounds for Examples 1-23 were named using ChemDraw. End connections for sample 24-150 were named using ACD v10. Intermediate compounds for Examples 24-150 were named using ChemDraw, unless otherwise noted.

Example 1

Dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(pyrrolidin-2.1-diyl))bis(3-methyl-1-oxobutyl-2.1-diyl)dicarbamate

Example 1A

N,N-bis(4-nitrobenzyl)aniline

United aniline (0,457 ml, 5 mmol), sodium bicarbonate (0,924 g, 11.00 mmol) and sodium dodecyl sulphate (0,020 g 0,070 mmol) in water (20 ml) and heated in an oil bath at 80°C for approximately 5 minutes. Was added 1-(methyl bromide)-4-nitrobenzene (2,376 g, 11.00 mmol) and continued heating at 80°C for approximately 1 hour. After 1 hour the reaction mixture was cooled to room temperature. The product was collected by filtration, washed with water and dried under vacuum. The product was recrystallized from a mixture of EtOAc and hexane to obtain the product (1,67 g, 92% yield, yellow powder).

Example 1B

N,N-bis(4-and inabensa)aniline

Method A. Combined product from Example 1A (436 mg, 1.2 mmol) and chloride of bismuth(III) (1,14 g of 3.60 mmol) in ethanol (12 ml) and cooled in a water bath. Portions was added sodium borohydride (726 mg, 19,20 mmol) (was the release of heat and gas bubbles) and the reaction mixture became a dark black color. Was stirred at room temperature for about 1 hour. Added MeOH and filtered through celite, washing with the aid of MeOH. Concentrated to half volume using a rotary evaporator, the mixture was diluted with 25% isopropanol/CHCl3and washed with 10% sodium bicarbonate solution. The organic layer was dried over Na2SO4, filtered and concentrated to obtain specified in the connection header (310,4 mg, 85% yield, yellow oil).

Method B. the product from Example 1A (200 mg, 0,550 mmol) in THF (20 ml) in a pressure vessel with a volume of 50 ml was added wet Ra-Ni A-7000 (200 mg, to 3.41 mmol) and the mixture was stirred for 2 hours under a pressure of 30 lb/inch2(2.1 kg/cm2) at room temperature. The mixture was filtered through a nylon membrane and the solvent evaporated to obtain specified in the title compound, which was used without further purification.

Example 1C

(2S,2'S)-tert-butyl 2,2'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))b is(octamethylene)dipyrrole-1-carboxylate

Dissolved the product from Example 1B (310,4 mg, 1,023 mmol) in DMSO (5,115 ml) was added N-(tert-butoxycarbonyl)-1-Proline (440 mg, 2,046 mmol), HATU (817 mg, 2,148 mmol) and base Hunya (0,715 ml, 4.09 to mmol). After stirring for 48 hours was added water and filtered to collect the solids. The solid was purified using chromatography on silica gel, elwira mixture 0-4% MeOH/CH2Cl2with obtaining specified in the connection header (339,4 mg, 47,5% yield, light yellow powder).

Example 1D

(2S,2'S)-N,N'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene))dipyrrole-2-carboxamide

To the product from Example 1C (150 mg, 0,215 mmol) in CH2Cl2(537 μl) was added TFOC (537 μl) and the reaction mixture was stirred in an atmosphere of N2within 45 minutes and was concentrated using a rotary evaporator. The residue was dissolved in a mixture of 25% isopropanol/CHCl3and washed polysystem solution of NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated to obtain specified in the connection header (93,8 mg, 88% yield, pale brown solid).

Example 1E

Dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis (octamethylene)bis(pyrrolidin-2.1-diyl))bis(3-methyl-1-oxobutyl-2.1-diyl)dicar the Amat

To a mixture of the product from Example 1D (0.01 g, at 0.020 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (8,80 mg, 0,050 mmol) and HATU (0,019 g 0,050 mmol) in DMSO (0.100 ml) was added to the base Hunya (0,021 ml, 0,121 mmol) and the reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with acetonitrile and water (0.1% TFUC) and was purified using reverse-phase chromatography (C18), elwira mixture of 10-100% acetonitrile in water (0.1% TFOC), with specified title compound (14 mg, 86% yield, white solid) in the form of a salt TFUCK.1H NMR (500 MHz, DMSO-d6) δ memorial plaques to 0.88 (d, J=of 6.71 Hz, 6H) of 0.93 (d, J=of 6.71 Hz, 6H) 1,81-2,04 (m, 8H) 2,08-2,19 (m, 2H) to 3.58-the 3.65 (m, 2H) of 3.77-of 3.85 (m, 2H) was 4.02 (t, J=8,54 Hz, 2H) was 4.42 (DD, J=8,16, to 4.81 Hz, 2H) 4,59 (s, 4H) to 6.57 (t, J=6,33 Hz, 1H) of 6.65 (d, J=to 7.32 Hz, 2H) 7,07 (t, J=7,86 Hz, 2H) 7,17 (d, J=8,70 Hz, 4H) 7,37 (d, J=8,39 Hz, 2H) 7,51 (d, J=8.54 in Hz, 4H) 10,01 (s, 2H).

Example 2

(R,2S,2'S)-N,N'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene))bis(1-((R)-2-(dimethylamino)-2-phenylacetyl)pyrrolidin-2-carboxamid)

To a mixture of the product from Example 1D (45 mg, 0,090 mmol), (R)-2-(dimethylamino)-2-phenylacetic acid (40.5 mg, 0,226 mmol) and HATU (86 mg, 0,226 mmol) in DMSO (0.45 ml) was added to the base Hunya (95 μl, 0,543 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted using EtOAc, followed by washing the of saturated salt solution. The organic layer was dried over Na2SO4, filtered and concentrated. Was purified using chromatography on silica gel, elwira mixture of 0-5% MeOH/CH2Cl2with obtaining specified in the title compound (7 mg, 9.4% of the output).1H NMR (500 MHz, DMSO-d6) δ m D. there is a 10.03 (Shir. s, 2H) 7,30-of 7.60 (m, 14H) 7,15-7,25 (m, 4H) 7,02-7,13 (m, 2H) 6,62-of 6.73 (m, 2H) 6,58 (t,J=7,17 Hz, 1H) br4.61 (s, 4H) or 4.31-and 4.40 (m, 2H) 3,82-3,91 (m, 2H) 3,10-of 3.60 (m, 16H) 1,74-2,12 (m, 8H).

Example 3

Dimethyl (1R,1'R)-2,2'-((2S,2'S)-2,2'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(pyrrolidin-2.1-diyl))bis(2-oxo-1-Penilaian-2.1-diyl)dicarbamate

To a mixture of the product from Example 1D (to 47.2 mg, 0,095 mmol), (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (49,6 mg, 0,237 mmol) and HATU (90 mg, 0,237 mmol) in DMSO (0,47 ml) was added to the base Hunya (99 μl, 0,569 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted using EtOAc, followed by washing with saturated saline solution. The organic layer was dried over Na2SO4, filtered and concentrated. Was purified using chromatography on silica gel, elwira mixture of 0-5% MeOH/CH2Cl2. The second time was purified using reverse-phase chromatography (C18), elwira mixture of 10-100% acetonitrile in water (0.1% TFOC), obtaining specified in the title compound (6.5 mg, 7.7% of the output).1H NMR (500 MHz, DMSO-d6) δ M. D. 9,79-10,11 (m, 2H) 7,60-of 7.97 (m, 2H) 7,46 to 7.62 (m, 3H) 7,28-7,46 (m, 10H) 7,13-7,27 (m, 4H) 7,03-7,14 (m, 3H) 6,63-6,74 (m, 2H) 6,54-6,63 (m, 1H) 5,28 is 5.54 (m, 2H) br4.61 (s, 4H) 4,34-4,50 (m, 2H) 3,63-of 3.85 (m, 2H) of 3.53 (s, 6H) a 3.06-3.24 in (m, 2H) 1.70 to of 2.09 (m, 8H).

Example 4

(2S,2'S)-benzyl 2,2'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)dipyrrole-1-carboxylate

The product from Example 1D (25 mg, 0,050 mmol) was combined with benzyl 2,5-dioxopiperidin-1-ylcarbamate (27.5 mg, 0,111 mmol) and triethylamine (0,021 ml, 0,151 mmol) in DMF (0.5 ml) and the mixture was stirred at room temperature overnight. Distributed between water (5 ml) and EtOAc (3×5 ml). The organic layer was dried over Na2SO4, filtered and concentrated. Was purified using chromatography on silica gel, elwira a mixture of 10-50% EtOAc in hexane, to obtain specified in the title compound as a colourless solid (9 mg, 23.4% of the output).1H NMR (500 MHz, DMSO-d6) δ memorial plaques becomes 9.97-10,06 (m, 2H) of 7.48-7,58 (m, 4H) 7,35-7,41 (m, 3H) 7,29-7,35 (m, 1H) 7.03 is-7,26 (m, 12H) 6,63-6,74 (m,J=8,32, 8,32 Hz, 2H) 6,54-6,63 (m, 1H) 5,02-5,12 (m, 3H) 4,93 (l,J=13,12 Hz, 1H) 4,58-of 4.67 (m, 4H) 4,28-4,39 (m, 2H) 3,38-3,55 (m, 4H) 2,14-2,31 (m, 2H) 1,77-to 1.98 (m, 6H).

Example 5

Dimethyl (2R,2'R)-1,1'-((2S,2'S)-2,2'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(pyrrolidin-2.1-diyl))bis(3-methyl-1-oxobutyl-2,1-Hai is)dicarbamate

To a solution of the product from Example 1D (12 mg, 0,024 mmol), (R)-2-(methoxycarbonylamino)-3-methylbutanoic acid (8,87 mg, 0,051 mmol) and HATU (19,25 mg, 0,051 mmol) in anhydrous DMSO (0.25 ml) was added to the base Hunya (of 0.013 ml, 0,072 mmol) and the resulting mixture was stirred at room temperature for 90 minutes. The mixture was distributed between water (5 ml) and EtOAc (3×5 ml) and the combined organic layers were dried over Na2SO4. The mixture was filtered and concentrated in vacuo, and the crude product was purified using chromatography on silica gel (C18), elwira with a gradient of 10-100% acetonitrile in water (0.1% TFUC). The fractions containing pure product were combined and concentrated in vacuum to obtain specified in the title compound as a solid (7 mg, 31%) as a salt of TFWC.1H NMR (500 MHz, DMSO-d6) δ M. D. 10,23 (s, 0.5 H) 9,67 (s, 1.5 H) 7,49-7,56 (m, 4H) 7,43 (l,J=8,39 Hz, 0.5 H) to 7.35 (d,J=8,24 Hz, 1,5 H) 7,14-7,22 (m, 4H) 7,03-7,11 (m, 2H) 6,65 (l,J=8,24 Hz, 2H) 6,57 (t,J=7,02 Hz, 1H) to 4.98 (d,J=8,09 Hz, 0.5 H) 4,56-4,63 (m, 4H) and 4.40 (DD,J=8,55, a 2.75 Hz, 1,5 H) of 4.05-4,11 (m, 2H) 3,75-a-3.84 (m, 2H) 3,56-the 3.65 (m, 3H) 3,51 of 3.56 (m, 6H) 3,42-to 3.49 (m, 1H) 2,05-of 2.15 (m, 2H) 1,87-2,04 (m, 6H) 0,83 with 0.93 (m, 12H).

Example 6

Dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis (octamethylene)bis(pyrrolidin-2.1-diyl))bis(3,3-dimethyl-1-oxobutyl-2.1-diyl)dicarbamate

To a solution of the product is from Example 1D (12 mg, 0,024 mmol) and (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid (9,58 mg, 0,051 mmol) in DMSO (0.2 ml) was added HATU (19,25 mg, 0,051 mmol) and base Hunya (of 0.013 ml, 0,072 mmol). The resulting mixture was stirred at room temperature for 90 minutes. The mixture was distributed between water (1 ml) and EtOAc (3×1 ml) and the combined organic layers were dried over Na2SO4. The crude product was purified using chromatography on silica gel (C18), elwira with a gradient of 10-100% acetonitrile in 0.1% aqueous solution of TFWC, obtaining specified in the title compound (8 mg, 34.8% of output) in the form of a salt TFUCK.1H NMR (500 MHz, DMSO-d6) δ M. D. 9,99 (s, 2H) 7,51 (d, J=8.54 in Hz, 4H) 7,17 (d, J=8,55 Hz, 4H) 7,02-7,13 (m, 4H) 6,66 (d, J=8,09 Hz, 2H) 6,53-of 6.61 (m, 1H) 4,58 (s, 4H) 4,43 (DD, J=7,93, of 5.34 Hz, 2H) is 4.21 (d, J=cent to 8.85 Hz, 2H) of 3.73-a 3.83 (m, 2H) of 3.64 (s, 2H) 3,54 (s, 6H) 2,09-of 2.20 (m, 2H) 1.93 and-2,04 (m, 2H) 1,79-of 1.92 (m, 4H) to 0.96 (s, 18H).

Example 7

Dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(6,6'-(phenylaziridine)bis(methylene)bis(1H-benzo[d]imidazole-6,2-diyl))bis(pyrrolidin-2.1-diyl))bis(3,3-dimethyl-1-oxobutyl-2.1-diyl)dicarbamate

Example 7A

(S)-Methyl 2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazole-5-carboxylate

Combined methyl 3,4-diaminobenzoate (5.0 g, to 30.1 mmol) EDAC (17.3 g, 90 mmol) and Boc-Proline (6,48 g, to 30.1 mmol) in a mixture of pyridine (50 ml) and DMF (50 ml) and the mixture is then left under stirring p. and room temperature over night. The mixture was evaporated, and the residue was dissolved in EtOAc and washed with water (3×200 ml), aqueous solution 10% NaHCO3and then saturated saline solution. The organic layer was dried over MgSO4, was filtered and was evaporated to obtain 10.4 g (95%) of light yellow solid, which was used without further purification.

The product from the first stage (10.4 g) was dissolved in acetic acid (75 ml) and the mixture was then left to warm with stirring at 70°C for 3 hours. The mixture was evaporated to dryness, and subjected to azeotropic distillation with toluene and then dried under vacuum. The residue was purified using chromatography on silica gel, elwira a mixture of 50-100% EtOAc in hexane, to obtain specified in the connection header (8,96 g, yield 91%) as a solid, painted in faint light yellowish/white color.

Example 7B

(S)-tert-Butyl 2-(5-(hydroxymethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-carboxylate

To a solution of the product from Example 7A (1,75 g 5,07 mmol) in CH2Cl2(40 ml) dropwise at -78°C was added DiBAL (15.7 ml, 1 M solution in CH2Cl2) and the mixture was left under stirring at -78°C for 15 minutes and then was allowed to warm to room temperature and was stirred for 1 hour. The reaction mixture was then cooled in an ice bath and slowly dropwise added MeOH (2 ml), followed the by adding a saturated solution of MgSO 4(60 ml) and the mixture was stirred for 30 minutes. Added EtOAc (200 ml) and the organic layer was separated, washed with saturated salt solution, dried (MgSO4), filtered and evaporated to obtain specified in the connection header (1,506 g, yield 94%) as a solid, painted in faint yellowish color.

Example 7C

(S)-tert-Butyl 2-(5-(methyl bromide)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-carboxylate

To a mixture of the product from Example 7B (0.50 g, 1.57 mmol) and polimerbetonov triphenylphosphine (2.1 g, a 3.15 mmol, 150-300 mesh) in THF at 0°C was added CBr4and the mixture was stirred at 0°C for 10 minutes and then left under stirring at room temperature for 1.5 hours. The mixture is then filtered and washed using THF. THF was evaporated obtaining specified in the title compound (493 mg, yield 82%) as a solid, painted in light yellow color, which was used without further purification.

Example 7D

(2S,2'S)-tert-Butyl 2,2'-(5,5'-(phenylaziridine)bis(methylene)bis(1H-benzo[d]imidazole-5,2-diyl))dipyrrole-1-carboxylate

A mixture of the product from Example 7C (0.20 g, 0,526 mmol), aniline is 0.019 ml, 0,210 mmol) and K2CO3(0,087 g, 0,631 mmol) in DMF (1.0 ml) was left under stirring at room temperature for 2 hours. Added extra is nitely product from Example 7C (0.10 g) together with an additional amount of K 2CO3(0,044 g) and the mixture was left under stirring overnight. The mixture was poured into EtOAc and the organic matter is then washed with water, saturated salt solution, dried (MgSO4), filtered and evaporated. The product was purified using chromatography on silica gel, elwira a mixture of 50-100% EtOAc in hexane, to obtain specified in the title compound (46 mg, yield 32%) as a colorless semi-solid substance.

Example 7E

N,N-bis((2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)methyl)aniline

To a solution of the product from Example 7D (46 mg, of 0.066 mmol) in CH2Cl2(1.0 ml) was added TFOC (1.0 ml) and the mixture was stirred at room temperature for 30 minutes. The solvent is evaporated and the residue used without further purification.

Example 7F

Dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(6,6'-(phenylaziridine)bis(methylene)bis(1H-benzo[d]imidazole-6,2-diyl))bis(pyrrolidin-2.1-diyl))bis(3,3-dimethyl-1-oxobutyl-2.1-diyl)dicarbamate

To a solution of the product from Example 7E (32.4 mg, of 0.066 mmol), (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid (26,2 mg, 0,139 mmol) and HATU (52,7 mg, 0,139 mmol) in anhydrous DMSO (0.5 ml) was added to the base Hunya (or 0.035 ml, 0,198 mmol) and the resulting mixture was stirred at room temperature for 90 minutes. The mixture was distributed between water (5 ml) and EtOAc (3×5 ml) and the volume of yennie organic layers were dried over Na 2SO4. The mixture was filtered and concentrated in vacuo, and the crude product was purified using reverse-phase chromatography (C18), elwira with a gradient of 10-100% acetonitrile in water (0.1% TFUC). The fractions containing pure product were combined and concentrated in vacuum to obtain specified in the title compound as a solid (14 mg, 18%) as a salt of TFWC.1H NMR (500 MHz, DMSO-d6) δ M. D. 14,55 (Shir. s, 2H) 7,72 (l,J=8,39 Hz, 2H) 7,56 (s, 2H) 7,41 (l,J=8,09 Hz, 2H) 7,31 (l,J=to 8.70 Hz, 2H) 7,07 for 7.12 (m, 2H) 6.73 x (l,J=8,09 Hz, 2H) 6,58-6,63 (m, 1H) 5,19 (DD,J=8,16, by 5.87 Hz, 2H) 4,85 is equal to 4.97 (m, 4H) 4,21 (l,J=to 8.70 Hz, 2H) 3,81-to 3.92 (m, 4H) 3,57 (s, 6H) 2,01 was 2.25 (m, 8H) of 0.85 (s, 18H)

Example 8

Dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(pyrrolidin-2.1-diyl))bis(1-oxopropyl-2.1-diyl)dicarbamate

The product from Example 1D (0,024 g 0,048 mmol), (S)-2-(methoxycarbonylamino)propanoic acid (0.015 g, 0,101 mmol), HATU (0,039 g, 0,101 mmol) and base Hunya (0,025 ml, 0,145 mmol) were mixed in DMSO (0.5 ml) and stirred at room temperature for 2.5 hours under nitrogen atmosphere. The reaction mixture was diluted with the help of CH2Cl2and washed with water. The organic extract was separated, dried over Na2SO4, was filtered and was evaporated. The product was purified using chromatography the on silica gel, elwira mixture of 0-5% MeOH in CH2Cl2with obtaining specified in the connection header (to 11.9 mg, 32.6% of the output).1H NMR (500 MHz, DMSO-d6) δ M. D. 9,92 (s, 2H) 7,50 (d,J=8,54 Hz, 4H) 7,34 (l,J=of 7.48 Hz, 2H) 7,17 (l,J=to 8.70 Hz, 4H) 7,06 (DD,J=cent to 8.85, to 7.32 Hz, 2H) 6,65 (l,J=to 7.93 Hz, 2H) 6,56 (t,J=to 7.25 Hz, 1H) 4,59 (s, 4H) to 4.41 (DD,J=8,24, was 4.42 Hz, 2H) 4,27 is 4.36 (m, 2H) 3,62-3,70 (m, 2H) 3,54-3,61 (m, 2H) of 3.60 (s, 6H) 2,07-to 2.18 (m, 2H) 1,95-2,04 (m, 2H) 1,81 is 1.96 (m, 4H) 1,18 (l,J=4,00 Hz, 6H).

Example 9

Dimethyl (2S,2'S,3S,3'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(pyrrolidin-2.1-diyl))bis(3-methyl-1-oxopent-2.1-diyl)dicarbamate

The product from Example 1D (0,0179 g, being 0.036 mmol), (2S,3S)-2-(methoxycarbonylamino)-3-methylpentanol acid (0,014 g, 0,076 mmol), HATU (0,029 g, 0,076 mmol) and base Chunga is 0.019 ml, to 0.108 mmol) was dissolved in DMSO (0,360 ml) and the reaction mixture was stirred at room temperature for 2 hours in nitrogen atmosphere. The reaction mixture was diluted with the help of CH2Cl2and washed with water. The organic extract was separated, dried over Na2SO4, was filtered and was evaporated. The product was purified using chromatography on silica gel, elwira mixture of 0-3% MeOH in CH2Cl2with obtaining specified in the title compound (12.6 mg, 41,1% yield).1H NMR (500 MHz, DMSO-d6) δ M. D. 9,98 (s, 2H) 7,51 (l,J=8,55 Hz, 4H) 7,37 (l,J=855 Hz, 2H) 7,17 (l,J=8,54 Hz, 4H) 7,07 (DD,J=8,77, of 7.25 Hz, 2H) 6,65 (l,J=8,09 Hz, 2H) 6,56 (t,J=to 7.25 Hz, 1H) 4,59 (s, 4H) 4,43 (DD,J=8,16, to 4.81 Hz, 2H) 4,07 (t,J=8,93 Hz, 2H) 3,79-3,86 (m, 2H) 3,57-3,66 (m, 2H) 3,52 (s, 6H) 2,08-to 2.18 (m, 2H) 1,95-2,05 (m, 2H) 1,82-of 1.93 (m, 4H) of 1.66 to 1.76 (m, 2H) 1,44-of 1.55 (m, 2H) 1,06-of 1.15 (m, 2H) 0,89 (l,J=of 6.71 Hz, 6H) 0,78 is 0.84 (m, 6H).

Example 10

Methyl (S)-1-((S)-2-(4-(((4-((S)-1-((R)-2-(dimethylamino)-2-phenylacetyl)pyrrolidin-2-carboxamido)benzyl)(phenyl)amino)methyl)phenylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutyl-2-ylcarbamate

Example 10A

Methyl (S)-3,3-dimethyl-1-oxo-1-((S)-2-(4-((phenyl(4-((S)-pyrrolidin-2-carboxamido)benzyl)amino)methyl)phenylcarbamoyl)pyrrolidin-1-yl)butane-2-ylcarbamate

The product from Example 1D (120 mg, 0,241 mmol) was combined with (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid (45,6 mg, 0,241 mmol), HATU (92 mg, 0,241 mmol) and the base Hunya (0,126 ml, 0,723 mmol) in DMSO (3.0 ml) and the mixture was stirred at room temperature for 45 minutes. Was diluted with water and collecting the solid by filtration. The product was purified using reverse-phase chromatography (C18), elwira mixture of 10-100% acetonitrile in water (0.1% TFOC), with specified title compound (32 mg, 19.8% of the output).

Example 10B

Methyl (S)-1-((S)-2-(4-(((4-((S)-1-((R)-2-(dimethylamino)-2-phenylacetyl)pyrrolidin-2-carboxamido)Ben who yl)(phenyl)amino)methyl)phenylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutyl-2-ylcarbamate

The product from Example 10A (15 mg, of 0.022 mmol) was combined with (R)-2-(dimethylamino)-2-phenylacetic acid (4,82 mg, or 0.027 mmol), HATU (9,38 mg of 0.025 mmol) and base Hunya (of 0.014 ml, 0,078 mmol) in DMSO (0.5 ml) and the mixture was stirred at room temperature for 45 minutes. Was diluted with water and collecting the solid by filtration. The product was purified using chromatography on silica gel, elwira mixture 0-4% MeOH in CH2Cl2with obtaining specified in the title compound (8 mg, 43% yield).1H NMR (500 MHz, CHLOROFORM-D) δ memorial plaques of 1.02 (s, 9H) 1,65-of 1.73 (m, 1H) 1,86-of 1.95 (m, 2H) 1,99-of 2.08 (m, 1H) 2,13-of 2.20 (m, 2H) and 2.26 (s, 6H) 2,49 (DD, J=12,21, 6,56 Hz, 1H) 2,53-2,60 (m, 1H) 3,32-3,39 (m, 1H) 3,65-3,68 (m, 1H) 3,69 (s, 3H) 3,74-of 3.80 (m, 1H) 3,81-a 3.87 (m, 1H) 4,01 (s, 1H) to 4.38 (d, J=9,77 Hz, 1H) 4,56 (s, 4H) was 4.76 (d, J=7,17 Hz, 1H) 4,80 (DD, J=8,01, 2,52 Hz, 1H) of 5.39 (d, J=being 9.61 Hz, 1H) 6,70 (t, J=7,25 Hz, 1H) 6.73 x (d, J=to 7.93 Hz, 2H) 7,12-7,19 (m, 6H) of 7.36-the 7.43 (m, 5H) 7,47-7,51 (m, 4H) of 9.30 (s, 1H) 9,71 (s, 1H).

Example 11

Dimethyl (1S,1'S)-2,2'-((2S,2'S)-2,2'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene)bis(ethanediyl)) bis(octamethylene)bis(pyrrolidin-2.1-diyl))bis(2-oxo-1-Penilaian-2.1-diyl)dicarbamate

The product from Example 1D (9.0 mg, 0.018 mmol) was combined with (S)-2-(methoxycarbonylamino)-2-phenylacetic acid (7,95 mg of 0.038 mmol), HATU (14,44 mg of 0.038 mmol) and the base Hunya (of 0.013 ml, 0,072 mmol) in DMSO (1.0 ml) and the mixture was stirred at room temperature for 45 minutes. Was diluted with water and collecting the solid by filtration. The product was purified using chromatography on silica gel, elwira mixture of 0-5% MeOH in CH2Cl2with obtaining specified in the title compound (7.2 mg, 45.2% of the output).1H NMR (500 MHz, CHLOROFORM-D) δ M. D. 1,78-to 1.87 (m, 2H) 1,89 of 1.99 (m, 4H) 2,38 at 2.45 (m, 2H) 3,15-up 3.22 (m, 2H) 3,52-to 3.67 (m, 8H) of 4.49 (s, 4H) 4,77 (DD, J=7,86, 1,91 Hz, 2H) 5,42 (d, J=7,78 Hz, 2H) 5,94 (d, J=7,78 Hz, 2H) 6,61-of 6.71 (m, 3H) 7,07-7,13 (m, 6H) 7,20-7,25 (m, 5H) 7,30 (DD, J=7,55, to 2.67 Hz, 9H) 8,87 (s, 2H).

Example 12

Methyl (S)-1-((S)-2-(4-(((4-((S)-1-((R)-2-(diethylamino)-2-phenylacetyl)pyrrolidin-2-carboxamido)benzyl)(phenyl)amino)methyl)phenylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutyl-2-ylcarbamate

The product from Example 10A (15 mg, of 0.022 mmol) was combined with (R)-2-(diethylamino)-2-phenylacetic acid (6,04 mg 0,029 mmol), HATU (9,38 mg of 0.025 mmol) and base Hunya (0,024 ml, is 0.135 mmol) in DMSO (1.0 ml) and the mixture was stirred at room temperature for 45 minutes. Was diluted with water and collecting the solid by filtration. The product was purified using chromatography on silica gel, elwira mixture of 0-5% MeOH in CH2Cl2with obtaining specified in the title compound (11 mg, 57,2% yield).1H NMR (500 MHz, CHLOROFORM-D) δ memorial plaques of 0.87 (t, J=7,10 Hz, 6H) of 0.94 (s, 9H) 1,59 by 1.68 (m, 1H) 1,78 is 1.86 (m, 2H) 1,92 is 2.00 (m, 1H) 2,04-2,12 (m, 2H) 2,43-2,52 (m, 2H) 2,55-to 2.67 (m, 4H) 3,23-3,30 (m, 1H) 3,56-3,61 (m, 2H) 3,62 (s, 3H) 3,71-of 3.78 (m, 1H) 4,30 (d, J=being 9.61 Hz, 1H) 4,48 (s, 4H) 4,55 (s, 1H) 4,72-of 4.77 (m, 2H) 5,31 (d, J=9,77 Hz, 1H) 6,63 (t, J=7,25 Hz, 1H) to 6.67 (d, J=to 7.93 Hz, 2H 7,06 for 7.12 (m, 6H) 7,24-to 7.32 (m, 3H) 7,33 (d, J=8.54 in Hz, 2H) 7,35-7,42 (m, 4H) which 9.22 (s, 1H) for 9.64 (s, 1H).

Example 13

Dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(pyrrolidin-2.1-diyl))bis(3,3-dimethyl-1-oxobutyl-2.1-diyl)dicarbamate

Example 13A

4-Fluoro-N,N-bis(4-nitrobenzyl)aniline

The product of Example 13A was obtained by methods used to obtain the product of Example 1A, substituting aniline for 4-ftoranila (4,78 g, 93% yield).

Example 13B

N,N-bis(4-aminobenzyl)-4-ftoranila

The product of Example 13B was obtained from the product of Example 13A, using the method And used to obtain the product of Example 1B (0,548 g, 100% yield).

Example 13C

(2S,2'S)-tert-Butyl 2,2'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)dipyrrole-1-carboxylate

The product of Example 13C was obtained from the product of Example 13B methods used to obtain the product of Example 1C (0,650 g, 53.3% of the output).

Example 13D

(2S,2'S)-N,N'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis (4,1-phenylene))dipyrrole-2-carboxamide

The product of Example 13D was obtained from the product of Example 13C methods used to obtain the product of Example 1D (0,650 g, 53.3% of the output).

Example 13E

Dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(pyrrolidin-2.1-diyl))bis(3,3-dimethyl-1-oxobutyl-2.1-diyl)dicarbamate

To a mixture of the product from Example 13D (0,100 g, 0,194 mmol), (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid (0,111 g, 0,388 mmol) and HATU (rate £ 0.162 g, 0,427 mmol) in DMF (2.0 ml) was added to the base Hunya (0,134 ml, 0,766 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was distributed between water and EtOAc. The organic phase was washed with saturated saline solution, dried (Na2SO4), filtered and concentrated. The residue was purified using chromatography on silica gel, elwira mixture of 0-3% MeOH in CH2Cl2with obtaining specified in the connection header (0,071 g, and 42.7% yield).1H NMR (500 MHz, DMSO-d6) δ memorial plaques to 0.96 (s, 18H), 1,81-1,90 (m, 4H), 1,94-2,02 (m, 2H), 2,11-to 2.18 (m, 2H), 3,54 (s, 6H), 3,61-3,66 (m, 2H), 3.75 to-3,81 (m, 2H), 4,21 (d, J=cent to 8.85 Hz, 2H), 4,43 (DD, J=8,24, 5,49 Hz, 2H), 4,55 (s, 4H), only 6.64 (DD, J=9,31, 4,43 Hz, 2H), 6,91 (DD, J=9,00, of 9.00 Hz, 2H), 7,09 (Shir. d, J=cent to 8.85 Hz, 2H), 7,15 (d, J=8,55 Hz, 4H), 7,51 (d, J=8.54 in Hz, 4H), 9,99 (Shir. s, 2H).

Example 14

Dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(pyrrolidin-2.1-diyl))bis(3-methyl-1-oxobutyl-2.1-diyl)dicarbamate

The product from Example 13D under the Yergali interaction with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid methods, used to obtain the product of Example 13E, obtaining specified in the connection header (to 0.108 g of 67.1% yield).1H NMR (500 MHz, DMSO-d6) δ memorial plaques of 0.87 (d, J=to 6.57 Hz, 6H), of 0.93 (d, J=6,72 Hz, 6H), 1,84-2,02 (m, 8H), 2,11-2,17 (m, 2H), 3,52 (s, 6H), 3,60-to 3.64 (m, 2H), of 3.77-a 3.83 (m, 2H), was 4.02 (DD, J=8,39, 8,39 Hz, 2H), 4,43 (DD, J=8,24, 4,88 Hz, 2H), 4,55 (s, 4H), 6,63 (DD, J=9,31, 4,43 Hz, 2H), 6,91 (DD, J=9,0, 9,0 Hz, 2H), 7,16 (d, J=8.54 in Hz, 4H), 7,32 (d, J=8,40, 2H), 7,51 (d, J=8.54 in Hz, 4H), 9,98 (s, 2H).

Example 15

Dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(pyrrolidin-2.1-diyl))bis(1-oxopropyl-2.1-diyl)dicarbamate

The product from Example 13D were subjected to interaction with (S)-2-(methoxycarbonylamino)propanoic acid methods used to obtain the product of Example 13E, obtaining specified in the title compound (0.083 g, 55.3% of the output).1H NMR (500 MHz, DMSO-d6) δ memorial plaques of 1.18 (d, J=of 7.48, 6H), 1,83-of 1.94 (m, 4H), 1,97-2,02 (m, 2H), 2,09-of 2.15 (m, 2H), 3,51 (s, 6H), 3,56-of 3.60 (m, 2H), 3,64 at 3.69 (m, 2H), 4,28-4,34 (m, 2H), 4,40 was 4.42 (DD, J=8,39, of 4.57 Hz, 2H), 4,55 (s, 4H), 6,63 (DD, J=9,46, 4,58 Hz, 2H), 6,91 (DD, J=9,00, of 9.00 Hz, 2H), 7,16 (d, J=8,55, 4H), 7,35 (d, J=7,47 Hz, 2H), 7,50 (d, J=8,55 Hz, 4H), 9,92 (s, 2H).

Example 16

Dimethyl (2R,2'R)-1,1'-((2S,2'S)-2,2'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(pyrrolidin-2.1-diyl))bis(1-oxopropyl-2.1-diyl)dicarbamate

The product from Example 13D p who has Dorgali interaction with (R)-2-(methoxycarbonylamino)propanoic acid methods, used to obtain the product of Example 13E, obtaining specified in the title compound (0.152 g, 72,9% yield).1H NMR (500 MHz, BENZENE-d6) δ memorial plaques to 0.97 (d, J=6,56 Hz, 6H), 1,19-of 1.29 (m, 2H), 1,58 by 1.68 (m, 2H), 2,30 is 2.33 (m, 2H), 2.49 USD of $ 2.53 (m, 2H), 3,02-of 3.06 (m, 2H), 3,37 (s, 6H), 4.09 to (s, 4H), 4,14-4,17 (m, 2H), to 4.52 (Shir. d, J=7,33 Hz, 2H), 5,51 (Shir. s, 2H), to 6.43 (DD, J=9,31, 4,43 Hz, 2H), 6,77 (DD, J=8,70, to 8.70 Hz, 2H), 6,95-7,00 (m, 6H), 7,95 (d, J=8,09 Hz, 4H), 9,43 (Shir. s, 2H).

Example 17

Dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(phenylaziridine)bis(methylene)bis(1H-benzo[d]imidazole-5,2-diyl))bis(pyrrolidin-2.1-diyl))bis(3-methyl-1-oxobutyl-2.1-diyl)dicarbamate

Combined product from Example 7E (17,4 mg, 0.035 mmol), HATU (33.6 mg, 0,088 mmol) and (S)-2-(methoxycarbonylamino)-3-methylbutanoyl acid (15,50 mg, 0,088 mmol) in DMSO (of 0.18 ml) was added basis Hunya (37,1 μl, 0,212 mmol). The mixture was stirred at room temperature for 1 hour, poured into water and was extracted using EtOAc. The organic layer was dried over Na2SO4, was filtered and was evaporated. The product was purified using chromatography (C18), elwira mixture of 10-100% acetonitrile in water (0.1% TFOC), obtaining specified in the connection header (14,0 mg, 49.1% of output) in the form of a salt TFUCK.1H NMR (500 MHz, DMSO-d6) δ M. D. 14,50 (Shir. s, 2H) 7,70 (l,J=8,39 Hz, 2H) rate of 7.54 (s, 2H) 7,39 (l,J=7,17 Hz, 2H) 7,33 (l,J=8,55 Hz, 2H) 7,07 for 7.12 (m, 2H) 6.73 x (l,J=8,09 Hz, 2H) 6,61 (t,J=to 7.25 Hz, 1H) 5,20 (DD,J=8,01, ,42 Hz, 2H) 4,84-4,96 (m, 4H) 4,11 (t,J=8,01 Hz, 2H) 3,81-3,90 (m, 4H) 3,54 (s, 6H) 2,15-2,22 (m, 2H) 2,02-of 2.15 (m, 4H) 1,92 is 2.01 (m, 2H) 0,74-0,89 (m, 14H).

Example 18

(2R,2'R)-1,1'-((2S,2'S)-2,2'-(5,5'-(phenylaziridine)bis(methylene)bis(1H-benzo[d]imidazole-5,2-diyl))bis(pyrrolidin-2.1-diyl))bis(2-(dimethylamino)-2-phenylethane)

The product from Example 7E were subjected to interaction with (R)-2-(dimethylamino)-2-phenylacetic acid by the methods used to obtain the product of Example 17, to obtain specified in the connection header level (0.041 g, 54,2% yield) in the form of a salt TFUCK.1H NMR (500 MHz, DMSO-d6) δ M. D. 9,90-the 10.40 (m, 2H) 7,47-of 7.70 (m, 12H) 6,90-7,44 (m, 4H) 6,68-to 6.80 (m, 4H) 6,56 of 6.66 (m, 1H) 4,78-of 5.81 (m, 8H) 4,01 (s, 12H) 2,83-of 3.12 (m, 4H) 1,87-of 2.28 (m, 8H).

Example 19

Dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4-dimethyl(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(thiazol-2-alazander)bis(methylene)bis(4,1-phenylene))bis(ethanediyl)bis(octamethylene)bis(pyrrolidin-2.1-diyl))bis(3,3-dimethyl-1-oxobutyl-2.1-diyl)dicarbamate

Example 19A

N,N-bis(4-nitrobenzyl)thiazol-2-amine

The product of Example 19A was obtained by methods used to obtain the product of Example 1A, substituting aniline for 2-aminothiazol(0,915 g, 42.9% of the output).

Example 19B

N,N-bis(4-aminobenzyl)thiazol-2-amine

The product of Example 19B was obtained from the product of Example 19A using method A, used for proceduredata of Example 1B (0,211 g, 56,2% yield).

Example 19C

(2S,2'S)-tert-butyl 2,2'-(4,4'-(thiazol-2-alazander)bis(methylene)bis(4,1-phenylene))bis(ethanediyl)bis(octamethylene)dipyrrole-1-carboxylate

The product of Example 19C received from the product of Example 19B methods used to obtain the product of Example 1C (0.25 g, 52.2% of the output).

Example 19D

(2S,2'S)-N,N'-(4,4'-(thiazol-2-alazander)bis(methylene)bis(4,1-phenylene))dipyrrole-2-carboxamide

The product of Example 19D received from the product of Example 19C methods used to obtain the product of Example 1D (0,058 g, 32.5 per cent of output).

Example 19E

Dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4-dimethyl(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(thiazol-2-alazander)bis(methylene)bis(4,1-phenylene))bis(ethanediyl)bis(octamethylene)bis(pyrrolidin-2.1-diyl))bis(3,3-dimethyl-1-oxobutyl-2.1-diyl)dicarbamate

To a mixture of the product from Example 19D (0,0581 g, 0,115 mmol), (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid (0,0529 g, 0,280 mmol) and HATU (0,100 g, 0,264 mmol) in CH2Cl2(2.5 ml) was added to the base Hunya (0,08 ml, 0,462 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water, and the organic phase was dried (MgSO4), filtered and concentrated. The residue was purified using chromatography on silica gel, elwira mixture 0-5% MeO in CH 2Cl2with obtaining specified in the connection header (0,047 g, 48.3% of the output).1H NMR (500 MHz, BENZENE-d6) δ 1.00 each (l,J=8,2, 18H), a 1.75-of 1.10 (m, 6H), 2,13-to 1.98 (m, 2H), 3,25-3,14 (m, 2H), 3,40-of 3.31 (m, 2H), 3,42 (s, 3H), 3,44 (s, 3H), 4,20 (s, 1H), or 4.31 (d,J=13,8, 1H), 4,49 (DD,J=24,6, 15,4, 4H) and 4.65 (DD,J=7,6, 5,3, 1H), 4,78 (DD,J=7,8, 4,7, 1H), 5,28 (l,J=4,4, 1H), 5,52 (l,J=11,0, 1H), 5.56mm (l,J=8,9, 1H), 5,79 (l,J=4,5, 1H), 6,84 (l,J=8,3, 2H), 7,66 (l,J=8,4, 2H), 7,81 (l,J=8,4, 2H), made up 9.77 (s, 1H), 9,88 (s, 1H).

Example 20

Methyl (S)-1-((S)-2-(5-(((4-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-carboxamido)benzyl)(phenyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutyl-2-ylcarbamate

Example 20A

N-(4-nitrobenzyl)aniline

United aniline book (6.16 g, 66,2 mmol) and 4-nitrobenzaldehyde (10.0 g, 66,2 mmol) in MeOH (165 ml) and toluene (165 ml) and was heated to 60°C for 3 hours. Cooled the mixture to room temperature, portions was added sodium borohydride (5,01 g, 132 mmol) and then stirred at room temperature for 1 hour. Was added a saturated solution of NaHCO3and was stirred for 1 hour. Was added water and was extracted using EtOAc. The combined extracts were washed with saturated salt solution, dried (MgSO4), filtered and evaporated to obtain an amber oil, which was purified using chrome is ographie on silica gel, elwira a mixture of CH2Cl2with obtaining specified in the title compound (9.0 g, 59.6% of the output).

Example 20B

(S)-tert-butyl 2-(5-(((4-nitrobenzyl)(phenyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-carboxylate

The product from Example 20A (0,530 g, 2.32 mmol) and K2CO3(0,802 g of 5.81 mmol) were combined in dry DMF (20 ml) at room temperature, and after the solution was barbotirovany nitrogen for 10 minutes. The product from Example 7C (1.0 g, 2,63 mmol) was added in three equal portions over a 20-minute intervals and the reaction mixture was stirred a total of 2.5 hours. The mixture was poured into ice water, extracted into EtOAc, washed with saturated salt solution. The organic layer was dried (MgSO4), filtered and evaporated. The product was purified using chromatography on silica gel, elwira mixture 0-4% MeOH in CH2Cl2and the second column purification, elwira mixture of 0-5% EtOAc in CH2Cl2with obtaining specified in the connection header (0,350 g, 28,6% yield).

Example 20C

(S)-tert-butyl 2-(5-(((4-aminobenzyl)(phenyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-carboxylate

The product of Example 20C received from the product of Example 20B using the method And used to obtain the product of Example 1B.

Example 20D

(S)-tert-Buti� 2-(4-((((2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)methyl)(phenyl)amino)methyl)phenylcarbamoyl)pyrrolidin-1-carboxylate

The product of Example 20D received from the product of Example 20C methods used to obtain the product of Example 1C (0.15 g, 38.1% of the output).

Example 20E

(S)-N-(4-((phenyl((2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)methyl)amino)methyl)phenyl)pyrrolidin-2-carboxamide

The product of Example 20E received from the product of Example 20D methods used to obtain the product of Example 1D (0,082 g, 77% yield).

Example 20F

Methyl (S)-1-((S)-2-(5-(((4-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-carboxamido)benzyl)(phenyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutyl-2-ylcarbamate

The product of Example 20F received from the product of Example 20E and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid methods used to obtain the product of Example 10B. Specified in the title compound was purified using chromatography on silica gel, elwira mixture of 0-5% MeOH in CH2Cl2with further elution with a mixture of 10-60% EtOAc in CH2Cl2(containing 0.5% NH4OH) (0,044 g, 32.8% of the output).1H NMR (500 MHz, DMSO-d6) δ memorial plaques from 0.76 (d, J=of 6.71 Hz, 3H) 0,78 (DD, J=of 6.71, to 2.75 Hz, 3H) 0,83 (d, J=to 7.32 Hz, 3H) 0,88 (d, J=of 6.71 Hz, 3H) 1,23-of 1.53 (m, 1H) 1,78 is 1.91 (m, 4H) 1,91 of 1.99 (m, 2H) 2,05-2,17 (m, 4H) 3,48 (d, J=5,19 Hz, 6H) 3,54-of 3.60 (m, 1H) 3,72-with 3.79 (m, 2H) 3,92-Android 4.04 (m, 2H) to 4.38 (DD, J=8,09, 4,88 Hz, 1H) 4,56 (s, 2H) and 4.68 (d, J=10,99 Hz, 2H) of 5.05-5,12 (m, 1H) 6,51 (TD, J=7,21, Android 4.04 Hz, 1H) 6,64 (d, J=8,4 Hz, 2H) of 6.96-7,05 (m, 3H) 7,14 (DD, J=8,62, of 2.21 Hz, 2H) 7,20 (s, 1H) 7,22-7,30 (m, 2H) 7,35 (DD, J=35,78, 8,32 Hz, 1H) 7,46 (DD, J=8,62, of 1.75 Hz, 2H) 9,94 (s, 1H) 11,98 (d, J=26,25 Hz, 1H).

Example 21

(R,2S,2'S)-N,N'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene))bis(1-((R)-2-(diethylamino)-2-phenylacetyl)pyrrolidin-2-carboxamid)

The product of Example 21 was obtained from the product of Example 1D and (R)-2-(diethylamino)-2-phenylacetic acid by the methods used to obtain the product of Example 10B. Specified in the title compound was purified using chromatography on silica gel, elwira mixture of 0-5% MeOH in CH2Cl2(9.0 mg, 14.6% of the output).1H NMR (500 MHz, DMSO-d6) δ memorial plaques to 0.96 (t, J=7,10 Hz, 12H) 1,81 is 1.96 (m, 4H) 2,00-2,07 (m, 2H) 2,08-2,17 (m, 2H) 2,49-of 2.56 (m, 4H) 2,63-of 2.72 (m, 4H) 3,42-3,47 (m, 2H) 3,82-to 3.89 (m, 2H) 4,45 (DD, J=8,16, 4,50 Hz, 2H) 4,67 (s, 4H) 4,74 (s, 2H) 6,64 (t, J=7,25 Hz, 1H) 6,74 (d, J=to 7.93 Hz, 2H) 7,12-to 7.18 (m, 2H) 7,26 (d, J=8.54 in Hz, 4H) 7,34 (t, J=7,17 Hz, 2H) 7,40 (t, J=7,40 Hz, 4H) 7,47 (d, J=7,17 Hz, 4H) to 7.59 (d, J=8.54 in Hz, 4H) there is a 10.03 (s, 2H).

Example 22

Dimethyl (2S,2'S,3S,3'S)-1,1'-((2S,2'S)-2,2'-(5,5'-(phenylaziridine)bis(methylene)bis(1H-benzo[d]imidazole-5,2-diyl))bis(pyrrolidin-2.1-diyl))bis(3-methyl-1-oxopent-2.1-diyl)dicarbamate

To a solution of the product from Example 7E (12 mg, 0,024 mmol), (2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid (9,70 mg, 0,051 mmol) and HATU (19,49 mg, 0,051 mmol) in anhydrous DMSO (0.2 ml) was added to the base Hunya (of 0.013 ml, 0,073 mmol) and the resulting mixture of paramashiva and at room temperature for 90 minutes. The mixture was distributed between water (2 ml) and EtOAc (3×2 ml) and the combined organic layers were dried over Na2SO4. The mixture was filtered and concentrated in vacuo, and the crude product was purified using chromatography on silica gel (C18), elwira with a gradient of 10-100% ACN in water (0.1% TFUC). The fractions containing pure product were combined and concentrated in vacuum to obtain specified in the title compound as a solid (9 mg, 31.4 percent) in the form of a salt TFUCK.1H NMR (500 MHz, DMSO-d6) δ M. D. 14,70 (Shir. s, 2H) 7,73 (d, J=8,39 Hz, 2H) 7,56 (s, 2H) 7,43 (d, J=8,39 Hz, 2H) 7,38 (d, J=to 8.70 Hz, 2H) 7,07 for 7.12 (m, 2H) of 6.73 (d, J=8,09 Hz, 2H) of 6.61 (t, J=7,25 Hz, 1H) to 5.21 (DD, J=8,16, to 5.57 Hz, 2H) 4,91 (s, 4H) 4,11-4,18 (m, 2H) 3,82-of 3.94 (m, 4H) 3,54 (s, 6H) 2,01-of 2.26 (m, 8H) of 1.64-1.77 in (m, 2H) of 1.27 to 1.37 (m, 2H) 0,96-1,10 (m, 2H) 0,71-of 0.90 (m, 12H).

Example 23

Dimethyl (1R,1'R)-2,2'-((2S,2'S)-2,2'-(5,5'-(phenylaziridine)bis(methylene)bis(1H-benzo[d]imidazole-5,2-diyl))bis(pyrrolidin-2.1-diyl))bis(2-oxo-1-Penilaian-2.1-diyl)dicarbamate

To a mixture of the product from Example 7E (12 mg, 0,024 mmol), (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (of 10.72 mg, 0,051 mmol) and HATU (19,49 mg, 0,051 mmol) in anhydrous DMSO (0.2 ml) was added to the base Hunya (of 0.013 ml, 0,073 mmol) and the resulting mixture was stirred at room temperature for 90 minutes. Distributed between water (2 ml) and EtOAc (2×2 ml) and the combined organic layers were dried over Na2SO4.Was filtered and concentrated in vacuum. The crude product was purified using chromatography on silica gel (C18), elwira with a gradient of 10-100% acetonitrile in water (0.1% TFUC). Pure fractions were combined and concentrated in vacuum to obtain specified in the title compound as a solid (13 mg, 43,8%) in the form of a salt TFUCK.1H NMR (500 MHz, DMSO-d6) δ M. D. 14,50 (Shir. s, 2H) 6.87 in-7,88 (m, 18H) 6,56-6,79 (m, 3H) are 5.36-to 5.58 (m, 2H) 5,22 to 5.35 (m, 2H) 4,94 (s, 4H) 3,69-3,99 (m, 4H) of 3.46 of 3.56 (m, 6H) 3,13-3,26 (m, 2H) 1,86-of 2.34 (m, 8H).

Example 24

Dimethyl ([(1-methylethyl)imino]bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3-methyl-1-oxobutyl-1,2-diyl]})bicarbonate

Example 24A

N,N-bis(4-nitrobenzyl)propan-2-amine

A mixture of bis(4-nitrobenzyl)amine (50 mg, 0,174 mmol) and acetone (51,1 μl, 0,696 mmol) in a mixture of methanol (752 ml)/acetic acid (39,6 ál)/CH2Cl2(79 μl) was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C was added cyanoborohydride sodium was 32.8 mg, 0,522 mmol). The mixture was stirred at 0°C for 1 hour and allowed to warm to room temperature and was stirred overnight. The reaction mixture was concentrated and the residue was distributed between EtOAc and saturated aqueous NaHCO3. The organic layer was washed with saturated saline solution, dried (Na2SO4), was filtered and concentrated in vacuum. Purification using flash chromatography (silica gel, 50% EtOAc/hexane) gave specified in the header of the product (or 42.8 mg, 75%). MS (ESI) m/z 329,9 (M+H)+.

Example 24B

4-(((4-aminobenzyl)(isopropyl)amino)methyl)aniline

To a solution of the product from Example 24A (or 42.8 mg, 0,130 mmol) in ethanol (1.3 ml) in an atmosphere of N2added trichloride bismuth (0,026 ml to 0.39 mmol). The mixture was cooled in a cold water bath and slowly portions, was added sodium borohydride (79 mg, 2,079 mmol) over several minutes. When the addition was completed, the resulting mixture was stirred at room temperature for 1 hour and then filtered through celite and washed with methanol. The filtrate was concentrated to ~1/2 of the volume, diluted with a mixture of 1:3 isopropanol:CH2Cl2and washed with saturated aqueous NaHCO3. The organic layer was dried (Na2SO4), filtered and concentrated in vacuum to obtain specified in the connection header (31.9 per mg). MS (APCI) m/s 270,5 (M+H)+.

Example 24C

(2S,2'S)-tert-butyl 2,2'-(4,4'-(isopropylidenedioxy)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)dipyrrole-1-carboxylate

To a solution of the product of Example 24B (31.9 per mg, the amount of 0.118 mmol) in anhydrous DMSO (592 ml) was added N-(tert-butoxycarbonyl)L-Proline (51 mg, 0,237 mmol), HATU (95 mg, 0,249 mmol) and base Hunya (83 μl, 0,474 mmol). The resulting mixture was stirred at room temperature for 2 hours and then distributed between water and ethyl acetate. The organic layer was washed with saturated saline solution, dried (Na2SO4), filtered and concentrated in vacuum. Purification using flash chromatography (silica gel, 50% EtOAc/hexane) gave specified in the title compound (24.3 mg, 31%). MS (ESI) m/z 664,4 (M+H)+.

Example 24D

(2S,2'S)-N,N'-(4,4'-(isopropylidenedioxy)bis(methylene)bis(4,1-phenylene))dipyrrole-2-carboxamide

To a solution of the product of Example 24C (24.3 mg, 0,037 mmol) in CH2Cl2(0.2 ml) was added triperoxonane acid (0.100 ml). The resulting mixture was stirred at room temperature for 1 hour and concentrated in vacuum. The residue was dissolved in a mixture of 1:3 isopropyl alcohol:CH2Cl2and washed with aqueous saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum to obtain specified in the title compound (10.4 mg, 61%). MS (ESI) m/z 464,2 (M+H)+.

Example 24E

Dimethyl ([(1-methylethyl)imino]bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3-methyl-1-oxobutyl-1,2-diyl]})bicarbonate

To a solution of the product of Example 24D (10.4 mg, of 0.022 mmol) in anhydrous DMSO (0.15 ml) is obavljale (S)-2-(methoxycarbonylamino)-3-methylbutanoyl acid (10,61 mg, 0,056 mmol), HATU (21,3 mg, 0,056 mmol) and base Hunya (23,5 μl, is 0.135 mmol). The resulting mixture was stirred at room temperature for 1 hour and then distributed between water and ethyl acetate. The organic layer was washed with saturated saline solution, dried (Na2SO4), filtered and concentrated in vacuum. Purification using a C18-reverse-phase HPLC (10-90% CH3CN/0.1% TFUK in water) gave specified in the title compound in the form of salt TFOC (7.5 mg).1H NMR (500 MHz, DMSO-d6) δ memorial plaques of 0.87 (t,J=7.5 Hz, 7H), of 0.93 (d,J=6,7 Hz, 5H), of 1.34 (d,J=6,6 Hz, 6H), 1,84-of 1.94 (m, 6H), 1,95-2,04 (m, 3H), 2,17 (TD,J=7,2, 4,8 Hz, 2H), 2,37-to 2.42 (m, 3H), 3,60 at 3.69 (m, 6H), 3,82 (l,J=9.5 Hz, 2H), 4,03 (t,J=8,5 Hz, 3H), 4,34 (l,J=to 13.4 Hz, 2H), 4,42-to 4.46 (m, 2H), 7,31 (l,J=8,4 Hz, 2H), 7,40 (t,J=9,2 Hz, 4H), to 7.64 (DD,J=to 8.7, 2.0 Hz, 4H), 9,10 (s, 1H), of 10.21 (s, 2H); MS (ECI) m/z 778,4 (M+H)+.

Example 25

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba (2S)pyrrolidin-2.1-diyl[(2S,3R)-3-hydroxy-1-oxobutyl-1,2-diyl]}]bicarbonate

Example 25A

(2S,3R)-3-hydroxy-2-(methoxycarbonylamino)butane acid

L-Threonine (0.50 g, 4.2 mmol) and sodium bicarbonate (1.13 g, a 13.4 mmol) was dissolved in water (20 ml) then cooled in an ice bath. Methylchloroform (0,36 inL, to 4.62 mmol) was dissolved in diethyl ether (2 ml) and added dropwise with thorough peremeci the years. The solution was stirred at ambient temperature for 5 hours, then brought the pH to 3 with concentrated hydrochloric acid and was extracted into ethyl acetate. The organic solution was dried over sodium sulfate, filtered and concentrated to obtain 0.12 g specified in the connection header in the form of a waxy solid.

Example 25B

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S,3R)-3-hydroxy-1-oxobutyl-1,2-diyl]}]bicarbonate

The product from Example 25A (0,027 g, 0.16 mmol) and the product from Example 1D (0.035 g, 0.07 mmol) were combined in dimethyl sulfoxide (1.5 ml) at ambient temperature and treated with diisopropylethylamine (0,061 ml, 0.35 mmol), followed by processing HATU (0,056 g, 0.15 mmol) and was stirred for 45 minutes. The solution was diluted with water and the solid product was filtered, then purified on a column of combi-flash c 4 g of silicon dioxide, elwira mixture of 0-10% methanol in dichloromethane, to obtain 0.025 g specified in the title compound as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ memorial plaques of 1.12 (d, J=6,41 Hz, 6H) 1,82 is 1.91 (m, 4H) 1,92 is 2.01 (m, 2H) 2,09-2,17 (m, 2H) 3,52 (s, 6H) 3,65-3,74 (m, 2H) 3,76-a-3.84 (m, 4H) 4,20 (t, J=7,40 Hz, 2H) was 4.42 (DD, J=8,39, 4,88 Hz, 2H) of 4.57 (s, 4H) to 4.81 (d, J=5,80 Hz, 2H) 6,55 (t, J=7,25 Hz, 1H) 6,64 (d, J=to 7.93 Hz, 2H) 7,02-7,11 (m, 4H) 7,16 (d, J=8.54 in Hz, 4H) 7,49 (d, J=8,70 Hz, 4H) 9,83 (s, 2H); MS (TFUC, ELSD+) m/z 816 (M+H) +.

Example 26

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S')-3-hydroxy-1-oxopropyl-1,2-diyl]}]bicarbonate

Example 26A

(S)-3-hydroxy-2-(methoxycarbonylamino)propanoic acid

L-serine (1.0 g, 9,52 mmol) were processed as in Example 25A, obtaining 0.125 g (8%) specified in the connection header in the form of a waxy solid.

Example 26B

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3-hydroxy-1-oxopropyl-1,2-diyl]}]bicarbonate

The product from Example 26A (0.025 mg, 0.16 mmol) and the product from Example 1D (0.035 g, 0.07 mmol) were processed as in Example 25B, obtaining 0,012 g (22%) indicated in the title compound as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ M. D. 1,87-of 1.97 (m, 6H) 2,09-2,17 (m, 2H) 3,19-of 3.25 (m, J=10,99 Hz, 2H) 3,52 (s, 6H) 3,55-3,63 (m, 2H) 3,66 is 3.76 (m, 2H) 4,08 (kV, J=of 5.29 Hz, 2H) 4,37-4,47 (m, 4H) of 4.57 (s, 4H) 5,10 (s, 2H) 6,55 (t, J=7,32 Hz, 1H) 6,63 (d, J=8,09 Hz, 2H) 7,02-was 7.08 (m, 2H) 7.15m (d, J=8.54 in Hz, 4H) 7,31 (d, J=7,78 Hz, 2H) of 7.48 (d, J=8.54 in Hz, 4H) 9,67 (s, 2H); MS (TFUC, ELSD+) m/z 788 (M+H)+.

Example 27

Dimethyl [(cyclopentylamine)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3-methyl-1-oxobutyl-1,2-diyl]}]bicarbonate

Example 27A

N,N-bis(4-nitrobenzyl)Cyclops is nanamin

To a solution of cyclopentylamine (0,148 ml, 1.5 mmol) in N,N-dimethylformamide (2 ml) was added potassium carbonate (622 mg, 4,50 mmol) followed by addition of 1-(methyl bromide)-4-nitrobenzene (648 mg, 3.00 mmol). The resulting mixture was stirred at room temperature for 16 hours, was added an additional amount of 1-(methyl bromide)-4-nitrobenzene (324 mg, 1.5 mmol)? and stirring was continued for additional 2 hours. The mixture was diluted with water, was extracted with the help of CH2Cl2and the organic layer was dried (Na2SO4), filtered and concentrated. The crude product was purified by precipitation from methanol to obtain specified in the title compound (554 mg, quantities.). MS (ESI) m/z 356,0 (M+H)+.

Example 27B

4-(((4-aminobenzyl)(cyclopentyl)amino)methyl)aniline

The product of Example 27A (231 mg, of 0.65 mmol) was subjected to processing by the method described in Example 24B, obtaining specified in the title compound (360 mg). MS (APCI) m/z 295,9 (M+H)+.

Example 27C

(2S,2'S)-tert-butyl 2,2'-(4,4'-(cyclopentylacetyl)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)dipyrrole-1-carboxylate

The product of Example 27B (360,3 mg, 1,220 mmol) was subjected to the procedure described in Example 24C, obtaining specified in the title compound (427 mg, 50%). MS (ESI) m/z 690,5 (M+H) .

Example 27D

(2S,2'S)-N,N'-(4,4'-(cyclopentylacetyl)bis(methylene)bis(4,1-phenylene))dipyrrole-2-carboxamide

The product of Example 27C (427,4 mg, 0,620 mmol) was subjected to the procedure described in Example 24D, obtaining specified in the title compound (255 mg, 84%). MS (ESI) m/z 490,2 (M+H)+.

Example 27E

Dimethyl [(cyclopentylamine)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3-methyl-1-oxobutyl-1,2-diyl]}]bicarbonate

The product of Example 27D (50 mg, is 0.102 mmol) was subjected to the procedure described in Example 24E, obtaining specified in the connection header in the form of a salt TFOC (11 mg).1H NMR (500 MHz, DMSO-d6) δ M. D. -0,00 (s, 1H), 0,85-of 0.91 (m, 8H), were 0.94 (t,J=6,0 Hz, 6H), 1,21-of 1.30 (m, 1H), 1,48-of 1.57 (m, 3H), 1,71 (s, 2H), 1.85 to was 1.94 (m, 8H), 1,97-2,02 (m, 4H), 2,13-2,22 (m, 2H), of 3.77-a 3.87 (m, 3H), a 4.03 (t,J=8.5 Hz, 2H), 4,14 (DD,J=13,4, a 5.3 Hz, 2H), 4.26 deaths (s, 2H), of 4.44 (DD,J=7,8, and 5.2 Hz, 2H), 7,32 (l,J=8,2 Hz, 2H), 7,40 (t,J=a 8.9 Hz, 4H), 7,62-to 7.67 (m, 4H), 9,52 (s, 1H), 10,22 (s, 2H); MS (ECI) m/z 804,4 (M+H)+.

Example 28

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3-hydroxy-3-methyl-1-oxobutyl-1,2-diyl]}]bicarbonate

Example 28A

(S)-3-hydroxy-2-(methoxycarbonylamino)-3-methylbutanoate acid

(S)-2-amino-3-hydroxy-3-methylbutanoyl acid (0.52 g, 3.9 mmol) were processed as in Example 25A to obtain 0.55 g (74%) indicated in the title compound in the form of a waxy solid.

Example 28B

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3-hydroxy-3-methyl-1-oxobutyl-1,2-diyl]}]bicarbonate

The product from Example 28A (0,029 mg, 0.16 mmol) and the product from Example 1D (0.035 g, 0.07 mmol) were processed as in Example 25B, obtaining 0,016 g (27%) indicated in the title compound as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ memorial plaques to 1.14 (s, 6H) to 1.21 (s, 6H) 1,84-of 1.97 (m, 6H) 2,11-of 2.20 (m, 2H) 3,54 (s, 6H) 3,64-to 3.73 (m, 2H) 3,84-3,93 (m, 2H) 4,37 (d, J=to 8.70 Hz, 2H) to 4.46 (DD, J=8,62, 3,74 Hz, 2H) 4,58 (s, 4H) 5,09 (s, 2H) 6,55 (t, J=7,25 Hz, 1H) 6,63 (d, J=to 7.93 Hz, 2H) 7,05 (DD, J=8,77, of 7.25 Hz, 2H) 7,14 (d, J=being 9.61 Hz, 2H) 7,16 (d, J=8,70 Hz, 4H) 7,51 (d, J=8,70 Hz, 4H) 9,65 (s, 2H); MS (TFUC, ELSD+) m/z 844 (M+H)+.

Example 29

Dimethyl [(cyclopentylamine)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]}]bicarbonate

The product of Example 27D (50 mg, is 0.102 mmol) was subjected to the procedure described in Example 24E, substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoyl acid to (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid, obtaining specified in the connection header in the form of a salt TFOC (9 mg).1H NMR (500 MHz, DMSO-d6) δ M. D. 0,81-0,89 (m, 2H), of 0.94-0.98 (m, 21H), 1,49-of 1.57 (m, 2H), 1,72 (l,J=3.2 Hz, 2H), 1,84-of 1.93 (m, 5H), 1,95-2,02 (m, 4H), 2,14-of 2.21 (m, 2H), 3,80 (l,J=8,9 Hz, 5H), is 4.15 (s, 3H), 4,22 (l,J=8,7 Hz, 3H), 4,28 (s, 1H), 4,42-4,47 (m, 2H), 7,09 (l,J=a 8.9 Hz, 2H), 7,40 (DD,J=12,6, 8.6 Hz, H), the 7.65 (DD,J=to 8.7, 2.3 Hz, 4H), to 9.50 (s, 1H), 10,22 (s, 2H); MS (ECI) m/z 832,4 (M+H)+.

Example 30

Dimethyl ([(1-methylethyl)imino]bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]})bicarbonate

The product of Example 24D (60,0 mg, 0,129 mmol) was subjected to the procedure described in Example 24E, substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoyl acid to (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid, obtaining specified in the connection header in the form of a salt TFOC (25 mg).1H NMR (500 MHz, DMSO-d6) δ M. D. 0,80-0,89 (m, 2H), of 0.91 (s, 1H), of 0.93 to 1.00 (m, 20H), 1,22-of 1.30 (m, 2H), 1,34 (l,J=6,6 Hz, 6H), 1,83-of 1.92 (m, 4H), 1,95-2,03 (m, 2H), 2,13-2,22 (m, 2H), 3,35 (s, 2H), 4,06 (DD,J=13,4, and 5.6 Hz, 4H), 4,21 (l,J=a 8.9 Hz, 2H), 4,34 (t,J=12,5 Hz, 2H), of 4.44 (d,J=6,6 Hz, 2H), 7,09 (l,J=a 8.9 Hz, 2H), 7,41 (DD,J=13,1, to 8.7 Hz, 4H), to 7.64 (DD,J=8,7, 2,9 Hz, 4H), 9,13 (s, 1H), 10,22 (s, 2H); MS (ECI) m/z 806,5 (M+H)+.

Example 31

(2S,2'S)-N,N'-[(phenylimino)bis(metandienon-4,1-diyl)]bis{1-[(2S)-3,3-dimethyl-2-(2-Oxymetazoline-1-yl)butanoyl]pyrrolidin-2-carboxamide}

The product of Example 1D (32 mg, 0,064 mmol) and (S)-3,3-dimethyl-2-(2-Oxymetazoline-1-yl)butane acid (to 39.6 mg, rate of 0.193 mmol) were processed using the method described in Example 43, to obtain 22 mg (40%) specified in the connection header.1H NMR (500 MHz, DMSO-d6) δ memorial plaques to 10.01 (s, 2H),7,58 (l, J=8,5 Hz, 4H), 7,24 (l,J=8,5 Hz, 4H), 7,13 (m, 2H), 6.73 x (l,J=8,1 Hz, 2H), 6,63 (t,J=7,3 Hz, 1H), 6,47 (s, 2H) and 4.65 (s, 4H), 4.53-in (s, 2H), 4,46 (DD,J=8,4, 5.0 Hz, 2H), to 3.67 (m, 6H), 3,55 (m, 2H), 3,24 (m, 4H), of 2.21 (m, 2H), 2,03 (m, 2H), 1.91 a (m, 4H), 1.06 a (s, 18H).

Example 32

Dimethyl ([(2-methoxyethyl)imino]bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]})bicarbonate

Example 32A

2-methoxy-N,N-bis(4-nitrobenzyl)ethanamine

To a solution of 2-methoxyethylamine (0,343 ml of 3.99 mmol) in DMF (20,0 ml) at room temperature was added potassium carbonate (0,964 ml, 15,98 mmol) followed by addition of 4-nitrobenzylamine (1,812 g, 8,39 mmol). The reaction mixture was stirred for 2 hours, then extinguished with water, was extracted using EtOAc and concentrated. The residue was purified using chromatography (mixture of from 20% to 40% EtOAc-hexane) to obtain specified in the connection header. MS (DCI) m/z 346 (M+H)+.

Example 32B

4-(((4-aminobenzyl)(2-methoxyethyl)amino)methyl)aniline

The product from Example 32A were processed using the method described in Example 1B (Method A), obtaining specified in the connection header. MS (ESI) m/z 286 (M+H)+.

Example 32C

(2S,2'S)-tert-butyl 2,2'-(4,4'-(2-methoxyestradiol)bis(methylene)bis(4,1-phenylene)bis(and anadoil))bis(octamethylene)dipyrrole-1-carboxylate

The product of Example 32B were processed using the method described in Example 1C, substituting DMSO dichloromethane to obtain specified in the connection header. MS (ESI) m/z 680 (M+H)+, 678 (M-H)+.

Example 32D

(2S,2'S)-N,N'-(4,4'-(2-methoxyestradiol)bis(methylene)bis(4,1-phenylene))dipyrrole-2-carboxamide

The product of Example 32C were processed using the method described in Example 1D, obtaining specified in the connection header. MS (ESI) m/z 480 (M+H)+, 478 (M-H)+.

Example 32E

Dimethyl ([(2-methoxyethyl)imino]bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]})bicarbonate

The product of Example 32D were processed using the method described in Example 6, replacing DMSO with dichloromethane, and purified using flash chromatography (silica gel, MeOH/dichloromethane) to obtain the specified title compound (7.5 mg, 3%).1H NMR (500 MHz, BENZENE-d6) δ of 1.02 (s, 18H), 1,39 is 1.16 (m, 5H), 1.56 to of 1.40 (m, 2H), 1,78 is 1.60 (m, 2H), 2,19-2,02 (m, 2H), 2,59 (t,J=5,9, 2H), 3,03 (s, 4H), 3,26-3,19 (m, 2H), 3,29 (t,J=5,9, 2H), 3,41-to 3.35 (m, 6H), 3,44 (s, 6H), 4.53-in (l,J=9,7, 2H), 4,82-4,63 (m, 2H), 5,69 (l,J=8,6, 2H), 7,80 (l,J=7,8, 4H), 9,81 (s, 2H); MS (ECI)m/z822 (M+H)+, 820 (M-H)+.

Example 33

Dimethyl [(isoxazol-3-elimina)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2)-3,3-dimethyl-1-oxobutyl-1,2-diyl]}]bicarbonate

Example 33A

N,N-bis(4-nitrobenzyl)isoxazol-3-amine

Specified in the title compound was obtained using the methods from Example 1A, substituting aniline for isoxazol-3-amine, with the receipt specified in the connection header (0,49 g, 23% yield).

Example 33B

N,N-bis(4-aminobenzyl)isoxazol-3-amine

Specified in the title compound was obtained using the methods of Example 1B substituting the product from Example 1A for the product from Example 33A, obtaining specified in the title compound (0.32 g, 79% yield).

Example 33C

(2S,2'S)-tert-butyl 2,2'-(4,4'-(isoxazol-3-alazander)bis(methylene)bis(4,1-phenylene))bis(ethanediyl)bis(octamethylene)dipyrrole-1-carboxylate

Specified in the title compound was obtained using the methods from Example 1C, substituting the product from Example 1B, the product from Example 33B, obtaining specified in the title compound (0.32 g, 43% yield).

Example 33D

(2S,2'S)-N,N'-(4,4'-(isoxazol-3-alazander)bis(methylene)bis(4,1-phenylene))dipyrrole-2-carboxamide

Specified in the title compound was obtained using the methods from Example 1D, substituting the product from Example 1C of the product of Example 33C, obtaining specified in the title compound (0.14 g, 62% yield).

Example 33E

Dima is Il [(isoxazol-3-elimina)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]}]bicarbonate

The product of Example 33D and (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid were subjected to interaction, using the method of Example 1E, and the product was purified using column chromatography, elwira mixture of 0-4% methanol in dichloromethane, to obtain specified in the title compound (37 mg, 31% yield).1H NMR (500 MHz, DMSO) δ 10,02 (s, 2H), 8,48 (l,J=a 1.8, 1H), 7,52 (d,J=to 8.5, 4H), 7,16 (l,J=to 8.5, 4H), to 7.09 (d,J=of 8.8, 2H), 6,36 (l,J=a 1.8, 1H), of 4.44 (DD,J=5,3, 8,1, 2H), 4,35 (s, 4H), 4,21 (l,J=of 8.8, 2H), 3,81-to 3.73 (m, 2H), 3,68-of 3.60 (m, 2H), 3,53 (l,J=10,5, 6H), 2.21 are of 2.10 (m, 2H), 2,03-of 1.93 (m, 2H), 1,92 and 1.80 (m, 4H), of 0.97 (s, 18H); MS (ECI; M+H) m/z=832.

Example 34

Methyl [(1S)-2-hydroxy-1-{[(2S)-2-(6-{[({2-[(2S)-1-{(2S)-3-hydroxy-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazole-6-yl}methyl)(phenyl)amino]methyl}-1H-benzimidazole-2-yl)pyrrolidin-1-yl]carbonyl}-2-methylpropyl]carbamate

The product of Example 7E (25 mg, 0,051 mmol) and (S)-3-hydroxy-2-(methoxycarbonylamino)-3-methylbutanoyl acid (21,4 mg, 0,112 mmol) were processed using the method described in Example 7F and HPLC fraction was neutralized with a saturated aqueous solution of NaHCO3followed by extraction with a mixture of isopropyl alcohol/CH2Cl2(ratio 1:3; 3×100 ml) and allocation to obtain 32 mg (53%) specified in the connection header.1H NMR (500 MHz, DMSO-d6) δ memorial plaques of 1.02 (s, 6H), 1.14 in (s, 6H), 1,91-of 2.16 (m, 6H, 2,29 is 2.43 (m, 3H), 2,53 (s, 2H), 3,18 (s, 2H), 3,55 (s, 6H), 3.72 points-is 3.82 (m, 2H), 3,97-4,06 (m, 2H), 4,37 (l,J=to 8.70 Hz, 4H), 4,88 (s, 4H), 4,90 (l,J=10,99 Hz, 2H), 5,26 (DD,J=8,24, 4,58 Hz, 2H), 6,56-6,62 (m, 1H), 6,72 (l,J=8,09 Hz, 2H),? 7.04 baby mortality for 7.12 (m, 3H), 7,18 (l,J=8,54 Hz, 2H), 7,37 (l,J=8,39 Hz, 2H), 7,52 (s, 2H), 7,66 (l,J=8,24 Hz, 2H), MS (ECI) m/z 838 (M+H)+.

Example 35

Methyl [(1S,2R)-2-hydroxy-1-{[(2S)-2-(6-{[({2-[(2S)-1-{(2S,3R)-3-hydroxy-2-[(methoxycarbonyl)amino]butanoyl}pyrrolidin-2-yl]-1H-benzimidazole-6-yl}methyl)(phenyl)amino]methyl}-1H-benzimidazole-2-yl)pyrrolidin-1-yl]carbonyl}propyl]carbamate

The product of Example 7E (25 mg, 0,051 mmol) and (2S,3R)-3-hydroxy-2-(methoxycarbonylamino)butane acid (to 19.8 mg, 0,112 mmol) were processed using the method described in Example 7F and HPLC fraction was neutralized with a saturated aqueous solution of NaHCO3followed by extraction with a mixture of isopropyl alcohol/CH2Cl2(ratio 1:3; 3×100 ml) and allocation to obtain 25 mg (43%) specified in the connection header.1H NMR (500 MHz, DMSO-d6) δ memorial plaques to 1.00 (d,J=6,26 Hz, 6H), 2.00 in of 2.20 (m, 7H), 2,34 is 2.44 (m, 4H), of 3.54 (s, 6H), a 3.87 (dt,J=12,40, 6,18 Hz, 2H), 4.26 deaths (DD,J=8,24, of 5.34 Hz, 2H), 4,90 (l,J=1,98 Hz, 4H), to 5.21 (DD,J=8,24, of 5.34 Hz, 2H), 6,60 (t,J=to 7.25 Hz, 1H), 6,72 (l,J=8,09 Hz, 2H), 6,99 (l,J=8,24 Hz, 2H), 7,05 for 7.12 (m, 2H), 7,41 (l,J=8,39 Hz, 2H), 7,54 (s, 2H), 7,71 (l,J=8,54 Hz, 2H), MS (ECI) m/z 810 (M+H)+.

Example 36

p> (2S,2'S)-N,N'-[(Phenylimino)bis(metandienon-4,1-diyl)]bis{1-[(2S)-3-methyl-2-(2-oxotetrahydrothalifendine-1(2H)-yl)butanoyl]pyrrolidin-2-carboxamide}

The product of Example 1D (30 mg, to 0.060 mmol) was subjected to the procedure described in Example 24E, substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoyl acid to (S)-3-methyl-2-(2-oxotetrahydrothalifendine-1(2H)-yl)butane acid, obtaining specified in the connection header in the form of a salt TFOC (10 mg).1H NMR (500 MHz, DMSO-d6) δ M. D. 0,78-0,85 (m, 7H), 0,88 (l,J=6,4 Hz, 6H), 1,68-to 1.77 (m, 4H), 1,79-of 1.88 (m, 4H), 1.97 of (l,J=6,0 Hz, 2H), 2.06 to of 2.16 (m, 4H), 3,05-3,13 (m, 6H), 3,54-3,63 (m, 2H), 3,80-3,88 (m, 2H), 4,36 (DD,J=8,2, 5.0 Hz, 2H), 4,59 (s, 4H), 4,78 (l,J=11,1 Hz, 2H), 6.30-in (s, 2H), 6,56 (t,J=7.2 Hz, 1H), 6,66 (l,J=8,2 Hz, 2H), 7,07 (t,J=7.9 Hz, 2H), 7,17 (l,J=8,4 Hz, 4H), 7,51 (l,J=8,5 Hz, 4H), 9,95 (s, 2H); MS (ECI) m/z 862,5 (M+H)+.

Example 37

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(4S)-5-oxopent-1-EN-5,4-diyl]}]bicarbonate

Example 37A

(S)-2-(methoxycarbonylamino)Penta-4-ANOVA acid

A mixture of (S)-2-aminoet-4-ene acid (1.0 g, 8.69 mmol) and NaHCO3(of 2.26 mg, 26.9 mmol) in H2O (40 ml) was cooled to 0°C. the Mixture methylcarbamate (740 μl, of 9.55 mmol), dissolved in Et2O (4 ml), was slowly added to the water mixture and was stirred for 20 hours, bringing to the ambient temperature. The pH of the mixture delivered and up to 3.0 using HCl (concentrated solution). The mixture was extracted using EtOAc and then dried (MgSO4), filtered and concentrated to obtain 1.25 g (83%) specified in the connection header. MS (ESI) m/z 174 (M+H)+.

Example 37B

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(4S)-5-oxopent-1-EN-5,4-diyl]}]bicarbonate

The product of Example 1D (50 mg, 0,100 mmol) and the product of Example 37A (34.8 mg, 0,201 mmol) were processed using the method described in Example 1E, to obtain 51 mg (53%) indicated in the title compound in the form of a salt TFUCK.1H NMR (500 MHz, DMSO-d6) δ M. D. 1,81-of 1.93 (m, 3H), 1,94-2,04 (m, 2H), 2,08-2,17 (m, 2H), 2,20-to 2.29 (m, 2H), 2,33-to 2.42 (m, 2H), 2,53 (s, 2H), 3,50 (s, 6H), 3,55-3,63 (m, 2H), 3,64-and 3.72 (m, 2H), 4,24-or 4.31 (m, 2H), 4,42 (DD,J=8,09, 4,27 Hz, 2H), 4,58 (s, 4H), to 5.03 (d,J=10,22 Hz, 2H), 5,13 (e,J=16,48 Hz, 2H), 5,75 and 5.86 (m, 2H), 6,56 (t,J=of 6.71 Hz, 1H), 6,65 (l,J=7,63 Hz, 2H), 7,06 (t,J=7,78 Hz, 2H), 7,16 (l,J=8,54 Hz, 4H), 7,34 (l,J=to 7.93 Hz, 2H), 7,49 (l,J=8,39 Hz, 4H), to 9.93 (s, 2H), MS (ECI) m/z 808 (M+H)+.

Example 38

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-1-oxobutyl-1,2-diyl]}]bicarbonate

Example 38A

(S)-2-(methoxycarbonylamino)butane acid

Connection (S)-2-aminobutanoic acid (1.0 g, to 9.70 mmol) were processed using the method described in Example 37A, with the receipt of 1.15 g (74%) specified in the connection header. MS (ESI) m/z 162 (M+H) .

Example 38B

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-1-oxobutyl-1,2-diyl]}]bicarbonate

The product of Example 1D (50 mg, 0,100 mmol) and the product of Example 38A (32 mg, 0,201 mmol) were processed using the method described in Example 1E, to obtain 34 mg (38%) indicated in the title compound in the form of a salt TFUCK.1H NMR (500 MHz, DMSO-d6) δ memorial plaques to 0.89 (t,J=7,40 Hz, 6H), 1,44-of 1.56 (m, 2H), 1,58 is 1.70 (m, 2H), 1,80-of 1.94 (m, 4H), 1,94-2,04 (m, 2H), 2,07-of 2.16 (m, 2H), 3,50 (s, 6H), 3,55-3,63 (m, 2H), 3,67-of 3.77 (m, 2H), 4,17 (DD,J=13,81, at 7.55 Hz, 2H), to 4.41 (DD,J=8,09, 4,58 Hz, 2H), 4,58 (s, 4H), 6,56 (t,J=6,87 Hz, 1H), 6,65 (l,J=7,78 Hz, 2H), 7,06 (t,J=7,86 Hz, 2H), 7,15 (l,J=8,54 Hz, 4H), 7,30 (m,J=7,78 Hz, 2H), 7,49 (l,J=8,39 Hz, 4H), 9,94 (s, 2H), MS (ECI) m/z 784 (M+H)+.

Example 39

Dimethyl {(phenylimino)bis[metandienon-4,1-Vilcabamba (2S)pyrrolidin-2.1-diyl{(1S)-2-oxo-1-[(3R)-tetrahydrofuran-3-yl]ethane-2,1-diyl}]}bicarbonat

The product from Example 1D (0.05 g, 0.10 mmol) and (S)-2-(methoxycarbonylamino)-2-((R)-tetrahydrofuran-3-yl)acetic acid (0,045 g, 0.22 mmol) were processed as in Example 25B, obtaining 0,039 g (45%) indicated in the title compound as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ memorial plaques of 1.65 to 1.76 (m, 2H) 1,82 is 1.91 (m, 6H) 1,94-2,03 (m, 2H) 2,09-to 2.18 (m, 2H) 3,43 (DD, J=of 8.47, 6,33 Hz, 2H) 3,51-of 3.54 (m, 6H) 3,57-3,70 (m, 7H) 3,70 is 3.76 (m, 3H) 3,80-a 3.87 (m, 2H) 4,22 (t, J=cent to 8.85 Hz, 2H) was 4.42 (DD, J=8,09, to 4.73 Hz, 2H) 4,58 (s, 4H) 6,55 t, J=7,25 Hz, 1H) 6,64 (d, J=8,24 Hz, 2H) 7,05 (t, J=8,01 Hz, 2H) 7,16 (d, J=8.54 in Hz, 4H) 7,50 (d, J=8.54 in Hz, 4H) to 7.59 (d, J=to 7.93 Hz, 2H) becomes 9.97 (s, 2H); MS ECI - m/z 866 (M-H)-.

Example 40

(2S,2'S)-N,N'-[(Phenylimino)bis(metandienon-4,1-diyl)]bis(1-{(2S)-2-[(methoxyacetyl)amino]-3,3-dimethylbutanol}pyrrolidin-2-carboxamid)

Example 40A

(S)-2-(2-methoxyacetyl)-3,3-dimethylbutanoate acid

(S)-2-Amino-3,3-dimethylbutanol acid (0.50 g, 3.8 mmol) and sodium bicarbonate (0,80 g, 9.5 mmol) was dissolved in water (20 ml), then cooled in an ice bath. Methoxyacetanilide (0,38 ml, 4.2 mmol) was dissolved in diethyl ether (5 ml) and added dropwise with thorough stirring. The solution was stirred at ambient temperature for 5 hours, then brought the pH to 3 with concentrated hydrochloric acid and was extracted into ethyl acetate. The organic solution was dried over sodium sulfate, filtered and concentrated to obtain 0.16 g (21%) indicated in the title compound in the form of a waxy solid.

Example 40B

(2S,2'S)-N,N'-[(phenylimino)bis(metandienon-4,1-diyl)]bis(1-{(2S)-2-[(methoxyacetyl)amino]-3,3-dimethylbutanol}pyrrolidin-2-carboxamid)

The product from Example 1D (0.05 g, 0.10 mmol) and the product from Example 40A (0,045 g, 0.22 mmol) were processed as in Example 25B, obtaining 0,006 grams (7%)indicated in the title compound as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ memorial plaques of 0.93 (s, 18H) 1,85-of 1.93 (m, 4H) 1,94-2,04 (m, 2H) 2,08-2,17 (m, 2H) 3,28 (s, 6H) 3,63 is 3.76 (m, 4H) 3,81-3,95 (m, 4H) to 4.38 (DD, J=8,54, of 3.05 Hz, 2H) 4,56-to 4.62 (m, 6H) 6,55 (t, J=7,17 Hz, 1H) 6,64 (d, J=8,09 Hz, 2H) 7,03-was 7.08 (m, 2H) 7.15m (d, J=8.54 in Hz, 4H) 7,38 (d, J=9,00 Hz, 2H) 7,51 (d, J=8.54 in Hz, 4H) 9,82 (s, 2H); MS ECI - m/z 866 (M-H)-.

Example 41

Di-tert-butyl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S,3S)-3-methyl-1-oxopent-1,2-diyl]}]bicarbonate

To a solution of the product from Example 1D (0,062 g, 0.125 mmol) in CH2Cl2(5 ml) at room temperature was added (2S,3S)-2-(tert-butoxycarbonylamino)-3-methylpentanol acid (Aldrich, 0,063 g, 0,274 mmol), N,N-diisopropylethylamine (0.100 ml) and HATU (0.104 g g 0,274 mmol). After 30 minutes the reaction mixture was washed with saturated brine and the organic phase was concentrated. The residue was purified using chromatography (1% gradient from 0 to 2% MeOH-CH2Cl2) to obtain 67 mg (58%) specified in the connection header.1H NMR (500 MHz, DMSO-d6) δ 0,81 (t, J=7,02 Hz, 6H) of 0.85 (d, J=of 6.71 Hz, 6H) 1,20-of 1.29 (m, 2H) to 1.37 (s, 18H) 1,44-of 1.53 (m, 2H) of 1.65 and 1.75 (m, 2H) 1,82-of 1.92 (m, 4H) 1,95-2,04 (m, 2H) 2,08-2,17 (m, 2H) 3,56-to 3.64 (m, 2H) 3.75 to a 3.83 (m, 2H) Android 4.04 (t, J=an 8.70 Hz, 2H) 4,43 (DD, J=7,93, 4,88 Hz, 2H) 4,59 (s, 4H) 6,56 (m, 1H) 6,65 (d, J=8,24 Hz, 2H) to 6.88 (d, J=8,39 Hz, 2H) 7,07 (m, 2H) 7,17 (d, J=8.54 in Hz, 4H) 7,51 (d, J=8,39 Hz, 4H) becomes 9.97 (s, 2H).

Example 42

(2S,2'S)-N,N'-[(Phenylimino)bis(metandienon-4,1-diyl)bis{1-[(2S)-3-methyl-2-(2-oxopyrrolidin-1-yl)butanoyl]pyrrolidin-2-carboxamide}

The product of Example 1D (30 mg, 0.06 mmol) and (S)-3-methyl-2-(2-oxopyrrolidin-1-yl)butane acid (24.6 mg, 0.133 mmol) were processed using the method described in Example 43, to obtain 21 mg (42%) specified in the connection header.1H NMR (500 MHz, DMSO-d6) δ M. D. 9,92 (s, 2H), 7,46 (l,J=8.6 Hz, 4H), 7,12 (d, J=8.5 Hz, 4H), 7,01 (m, 2H), 6,61 (l,J=8,1 Hz, 2H), 6,51 (t, J=7.2 Hz, 1H), 4,54 (s, 4H), and 4.40 (d, J=11.0 cm Hz, 2H), 4,33 (m, 2H), 3,62 (m, 4H), to 3.35 (m, 2H), 3,23 (m, 2H), of 2.21 (m, 4H), of 2.08 (m, 4H), 1.91 a (m, 2H), 1,82 (s, 8H), of 0.87 (d,J=6,6 Hz, 6H), 0,72 (l,J=6,6 Hz, 6H).

Example 43

(2S,2'S)-N,N'-[(Phenylimino)bis(metandienon-4,1-diyl)]bis{1-[(2R)-2-(acetylamino)-2-phenylacetyl]pyrrolidin-2-carboxamide}

The product of Example 1D (40 mg, 0.08 mmol), (R)-2-acetamido-2-phenylacetic acid (34,2 mg, 0,177 mmol) and HATU (67,2, 0,177 mmol) was dissolved in DMSO (3 ml) was then added to the base Hunya (0,07 ml, 0,402 mmol) and the mixture was stirred at room temperature for 1 hour. To the solution was added dichloromethane and the mixture was extracted with water. The organic extract was then dried, filtered, concentrated and purified via chromatography (silica gel, 0-20% methanol in dichloromethane) to give 8 mg (12%) specified in the connection header.1H NMR (500 MHz, DMSO - d6) δ M. D. 9,73 (s, 2H), at 8.60 (d,J=7.9 Hz, 2H), 7,52 (m, 4H), 7,35 (m, 7H), 7,13 (m, 4H), 7,02 (m, 2H), 6,61 (l,J=8,2 Hz, 2H), 4,56 (m, 4H), to 4.33 (m, 2H), 3,78 (m, 2H), 3,21 (m, 2H), 2.49 USD (s, 6H), 1,90 (who, 8H).

Example 44

Dimethyl ([(3R)-tetrahydrofuran-3-elimina]bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]})bicarbonate

Example 44A

(R)-N,N-bis(4-nitrobenzyl)tetrahydrofuran-3-amine

Specified in the title compound was obtained using the methods from Example 1A, substituting aniline (R)-tetrahydrofuran-3-amine, with the receipt specified in the title compound (1.12 g, 59% yield).

Example 44B

(R)-N,N-bis(4-aminobenzyl)tetrahydrofuran-3-amine

Specified in the title compound was obtained using the methods of Example 1B substituting the product from Example 1A for the product from Example 44A, obtaining specified in the connection header (1,02 g, 109% yield).

Example 44C

(2S,2'S)-tert-butyl 2,2'-(4,4'-((R)-tetrahydrofuran-3-alazander)bis(methylene)bis(4,1-phenylene))bis(ethanediyl)bis(octamethylene)dipyrrole-1-carboxylate

Specified in the title compound was obtained using the methods from Example 1C, substituting the product from Example 1B, the product from Example 44B, obtaining specified in the connection header (0,78 g, 33% yield).

Example 44D

(2S,2'S)-N,N'-(4,4'-((R)-tetrahydrofuran-3-alazander)bis(methylene)bis(4,1-phenylene))dipyrrole the DIN-2-carboxamide

Specified in the title compound was obtained using the methods from Example 1D, substituting the product from Example 1C for the product from Example 44C, obtaining specified in the title compound (0.39 g, 70% yield).

Example 44E

Dimethyl ([(3R)-tetrahydrofuran-3-elimina]bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]})bicarbonate

The product of Example 44D and (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid were subjected to interaction, using the method of Example 1E, and the product was purified using column chromatography, elwira with ethyl acetate, to obtain specified in the title compound (100 mg, 31% yield).1H NMR (500 MHz, BENZENE-d6) δ 9,77 (Shir. s, 2H), 7,74 (l,J=8,1, 4H), 6,99 (l,J=of 8.3, 4H), 5,50 (l,J=of 9.6, 2H), 4,73-of 4.66 (m, 2H), 4,50 (l,J=9,7, 2H), of 3.77 (dt,J=4,3, and 8.4, 1H), 3,70 (DD,J=5,4, 9,0, 1H), 3,59-of 3.53 (m, 1H), 3,48-to 3.41 (m, 7H), to 3.33 (d,J=12,9, 4H), 3,23-3,13 (m, 5H), 2,11 (TD,J=6,1, 11,8, 2H), 1,71-of 1.53 (m, 4H), 1,52-of 1.42 (m, 2H), 1,26-of 1.16 (m, 2H), 0,99 (s, 18H); MS (ECI; M+H) m/z=835.

Example 45

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-4-methyl-1-oxopent-1,2-diyl]}]bicarbonate

The product of Example 1D (35 mg, 0,070 mmol) was subjected to the procedure described in Example 24E, substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoyl acid to (S)-2-(methoxycarbonylamino)-4-methylpentanol acid, is obtaining specified in the connection header in the form of a salt TFOC (18 mg). 1H NMR (500 MHz, DMSO-d6) δ memorial plaques of 0.85 to 0.92 (m, 15H), 1,40 (DD,J=9,3, 4,1 Hz, 2H), 1,42 of 1.46 (m, 2H), 1,62-1,71 (m, 2H), 1,86 (dt,J=11,6, 5.7 Hz, 2H), 1,90-of 1.94 (m, 2H), 1,96-2,05 (m, 2H), and 2.14 (TD,J=7,6, 4.6 Hz, 2H), 3,67 of 3.75 (m, 3H), 4,23-or 4.31 (m, 2H), 4,42 (DD,J=8,2, a 4.7 Hz, 3H), 4,59 (s, 5H), to 6.57 (s, 1H), 6,66 (l,J=8,1 Hz, 2H), 7,07 (t,J=7,9 Hz, 3H), 7,17 (l,J=8,5 Hz, 5H), 7,34 (l,J=8,1 Hz, 2H), 7,50 (d,J=8,5 Hz, 5H), 9,96 (s, 2H); MS (ECI) m/z 840,5 (M+H)+.

Example 46

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-1-oxopent-1,2-diyl]}]bicarbonate

The product of Example 1D (35 mg, 0,070 mmol) was subjected to the procedure described in Example 24E, substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoyl acid to (S)-2-(methoxycarbonylamino)pentane acid, obtaining specified in the connection header in the form of a salt TFOC (29 mg).1H NMR (500 MHz, DMSO-d6) δ M. D. 0,83-of 0.90 (m, 9H), 1,22-of 1.30 (m, 3H), 1,30-1,40 (m, 4H), 1,43-of 1.52 (m, 3H), 1,53-of 1.62 (m, 2H), 1,83-of 1.93 (m, 4H), 1,95-2,04 (m, 2H), 2,08-2,17 (m, 2H), and 3.72 (dt,J=9,5, 6,8 Hz, 2H), 4,24 (TD,J=to 8.1, 5.4 Hz, 2H), 4,42 (DD,J=8,2, a 4.7 Hz, 2H), 4,59 (s, 4H), to 6.57 (t,J=7,1 Hz, 1H), 6,66 (l,J=8,1 Hz, 2H), 7,07 (t,J=7.9 Hz, 2H), 7,17 (l,J=8,5 Hz, 4H), 7,32 (l,J=7.8 Hz, 2H), 7,50 (d,J=8,5 Hz, 4H), 9,95 (s, 2H); MS (ECI) m/z 812,4 (M+H)+.

Example 47

Dimethyl [(phenylimino)bis{metandienon-4,1-valimine[(2S)-1-oxoprop-1,2-diyl](methylimino)[(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]}]bi the carbamate

Example 47A

Tert-butyl (2S,2'S)-1,1'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(1-oxopropyl-2.1-diyl)bis(methylcarbamate)

The product from Example 1B and (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (Aldrich) were processed using the method described in Example 41. The crude residue was purified using chromatography on silica gel (40% ethyl acetate-hexane) to obtain specified in the title compound MS (ESI, M+H) m/z=674.

Example 47B

(2S,2'S)-N,N'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene))bis(2-(methylamino)propanamide)

A solution of the product from Example 47A (0,469 g, 0,696 mmol) in CH2Cl2(10 ml) at room temperature was treated with TFOC (5,00 ml), and stirring was continued over night. The reaction mixture was concentrated, and the residue was distributed between saturated solution of NaHCO3and 25% IPA-CHCl3. The organic phase was dried (Na2SO4) and concentrated to obtain 210 mg (64%) indicated in the title compound MS (ESI, M+H) m/z=474.

Example 47C

Dimethyl [(phenylimino)bis{metandienon-4,1-valimine[(2S)-1-oxoprop-1,2-diyl](methylimino)[(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]}]bicarbonate

The product of Example 47B and (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid (DeGussa) was treated with ispolzovaniem, described in Example 41. The crude residue was purified using chromatography on silica gel (2% MeOH-CH2Cl2) to give 122 mg (34%) specified in the connection header.1H NMR (500 MHz, DMSO-d6) δ 0,96 (m, 18H) of 1.33 (d, J=7.18 in Hz, 6H) of 2.68 (m, 2H) 3,09 (Shir. s, 4H) 3,53 (Shir. s, 4H) to 3.58 (Shir. s, 2H) 4,45 (m, 2H) 4,59 (m, 4H) of 5.03 (m, 2H) 6,56 (t, J=7,25 Hz, 1H) 6,65 (d, J=to 8.70 Hz, 2H)? 7.04 baby mortality-7,10 (m, 3H) 7,15-7,21 (m, 4H) 7,47-7,52 (m, 4H) 7,62 (d, J=8,39 Hz, 1H) 9,79 (s, 2H).

Example 48

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba[(2S,4R)-4-hydroxypyrrolidine-2.1-diyl][(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]}]bicarbonate

Example 48A

(3R,3'R,5S,5'S)-tert-butyl 5,5'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(3-hydroxypyrrolidine-1-carboxylate)

The product from Example 1B and (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (Chem-Impex) were processed using the method described in Example 41. The reaction mixture was filtered, the solid is washed with the help of CH2Cl2and dried in a vacuum oven to obtain 414 mg (69%) specified in the connection header. MS (DCI; (M+H) m/z=730.

Example 48B

(2S,2'S,4R,4'R)-N,N'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene))bis(4-hydroxypyrrolidine-2-carboxamido)

The product from Example 48A was processed using the-W method, described in Example 47B, obtaining specified in the connection header. MS (DCI; (M+H) m/z=530.

Example 48C

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba[(2S,4R)-4-hydroxypyrrolidine-2.1-diyl][(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]}]bicarbonate

The product of Example 48B and (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid (DeGussa) were processed using the method described in Example 41. The crude residue was purified using chromatography on silica gel (0% to 7% MeOH-CH2Cl2) to obtain 60 mg (25%) specified in the connection header.1H NMR (500 MHz, DMSO-d6) δ 0,94 (s, 18H) at 1.91 (DDD, J=12,86, 8,81, 4,43 Hz, 2H) 2,04-2,12 (m, 2H) 3,54 (s, 6H) 3,62-3,71 (m, 4H) 4,20 (d, J=9,31 Hz, 2H) 4,36 (Shir. s, 2H) of 4.49 (t, J=8,09 Hz, 2H) 4,58 (s, 4H) 5,18 (d, J=3,36 Hz, 2H) 6,56 (t, J=7,25 Hz, 1H) 6,65 (d, J=8,09 Hz, 2H) 7,00-to 7.09 (m, 4H) 7,17 (d, J=8,55 Hz, 4H) 7,51 (d, J=8.54 in Hz, 4H) there is a 10.03 (s, 2H).

Example 49

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S,3S)-3-hydroxy-1-oxobutyl-1,2-diyl]}]bicarbonate

Example 49A

(2S,3S)-3-hydroxy-2-(methoxycarbonylamino)butane acid

(2S,3S)-2-Amino-3-hydroxybutanoic acid (0.54 g, a 4.53 mmol) were processed as in Example 25A, obtaining 0,139 g (17%) indicated in the title compound in the form of a waxy solid.

Example 49B

Dimethyl [(phenylimino)bis{metand albenza-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S,3S)-3-hydroxy-1-oxobutyl-1,2-diyl]}]bicarbonate

The product from Example 1D (0.05 g, 0.10 mmol) and the product from Example 49A (0,039 g, 0.22 mmol) were processed as in Example 25B, obtaining 0,041 g (51%) indicated in the title compound in the form of not-quite-white solid.1H NMR (500 MHz, DMSO-d6) δ memorial plaques of 1.16 (d, J=6,10 Hz, 6H) 1,82-1,89 (m, 2H) 1,90-2,00 (m, 4H) 2,08-2,17 (m, 2H) 3,52 (s, 6H) 3,66-to 3.73 (m, 2H) of 3.77-a 3.87 (m, 4H) 4,19 (t, J=8,39 Hz, 2H) to 4.46 (DD, J=8,39, 3,66 Hz, 2H) 4,58 (s, 4H) of 5.29 (d, J=4,58 Hz, 2H) 6,55 (t, J=7,17 Hz, 1H) 6,63 (d, J=8,09 Hz, 2H) 7,05 (DD, J=8,77, of 7.25 Hz, 2H) 7,16 (d, J=8,70 Hz, 4H) 7,42 (d, J=8,24 Hz, 2H) 7,47 (d, J=8.54 in Hz, 4H) 9,49 (s, 2H); MS ECI+m/z 816 (M+H)+; m/z 833 (M+NH4)+.

Example 50

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S,3R)-3-methyl-1-oxopent-1,2-diyl]}]bicarbonate

Example 50A

(2S,3R)-2-(methoxycarbonylamino)-3-methylpentanoic acid

(2S,3R)-2-Amino-3-methylpentanol acid (0,965 g, 7.36 mmol) was treated as in Example 25A, with the receipt of 1.16 g (83%) indicated in the title compound in the form of a waxy solid.

Example 50B

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S,3R)-3-methyl-1-oxopent-1,2-diyl]}]bicarbonate

The product from Example 1D (0.05 g, 0.10 mmol) and the product from Example 50A (0,042 g, 0.22 mmol) were processed as in Example 25B, obtaining 0,044 g (52%) indicated in the title compound in the form of not-quite-white solid which substances. 1H NMR (500 MHz, DMSO-d6) δ memorial plaques to 0.80 (d, J=of 6.71 Hz, 6H) of 0.85 (t, J=to 7.32 Hz, 6H) 1,06-of 1.15 (m, 2H) 1,42 of 1.50 (m, 2H) 1,73-to 1.79 (m, 2H) 1,81-of 1.92 (m, 4H) 1,95-2,03 (m, 2H) 2,10-of 2.16 (m, 2H) 3,23-3,30 (m, 2H) 3,51 (s, 6H) 3,54-3,63 (m, 1H) 3,69-with 3.79 (m, 1H) 4,19-4,24 (m, 2H) to 4.41 (DD, J=8,01, 5,26 Hz, 2H) of 4.57 (s, 4H) 6,55 (t, J=7,25 Hz, 1H) 6,64 (d, J=8,09 Hz, 2H) 7,05 (DD, J=8,77, of 7.25 Hz, 2H) 7,12-7,19 (m, 6H) 7,49 (d, J=8.54 in Hz, 4H) 9,95 (s, 2H); MS ECI-m/z 838 (M-H)-.

Example 51

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S,3R)-3-methoxy-1-oxobutyl-1,2-diyl]}]bicarbonate

Example 51A

(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butane acid

(2S,3R)-2-Amino-3-methoxybutanol acid (1.0 g, 7,51 mmol) were processed as in Example 25A, to obtain 0.28 g (20%) specified in the connection header in the form of a waxy solid.

Example 51B

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S,3R)-3-methoxy-1-oxobutyl-1,2-diyl]}]bicarbonate

The product from Example 1D (0.05 g, 0.10 mmol) and the product of Example 51A (0,042 g, 0.22 mmol) were processed as in Example 25B, getting to 0.060 g (71%) indicated in the title compound in the form of not-quite-white solid.1H NMR (500 MHz, DMSO-d6) δ memorial plaques of 1.12 (d, J=6,26 Hz, 6H) 1,82-1,90 (m, 4H) 1,94-2,04 (m, 2H) 2,10-to 2.18 (m, 2H) 3,23 (s, 6H) 3,42-of 3.48 (m, 2H) 3,52 (s, 6H) 3,62-3,70 (m, 2H) 3,79-3,86 (m, 2H) 4.25 in (t, J=7,78 Hz, 2H) and 4.40 (DD, J=8,24, 5,04 Hz, 2H) of 4.57 (s, 4H) 6,55 (t, J=7,25 is C, 1H) 6,64 (d, J=8,09 Hz, 2H) 7,05 (DD, J=8,77, of 7.25 Hz, 2H) 7,16 (d, J=8,70 Hz, 4H) to 7.32 (d, J=to 7.93 Hz, 2H) 7,49 (d, J=8.54 in Hz, 4H) to 9.93 (s, 2H); MS ECI - m/z 842 (M-H)-.

Example 52

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3-methoxy-3-methyl-1-oxobutyl-1,2-diyl]}]bicarbonate

Example 52A

(S)-3-methoxy-2-(methoxycarbonylamino)-3-methylbutanoate acid

(S)-2-Amino-3-methoxy-3-methylbutanoyl acid (0.55 g, 3.72 mmol) were processed as in Example 25A, to obtain 0.18 g (24%) indicated in the title compound in the form of a waxy solid.

Example 52B

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3-methoxy-3-methyl-1-oxobutyl-1,2-diyl]}]bicarbonate

The product from Example 1D (0.05 g, 0.10 mmol) and the product from Example 52A (0,045 g, 0.22 mmol) were processed as in Example 25B, with the receipt of 0.015 g (17%) indicated in the title compound in the form of not-quite-white solid.1H NMR (500 MHz, DMSO-d6) δ memorial plaques to 1.14 (s, 6H) 1,83-of 1.92 (m, 4H) 1,92-2,02 (m, 2H) 2,10 (DD, J=to 20.52, 12,13 Hz, 2H) 2,53 (s, 6H) 3,11 (d, J=4,27 Hz, 6H) of 3.53 (s, 6H) 3,63-3,81 (m, 4H) 4,33-4,43 (m, 2H) 4,50 (DD, J=13,12, cent to 8.85 Hz, 2H) of 4.57 (s, 4H) 6,55 (t, J=7,25 Hz, 1H) 6,64 (d, J=8,39 Hz, 2H) 7,05 (t, J=8,01 Hz, 2H) 7,09-7,25 (m, 6H) of 7.48 (DD, J=17,85, 8,54 Hz, 4H) 9,73 (d, J=7,02 Hz, 2H); MS ECI - m/z 870,5 (M-H)-.

Example 53

N-(Methoxycarbonyl)-3-meth is l-L-poured-N-(4-{[{4-[(1-{(2S)-2-[(methoxycarbonyl)amino]-2-[(3R)-tetrahydrofuran-3-yl]acetyl}-L-prolyl)amino]benzyl}(phenyl)amino]methyl}phenyl)-L-prolinamide

The product of Example 10A (0.035 g, 0.052 mmol) and (S)-2-(methoxycarbonylamino)-2-((R)-tetrahydrofuran-3-yl)acetic acid were processed as in Example 25B, obtaining 0,030 g (67%) indicated in the title compound as a thick oil.1H NMR (500 MHz, DMSO-d6) δ memorial plaques of 0.91 (s, 9H) of 1.66 (DDD, J=20,03, 7,21, 7,10 Hz, 1H) 1.77 in-a 1.88 (m, 6H) 1,90 of 1.99 (m, 2H) 2.06 to and 2.14 (m, 2H) 3,48 (s, 6H) 3,54-the 3.65 (m, 4H) 3,66 of 3.75 (m, 3H) 3,78-of 3.85 (m, 1H) 4,14-4,22 (m, 2H) to 4.38 (DD, J=8,09, 5,04 Hz, 2H) a 4.53 (s, 4H) 6,51 (t, J=7,25 Hz, 1H) 6,60 (d, J=8,09 Hz, 2H) 6,99-7,06 (m, 3H) for 7.12 (d, J=of 7.48 Hz, 4H) was 7.45 (d, J=7,93 Hz, 4H) at 7.55 (d, J=to 7.93 Hz, 1H) to 9.93 (d, J=6,26 Hz, 2H); MS ECI - m/z 852,5 (M-H)-.

Example 54

(2S,2'S)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis{1-[(2R)-2-(diethylamino)-2-phenylacetyl]pyrrolidin-2-carboxamide}

The product from Example 13D (by 0.055 g, 0,107 mmol) and (R)-2-(diethylamino)-2-phenylacetic acid (0,048 g, 0.24 mmol) were processed as in Example 25B, obtaining 0,046 g (48%) indicated in the title compound in the form of not-quite-white solid. MS (TFUC, ELSD+) m/z 895 (M+H)+.

Example 55

(2S,2'S)-N,N'-[(Phenylimino)bis(metandienon-4,1-diyl)]bis{1-[(2R)-2-phenyl-2-pyrrolidin-1-ylacetic]pyrrolidin-2-carboxamide}

Example 55A

(R)-2-phenyl-2-(pyrrolidin-1-yl)acetic acid

To (R)-2-amino-2-phenylacetic acid (1.0 g, 6.62 mmol), 1,4-dibromobutane (1,57 g, 0,727 mmol) and sodium carbonate (2,103 g, 19,85 mmol) was added ethanol (40 ml) and the floor is obtained mixture was heated at 100°C for 65 hours. After cooling, the resulting solid substance was removed by filtration and washed with ethanol. The filtrate was concentrated and then dissolved in ethanol, then added 4 N. aqueous solution of hydrochloric acid. The obtained solid substance was removed and discarded. The filtrate was concentrated and purified using reverse-phase chromatography (C18), elwira mixture of 10-100% acetonitrile in water (0.1% TFOC), obtaining specified in the connection header. MS (ESI) m/z 206 (M+H)+.

Example 55B

(2S,2'S)-N,N'-[(phenylimino)bis(metandienon-4,1-diyl)]bis{1-[(2R)-2-phenyl-2-pyrrolidin-1-ylacetic]pyrrolidin-2-carboxamide}

The product of Example 1D (30 mg, to 0.060 mmol) and the product of Example 55A (40,8 mg, 0,199 mmol) were processed using the method described in Example 43, to obtain 34 mg (65%) specified in the connection header.1H NMR (500 MHz, DMSO-d6) δ M. D. 10,08 (Shir. s, 2H), 7,55 (m, 4H), 7,49 (m, 10H), 7,16 (l,J=8,4 Hz, 4H), 7,03 (m, 2H), 6,61 (l,J=8,2 Hz, 2H), 6,53 (t,J=7.2 Hz, 1H), 5,50 (m, 2H), 4,57 (s, 4H), to 4.38 (m, 2H), 3,84 (m, 2H), 3,50 (m, 2H), 3,10 (m, 6H), 3,86 (m, 2H, in), 3.75 (m, 2H), 2,02 (m, 4H), 1,90 (m, 8H), to 1.76 (s, 4H).

Example 56

N-(Methoxycarbonyl)-3-methyl-L-poured-N-[4-({phenyl[4-({1-[(2R)-2-phenyl-2-pyrrolidin-1-ylacetic]-L-prolyl}amino)benzyl]amino}methyl)phenyl]-L-prolinamide

The product from Example 10A (40 mg, to 0.060 mmol) and the product of Example 55A (18,4 mg, 0,090 mmol) was treated with BL is reattaching the way described in Example 43, to obtain 31 mg (60%) specified in the connection header.1H NMR (500 MHz, DMSO-d6) δ M. D. 9,94 (Shir. s, 1H), 9,90 (Shir. s, 1H), 7,46 (m, 3H), 7,41 (m, 2H), 7,27 (m, 3H), to 7.15 (m, 4H), 7,02 (m, 3H), of 6.61 (d,J=8,2 Hz, 2H), 6,52 (t,J=7,3 Hz, 1H), 4,55 (Shir. s, 4H), to 4.38 (m, 1H), 4,27 (m, 1H), 4,17 (m, 2H), 3,79 (m, 1H), and 3.72 (m, 1H), to 3.58 (m, 1H), 3,49 (s, 3H), 3,40 (m, 1H), 2,43 (m, 3H), to 2.29 (m, 2H), 2,09 (m, 1H), 1,95 (m, 3H), 1,89 (m, 4H), of 1.57 (m, 3H), of 0.91 (s, 9H).

Example 57

(2S,2'S)-N,N'-[(Phenylimino)bis(metandienon-4,1-diyl)]bis{1-[(2R)-2-morpholine-4-yl-2-phenylacetyl]pyrrolidin-2-carboxamide}

Example 57A

(R)-2-morpholino-2-phenylacetic acid

To (R)-2-amino-2-phenylacetic acid (1.0 g, 6.62 mmol), 1-bromo-2-(2-bromoethoxy)ethane (1,686 g, 0,727 mmol) and sodium carbonate (2,103 g, 19,85 mmol) was added ethanol (40 ml) and the resulting mixture was heated at 100°C for 45 hours. After cooling, the resulting solid substance was removed by filtration and washed with ethanol. The filtrate was concentrated and then dissolved in ethanol, then added 4 N. aqueous solution of hydrochloric acid until the pH of the solution is equal to 3. The obtained solid substance was removed and discarded. The filtrate was concentrated and purified using reverse-phase chromatography (C18), elwira mixture of 10-100% acetonitrile in water (0.1% TFOC), obtaining specified in the connection header. MS (ESI) m/z 222 (M+H)+.

the example 57B

(2S,2'S)-N,N'-[(phenylimino)bis(metandienon-4,1-diyl)]bis{1-[(2R)-2-morpholine-4-yl-2-phenylacetyl]pyrrolidin-2-carboxamide}

The product of Example 1D (30 mg, to 0.060 mmol) and the product of Example 57A (44 mg, 0,199 mmol) were processed using the method described in Example 43, to obtain 41 mg (75%) specified in the connection header.1H NMR (500 MHz, DMSO-d6) δ memorial plaques to 9.93 (Shir. s, 2H), 7,47 (l,J=8,4 Hz, 4H), 7,41 (l,J=7,0 Hz, 4H), 7,28 (m, 6H), 7,14 (m, 4H), 7,03 (m, 2H), 6,62 (l,J=8,1 Hz, 2H), 6,52 (t,J=7.2 Hz, 1H), 4,56 (Shir. s, 4H), 4,24 (m, 4H), 3,81 (m, 2H), 3.45 points (m, 8H), 3,40 (m, 2H), 2.63 in (m, 8H), 2,39 (m, 4H), to 2.29 (m, 4H), of 1.95 (m, 4H), 1.77 in (m, 4H).

Example 58

N-(Methoxycarbonyl)-3-methyl-L-poured-N-[4-({[4-({1-[(2R)-2-morpholine-4-yl-2-phenylacetyl]-L-prolyl}amino)benzyl](phenyl)amino}methyl)phenyl]-L-prolinamide

The product from Example 10A (40 mg, to 0.060 mmol) and the product of Example 57A (19.9 mg, 0,090 mmol) were processed using the method described in Example 43, to obtain 35 mg (67%) specified in the connection header.1H NMR (500 MHz, DMSO-d6) δ M. D. 9,80 (s, 1H), 9,78 (s, 1H), 7,35 (m, 3H), 7,28 (m, 2H), 7,14 (m, 3H), 6,97 (m, 4H), to 6.88 (m, 3H), 6,46 (l,J=8,1 Hz, 2H), 6,37 (t,J=7.2 Hz, 1H), 4,40 (Shir. s, 4H), 4,22 (m, 1H), 4,11 (m, 1H), of 4.05 (m, 2H), to 3.67 (m, 1H), only 3.57 (m, 1H), 3.43 points (m, 1H), 3,34 (s, 3H), 3,30 (m, 3H), 3,24 (m, 2H), 2.49 USD (C, 8H), 2,22 (m, 2H), 2,12 (m, 2H), 1,92 (m, 1H), 1,79 (m, 3H), of 1.62 (m, 4H), of 0.77 (s, 9H).

Example 59

Methyl (3S)-tetrahydrofuran-3-yl [(phenylimino)bis {met neilbenson-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]}]bicarbonate

Example 59A

(S)-tert-butyl 3,3-dimethyl-2-(((S)-tetrahydrofuran-3-yloxy)carbylamine)butanoate

A mixture of (S)-tert-butyl 2-amino-3,3-dimethylbutanoate (0.05 g, 0,223 mmol), tetrahydrofuran-3-ylcarbamate (S)-2,5-dioxopiperidin-1-yl (0,056 g, 0,246 mmol) and substrate Hunya (0,078 ml, 0,447 mmol) in THF (2.25 ml) was stirred at room temperature for 12 hours. The solvent is evaporated, and the product was purified using chromatography on silica gel, elwira mixture 0-15% ethyl acetate in dichloromethane, to obtain specified in the title compound (0.037 g, 55% yield).

Example V

(S)-3,3-dimethyl-2-(((S)-tetrahydrofuran-3-yloxy)carbylamine)butane acid

To a solution of the product from Example 59A (0.037 g, 0,123 mmol) in dichloromethane (1.2 ml) was added triperoxonane acid (1.2 ml) and the mixture was stirred at room temperature for 2 hours. The solvent is evaporated to obtain specified in the title compound, which was used without further purification.

Example 59C

Methyl (3S)-tetrahydrofuran-3-yl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]}]bicarbonate

To a solution of the product from Example 10A (0.025 g, 0,037 mmol) in DMSO (0,374 ml) at room temperature was added the product from Example 59B (0,011 g 0,045 m is ol), HATU (0,017 g, 0.045 mmol) and base Hunya (0,033 ml, 0,187 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated solution of NaHCO3, water and saturated NaCl solution. The organic was dried over MgSO4, was filtered and was evaporated. The product was purified using reverse-phase chromatography (C18), elwira mixture of 10-100% acetonitrile in water (0.1% TFOC), obtaining specified in the connection header in the form of a salt TFOC (0,032 g).1H NMR (500 MHz, DMSO-d6) δ memorial plaques to 0.96 (s, 18H) 1,80-of 1.92 (m, 5H) 1,93-2,03 (m, 2H) 2,05-of 2.21 (m, 3H) 3,54 (s, 3H) to 3.58-of 3.85 (m, 7H) 4,20 (DD, J=10,76, the remaining 9.08 Hz, 2H) 4,43 (DD, J=8,09, of 5.34 Hz, 2H) 4,59 (s, 4H) 5,10 (DD, J=by 5.87 and 4.65 Hz, 1H) of 6.49-of 6.61 (m, 1H) of 6.66 (d, J=7,17 Hz, 2H) 7,02-7,14 (m, 3H) 7,17 (d, J=8,55 Hz, 4H) of 7.48-7,56 (m, 4H) 9,99 (s, 2H), MS (ECI) m/z 896,5 (M+H)+.

Example 60

(2S,2'S)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis{1-[(2R)-2-(dimethylamino)-2-phenylacetyl]pyrrolidin-2-carboxamide}

Specified in the title compound was obtained using the methods of Example 2, replacing the product of Example 1D to the product from Example 13D, obtaining specified in the title compound (105 mg, 22% yield).1H NMR (500 MHz, DMSO) δ 9,96 (s, 2H), 7,54-7,49 (m, 4H), 7,46-7,40 (m, 4H), 7,35-7,26 (m, 6H), 7,20-7,14 (m, 4H), to 6.95-6.87 in (m, 2H), 6,67-6,60 (m, 2H), 4,56 (s, 4H), 4,34-4,27 (m, 2H), 4,14 (s, 2H), a 3.87-with 3.79 (m, 2H), 3.46 in-3,39 (m, 2H), 2,11 (s, 12H), 2.05 is-of 1.93 (m, 4H), 1,88-1,72 (m, 4H), MS (ECI; M+H) m/z=839b> .

Example 61

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-1-oxo-3-phenylpropane-1,2-diyl]}]bicarbonate

The product from Example 1D (0,030 g to 0.060 mmol) was subjected to the procedure described in Example 24E, substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoyl acid to (S)-2-(methoxycarbonylamino)-3-phenylpropane acid, obtaining specified in the connection header in the form of a salt TFOC (16 mg).1H NMR (500 MHz, DMSO-d6) δ M. D. 1,85-to 2.06 (m, 8H), 2,10-2,19 (m, 2H), 2,74 (DD,J=14,0, 10.1 Hz, 2H), 2,96 (DD,J=14,0, and 3.7 Hz, 2H), 3,44 (s, 6H), 4,37-4,43 (m, 2H), 4,46 (DD,J=to 8.2 and 4.2 Hz, 2H), 4,60 (s, 4H), to 6.57 (t,J=6,9 Hz, 1H), 6,67 (l,J=8,1 Hz, 2H), 7,07 (t,J=7.9 Hz, 2H), 7,17-7,22 (m, 6H), 7,26 (t,J=7,4 Hz, 4H), 7,30-7,33 (m, 4H), of 7.48-of 7.55 (m, 6H), 9,95 (s, 2H); MS m/z 908,9 (M+H)+.

Example 62

N-(Methoxycarbonyl)-3-methyl-L-poured-N-(4-{[{4-[(1-{(2S)-2-[(methoxycarbonyl)amino]butanoyl}-L-prolyl)amino]benzyl}(phenyl)amino]methyl}phenyl)-L-prolinamide

The product from Example 10A (0,028 g, 0,054 mmol) was subjected to the procedure described in Example 10B, substituting (R)-2-(dimethylamino)-2-phenylacetic acid for (S)-2-(methoxycarbonylamino)butane acid, and the product was purified using the conditions for HPLC Example 1E, obtaining specified in the connection header in the form of a salt TFOC (6.4 mg).1H NMR (500 MHz, DMSO-d6) δ memorial plaques from 0.88 to 0.92 (m, 3H), of 0.96 (s, 9H), 1,52 DD, J=14,5, 6,9 Hz, 1H), 1,65 (DD,J=14,0, 6,7 Hz, 1H), 1,81-2,04 (m, 8H), 2,09-to 2.18 (m, 2H), 3,52 (s, 3H), of 3.54 (s, 3H), 4,14-to 4.23 (m, 2H), 4,40-to 4.46 (m, 2H), 4,59 (s, 4H), to 6.57 (t,J=7,1 Hz, 1H), 6,66 (l,J=8,1 Hz, 2H),? 7.04 baby mortality-7,11 (m, 2H), 7,17 (l,J=8,5 Hz, 4H), to 7.50 (d, 4H), for 9.95 (s, 1H), 9,99 (s, 1H); MS m/z 812,1 (M+H)+.

Example 63

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba[(3S,6R,9aS)-5-oxoacetate-1H-pyrrolo[1,2-and]azepin-3,6-diyl]}]bicarbonate

Example 63A

(3S,6R,9aS)-tert-butyl 6-(tert-butoxycarbonylamino)-5-oxoacetate-1H-pyrrolo[1,2-a]azepin-3-carboxylate

Specified in the title compound was obtained in accordance with the described procedures (Angiolini et al. Eur. J. Org. Chem. 2000, 2571-2581).

Example 63B

(3S,6R,9aS)-6-(methoxycarbonylamino)-5-oxoacetate-1H-pyrrolo[1,2-a]azepin-3-carboxylic acid

To a solution of the product from Example 63A (45 mg, 0 122 mmol) in 1,4-dioxane (0.2 ml) was added 2 n HCl solution in 1,4-dioxane (0.3 ml, 1.2 mmol). The resulting solution was stirred at room temperature overnight and then concentrated in vacuum. The residue was dissolved in H2O (0 4 ml), was added NaHCO3(33 mg, 0,39 mmol) and the resulting mixture was stirred at 0°C until was added dropwise a solution of methylchloroform (0,012 ml, 0,156 mmol) in Et2O (0.100 ml). The resulting mixture was stirred at room temperature for 3 the aces and then distributed between 0.2 N. aqueous solution of HCl and CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated in vacuum to obtain specified in the title compound as a solid (33 mg, quantitative yield).

Example 63C

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba[(3S,6R,9aS)-5-oxoacetate-1H-pyrrolo[1,2-a]azepin-3,6-diyl]}]bicarbonate

The product from Example 1B (10 mg, 0,033 mmol) was subjected to the processing conditions described in Example 24C, substituting N-(tert-butoxycarbonyl)-L-Proline for the product of Example 63B (19 mg, 0,070 mmol), to obtain specified in the connection header in the form of a salt TFOC (10 mg).1H NMR (500 MHz, DMSO-d6) δ M. D. 1,51 is 1.86 (m, 14H), 1,90 for 2.01 (m, 4H), 2,02-2,11 (m, 2H), 3,55 (s, 6H), 3.96 points-Android 4.04 (m, 2H), 4,14 (t,J=5,95 Hz, 2H), of 4.44 (d,J=9,46 Hz, 2H), 4,59 (s, 4H), to 6.57 (t,J=7,10 Hz, 1H), 6,66 (l,J=to 7.93 Hz, 2H), 7,07 (t,J=7,86 Hz, 2H), 7,17 (l,J=8,54 Hz, 4H), 7,44 (s, 2H), 7,52 (d,J=8,55 Hz, 4H), 9,99 (s, 2H); MS m/z 809 (M+H)+.

Example 64

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba[(2S,5R)-5-prop-2-EN-1-imperiality-2.1-diyl][(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]}]bicarbonate

Example 64A

(2S,5R)-1-tert-butyl 2-ethyl 5-arylpyrimidine-1,2, in primary forms

Specified in the title compound was obtained in accordance with the described procedures (Zhang et al. Org. Lett. 2002, 4, 4029-4032).

Example 64B

(2S,5R)-5-allyl-1-(tert-buto is dicarbonyl)pyrrolidin-2-carboxylic acid

A solution of the product of Example 64A (0.35 g, 1,24 mmol) in MeOH (10 ml) was treated with a 3.0 M aqueous NaOH solution (to 2.06 ml, 6,18 mmol) and the resulting mixture was stirred at room temperature for 3 hours. Added 1 HCl solution to reach pH 2, MeOH was removed in vacuo, and the aqueous layer was extracted with the help of CH2Cl2(2x). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum to obtain specified in the connection header.

Example 64C

(2R,2'R,5S,5'S)-tert-butyl 5,5'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(2-arylpyrimidine-1-carboxylate)

The product from Example 1B (119 mg, 0,392 mmol) was subjected to the procedure described in Example 24C, substituting N-(tert-butoxycarbonyl)-L-Proline for the product from Example 64B (0,22 g, 0,862 mmol), to obtain the specified title compound (0.24 g, 79%).

Example 64D

(2S,2'S,5R,5'R)-N,N'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene))bis(5-arylpyrimidine-2-carboxamide)

The product from Example 64C (0.24 g, 0.31 mmol) was subjected to the processing conditions described in Example 1D, obtaining specified in the title compound (0.17 g, 95%).

Example 64X

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba[(2S,5R)-5-prop-2-EN-1-imperiality-2.1-diyl][(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]}]bicarbonate

About the TPC of Example 64D (20 mg, 0.035 mmol) was subjected to the processing conditions described in Example 24E, substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoyl acid to (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid, obtaining specified in the connection header in the form of a salt TFOC (17 mg).1H NMR (500 MHz, DMSO-d6) δ M. D. 0,89-a 1.01 (m, 18H), 1,73-of 1.95 (m, 5H), 2,02-of 2.28 (m, 3H), 3,50-3,60 (m, 6H), 3,97 is 4.13 (m, 1H), 4,20 (l,J=9,46 Hz, 2H), 4.26 deaths is 4.45 (m, 3H), 4,54 with 4.65 (m, 4H), 4.95 points-to 5.21 (m, 4H), 5,71-to 5.93 (m, 2H), 6,57 (t,J=to 7.25 Hz, 1H), 6,66 (l,J=8,24 Hz, 2H), 6,88-of 6.96 (m,J=being 9.61 Hz, 1H), 7.03 is-7,10 (m, 2H), 7,13-of 7.23 (m, 4H), 7,38 (d,J=9,46 Hz, 1H), 7,47-7,56 (m, 4H), 9,98 (s, 2H); MS (ECI) m/z 920,5 (M+H)+.

Example 65

N,N-Bis[(2-{(2S)-1-[(2R)-2-(diethylamino)-2-phenylacetyl]pyrrolidin-2-yl}-1H-benzimidazole-5-yl)methyl]aniline

The product from Example 7E (18 mg, 0,037 mmol) was subjected to the procedure described in Example 24E, substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoyl acid the hydrochloride of (R)-2-(diethylamino)-2-phenylacetic acid, to obtain specified in the connection header in the form of a salt TFOC (25 mg).1H NMR (500 MHz, DMSO-d6) δ memorial plaques of 0.93 to 1.37 (m, 12H), 1,84 with 2.14 (m, 8H), 2,15-of 2.28 (m, 2H), 2.77-to 3,40 (m, 10H), 4,10-4,18 (m, 2H), 4,79-of 4.95 (m, 4H), 5,22 (DD,J=8,32, 2.37 Hz, 2H), of 5.45 (s, 2H), 6,54-6,85 (m, 4H), 6,99-to 7.18 (m, 3H), 7.23 percent-7,40 (m, 1H), for 9.64-9,86 (m, 2H); MS (ECI) m/z 870,6 (M+H)+.

Example 66

N,N-Bis[(2-{(2S)-1-[(2R)-2-phenyl-2-pyrrolidin-1-ylacetic]pyrrolidin-2-yl}-1H-benzimida the evil-5-yl)methyl]aniline

The product of Example 7E (20 mg, 0,041 mmol) was subjected to the procedure described in Example 24E, substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoyl acid (R)-2-phenyl-2-(pyrrolidin-1-yl)acetic acid, to obtain specified in the connection header in the form of a salt TFOC (14 mg).1H NMR (500 MHz, DMSO-d6) δ M. D. 1,22-of 1.29 (m, 3H), 1,87 is 1.96 (m, 9H), 1,99 (s, 2H), 2,01 is 2.10 (m, 7H), 2,18-of 2.28 (m, 3H), 2.95 and totaling 3.04 (m, 5H), is 4.03 (d,J=8,7 Hz, 5H), 4.92 in (s, 4H), 5,49 (s, 3H), 6.75 in (q,J=8,1 Hz, 3H), 7,08-7,17 (m, 3H), 7,39 (l,J=8,4 Hz, 3H), EUR 7.57 (DD,J=6,9, 2.7 Hz, 8H), to 7.61-to 7.67 (m, 5H), of 7.70 (d,J=8,4 Hz, 3H); MS (ECI) m/z 866,3 (M+H)+.

Example 67

N,N-Bis[(2-{(2S)-1-[(2R)-2-morpholine-4-yl-2-phenylacetyl]pyrrolidin-2-yl}-1H-benzimidazole-5-yl)methyl]aniline

The product of Example 7E (20 mg, 0,041 mmol) was subjected to the procedure described in Example 24E, substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoyl acid (R)-2-morpholino-2-phenylacetic acid, to obtain specified in the connection header in the form of a salt TFOC (17 mg).1H NMR (500 MHz, DMSO-d6) δ memorial plaques at 1.91 (d,J=2,6 Hz, 4H), 2,02-2,11 (m, 7H), 2,23 (l,J=6,6 Hz, 4H), 3.04 from (l,J=7.2 Hz, 6H), of 4.90 (s, 7H), and 5.30 (DD,J=to 8.4, 2.0 Hz, 3H), 5,49 (s, 3H), of 6.61 (s, 2H), 6,74 (l,J=8,2 Hz, 4H), 7,07-7,14 (m, 3H), 7,37 (l,J=8,2 Hz, 3H), 7,53-to 7.59 (m, 11H), to 7.59-to 7.64 (m, 6H), 7,68 (l,J=8,4 Hz, 3H); MS (ECI) m/z 898,6 (M+H)+.

Example 68

Dimethyl [(acetylimino)bis{metandienon-4,1-Vilcabamba(2S)PI is Raiden-2.1-diyl[(2S)-3-methyl-1-oxobutyl-1,2-diyl]}]bicarbonate

Example 68A

N,N-bis(4-nitrobenzyl)ndimethylacetamide

To a solution of bis(4-nitrobenzyl)amine (500 mg, 1,741 mmol) in pyridine (9 ml) with a syringe was slowly added acetic anhydride (0,18 ml, 1.92 mmol). The resulting mixture was stirred at room temperature for 2 hours and the reaction mixture was concentrated in vacuum. The residue was dissolved in toluene and evaporated to dryness in vacuum. The residue was dissolved in a mixture of 19:1 EtOAc:methanol, washed with water and saturated saline solution, dried (Na2SO4), filtered and concentrated to obtain specified in the header of the compound (551 mg, 96%). MS (APCI) m/z 330,2 (M+H)+.

Example 68B

N,N-bis(4-aminobenzyl)ndimethylacetamide

A mixture of the product from Example 68A (250 mg, 0,759 mmol), iron powder (424 mg, to 7.59 mmol) and ammonium chloride (203 mg, of 3.80 mmol) in ethanol (1 ml), tetrahydrofuran (1 ml) and water (0,250 ml) was heated at 80°C for 18 hours. The mixture was allowed to cool to room temperature, filtered, washed with methanol and concentrated in vacuum. The residue was distributed between EtOAc and H2O, and the organic layer was dried (Na2SO4), filtered and concentrated in vacuum to obtain specified in the title compound (226 mg, 90 %). MS (ESI) m/z 269,9 (M+H)+.

Example 68

(2S,2'S)-tert-butyl 2,2'-(4,4'-(ACET ethanediyl)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)dipyrrole-1-carboxylate

The product from Example 68B (264,4 mg, 0,982 mmol) was subjected to the procedure described in Example 24C, obtaining specified in the title compound (684 mg, quantitative yield). MS (ESI) m/z 664,4 (M+H)+.

Example 68D

(S)-N-(4-((N-(4-((S)-pyrrolidin-2-carboxamido)benzyl) acetamido)methyl)phenyl)pyrrolidin-2-carboxamide

The product from Example 68 (684 mg, 1,030 mmol) was subjected to the procedure described in Example 24D, obtaining specified in the title compound (141 mg, 29%) MS (ESI) m/z 464,2 (M+H)+

Example 68E

Dimethyl [(acetylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3-methyl-1-oxobutyl-1,2-diyl]}]bicarbonate

The product from Example 68D (35 mg, 0,076 mmol) was subjected to the procedure described in Example 2, substituting (R)-2-(dimethylamino)-2-phenylacetic acid for (S)-2-(methoxycarbonylamino)-3-methylbutanoyl acid, obtaining specified in the title compound (22 mg, 37%).1H NMR (500 MHz, DMSO-d6) δ memorial plaques to 0.88 (d,J=6,7 Hz, 6H), were 0.94 (d,J=6.9 Hz, 6H), 1.85 to was 1.94 (m, 6H), 1,96-2,04 (m, 2H), 2,10 (s, 3H), 2,11-2,19 (m, 2H), 3,50 of 3.56 (m, 6H), 3,59-3,66 (m, 2H), 3,78-of 3.85 (m, 2H), 4,03 (t,J=8.5 Hz, 2H), to 4.38 (s, 4H), of 4.44 (DD,J=8,1, 4,9 Hz, 2H), 7,10-7,16 (m, 4H), 7,32 (l,J=8,4 Hz, 2H), 7,50-to 7.59 (m, 4H), 10,04 (l,J=20.0 Hz, 2H); MS (ECI) m/z 778,4 (M+H)+.

Example 69

N-(Methoxycarbonyl)-3-methyl-L-poured-N-(4-{[{4-[(1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-L-ol is a Lil)amino]benzyl}(phenyl)amino]methyl{phenyl)-L-prolinamide

Example 69A

Methyl R-2-oxo-1-phenyl-2-((S)-2-(4-((phenyl(4-((S)-pyrrolidin-2-carboxamido)benzyl)amino)methyl)phenylcarbamoyl)pyrrolidin-1-yl)ethylcarbamate

To a solution of the product from Example 1D (1,198 g 2,408 mmol) in DMSO (24 ml) was added R-2-(methoxycarbonylamino)-2-phenylacetic acid (0,403 g, 1,926 were mmol), HATU (0,732 g, 1,926 were mmol) and base Hunya (0,673 ml of 3.85 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was poured into water to obtain a colorless precipitate, which was filtered and washed with water. The solid was dissolved in CH2Cl2, dried over anhydrous solution of sodium sulfate, filtered and concentrated in vacuum. The crude product was purified using column chromatography on silica gel using a gradient solvent 0-8% MeOH in CH2Cl2with obtaining specified in the connection header (0,387 g, 24%).

Example 69B

N-(methoxycarbonyl)-3-methyl-L-poured-N-(4-{[{4-[(1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-L-prolyl)amino]benzyl}(phenyl)amino]methyl{phenyl)-L-prolinamide

The product from Example 69A (0,031 g, 0.045 mmol) was subjected to the procedure described in Example 10B, substituting (R)-2-(dimethylamino)-2-phenylacetic acid for (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid, obtaining specified in the title compound (11 mg, 28%).1H NMR (500 MHz, the MCO-d 6) δ memorial plaques to 0.96 (s, 9H), 1,80-2,05 (m, 8H), 2,10-to 2.18 (m, 2H), 3,53 (s, 3H), of 3.54 (s, 3H), 3,60-3,68 (m, 1H), 3,74-of 3.85 (m, 2H), 4,21 (l,J=a 8.9 Hz, 2H), 4,37 (DD,J=8,1, 3,4 Hz, 1H), of 4.44 (DD,J=8,2, a 5.3 Hz, 1H), 4,59 (s, 4H), to 6.57 (t,J=7.2 Hz, 1H), 6,66 (l,J=8,1 Hz, 2H),? 7.04 baby mortality-7,11 (m, 2H), 7,15-7,21 (m, 4H), 7,29-7,42 (m, 5H), of 7.48-7,56 (m, 4H), 7,69 (l,J=7.8 Hz, 1H), 9,83 (s, 1H), 9,99 (s, 1H); MS m/z 860,8 (M+H)+.

Example 70

N-(Methoxycarbonyl)-L-poured-N-(4-{[{4-[(1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-L-prolyl) amino]benzyl}(phenyl)amino]methyl}phenyl)-L-prolinamide

The product from Example 69A (0,031 g, 0.045 mmol) was subjected to the procedure described in Example 10B, substituting (R)-2-(dimethylamino)-2-phenylacetic acid for (S)-2-(methoxycarbonylamino)-3-methylbutanoyl acid, obtaining specified in the connection header (0,0135 g, 36%).1H NMR (500 MHz, DMSO-d6) δ memorial plaques to 0.88 (d,J=6,7 Hz, 3H), of 0.93 (d,J=6,7 Hz, 3H), 1,80-2,05 (m, 8H), 2,09-of 2.20 (m, 2H), 3,52 (s, 3H), 3,53 (s, 3H), 3,57-to 3.67 (m, 2H), 3,76-3,86 (m, 2H), was 4.02 (t,J=8.5 Hz, 2H), 4,37 (DD,J=8,1, 3,4 Hz, 1H), 4,43 (DD,J=8,2, 4.8 Hz, 1H), 4,59 (s, 4H), to 6.57 (t,J=7.2 Hz, 1H), 6,66 (l,J=8,1 Hz, 2H),? 7.04 baby mortality-7,10 (m, 2H), 7,15-7,21 (m, 4H), 7,29-7,42 (m, 5H), of 7.48-EUR 7.57 (m, 4H), 7,69 (l,J=7.9 Hz, 1H), 9,83 (s, 1H), 9,98 (s, 1H); MS m/z 846,3 (M+H)+.

Example 71

Methyl {(1R)-2-[(2S)-2-{[4-({[4-({[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]butanoyl}pyrrolidin-2-yl]carbonyl}amino)benzyl](phenyl)amino}methyl)phenyl]carbarnoyl]-pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carb is at

The product from Example 69A (0,031 g, 0.045 mmol) was subjected to the procedure described in Example 10B, substituting (R)-2-(dimethylamino)-2-phenylacetic acid for (S)-2-(methoxycarbonylamino)butane acid, obtaining specified in the connection header (0,0126 g, 34%).1H NMR (500 MHz, DMSO-d6) δ memorial plaques of 0.90 (t,J=7,4 Hz, 3H), 1,46 is 1.58 (m, 1H), 1,61-1,71 (m, 1H), 1,73-2,05 (m, 8H), 2,07-of 2.20 (m, 2H), 3,52 (s, 3H), 3,53 (s, 3H), 3,56-to 3.64 (m, 2H), 3,69 is 3.76 (m, 1H), of 3.77-a-3.84 (m, 1H), 4,14-is 4.21 (m, 1H), 4,37 (DD,J=8,2, 3,4 Hz, 1H), 4,43 (DD,J=8,1, 4.6 Hz, 1H), 4,59 (s, 4H), to 6.57 (t,J=7.2 Hz, 1H), 6,66 (l,J=8,1 Hz, 2H),? 7.04 baby mortality-7,11 (m, 2H), 7,18 (DD,J=8,5 and 5.9 Hz, 4H), 7,29-7,42 (m, 5H), of 7.48-7,56 (m, 4H), 7,69 (l,J=7.8 Hz, 1H), 9,83 (s, 1H), 9,95 (s, 1H); MS m/z 832,2 (M+H)+.

Example 72

Methyl {(1S)-2-[(2S)-2-{[4-({[4-({[(2S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}pyrrolidin-2-yl]carbonyl}amino)benzyl](phenyl)amino}methyl)phenyl]carbarnoyl}-pyrrolidin-1-yl]-2-oxo-1-[(3R)-tetrahydrofuran-3-yl]ethyl}carbamate

The product from Example 69A (0,031 g, 0.045 mmol) was subjected to the procedure described in Example 10B, substituting (R)-2-(dimethylamino)-2-phenylacetic acid for (S)-2-(methoxycarbonylamino)-2-((R)-tetrahydrofuran-3-yl)acetic acid, to obtain specified in the connection header (0,0219 g, 55%).1H NMR (500 MHz, DMSO-d6) δ M. D. 1,21-of 1.29 (m, 4H), was 1.69 and 1.80 (m, 2H), 1,81-2,05 (m, 8H), 2,11-of 2.20 (m, 2H), 3,53 (s, 3H), 3,53 (s, 3H), to 3.58-3,71 (m, 2H), 3,71-to 3.89 (m, 2H), 4,23 (t,J=a 8.9 Hz, 1H), 4,37 (DD,J=8,1, 3.2 Hz, 1H), of 4.44 (DD,J=8,2, the 4.7 is C, 1H), 4,60 (s, 4H), to 6.57 (t,J=7.2 Hz, 1H), 6,66 (l,J=8,1 Hz, 2H),? 7.04 baby mortality-7,11 (m, 2H), 7,18 (DD,J=8,6, 3,4 Hz, 3H), 7,32-7,42 (m, 5H), 7,53 (DD,J=13,5, 8.5 Hz, 4H), to 7.61 (d,J=7.9 Hz, 1H), 7,69 (l,J=7.8 Hz, 1H), 9,83 (s, 1H), 9,98 (s, 1H); MS m/z 874,3 (M+H)+.

Example 73

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba[(2S)-4,4-giftability-2.1-diyl][(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]}]bicarbonate

Example 73A

(5S,5'S)-tert-butyl 5,5'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(3,3-giftability-1-carboxylate)

The product from Example 1B and N-BOC-4,4-debtor-L-Proline (Aldrich) were processed using the method described in Example 41, with getting 457 mg (87%) specified in the connection header. MS (ESI, M+H) m/z=770.

Example 73B

(2S,2'S)-N,N'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene))bis(4,4-giftability-2-carboxamide)

The product from Example 73A were processed using the method described in Example 47B, to obtain 236 mg (70%) specified in the connection header. MS (DCI; (M+H) m/z=570.

Example 73C

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba [(2S)-4,4-giftability-2.1-diyl][(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]}]bicarbonate

The product from Example 73B and (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid (DeGussa) was treated with use the of way described in Example 41, to obtain 35 mg (9%) specified in the connection header.1H NMR (400 MHz, DMSO-d6) δ 0,97 (s, 18H) 2,37-of 2.50 (m, 2H) 2,78-to 2.85 (m, 2H) 3,54 (s, 6H) 4,00-4,20 (m, 4H) 4,28-4,39 (m, 2H) 4,59 (Shir. s, 4H) with 4.64 (t, J=8,02 Hz, 2H) to 6.57 (t, J=7,21 Hz, 1H) 6,65 (d, J=8,24 Hz, 2H) 7,07 (t, J=a 7.92 Hz, 2H) 7,19 (d, J=8,57 Hz, 4H) 7,29 (d, J=8,13 Hz, 2H) 7,50 (d, J=8,57 Hz, 4H) 10,13 (s, 2H).

Example 74

N-(Methoxycarbonyl)-3-methyl-L-poured-N-(4-{[{4-[(1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylacetyl}-L-prolyl)amino]benzyl}(phenyl)amino]methyl{phenyl)-L-prolinamide

The product of Example 10A (150 mg, 0,224 mmol) was subjected to the procedure described in Example 10B, substituting (R)-2-(dimethylamino)-2-phenylacetic acid for (R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (62,0 mg, 0,247 mmol), to obtain the specified title compound (145 mg, 71 %).1H NMR (500 MHz, DMSO-d6) δ M. D. 0,94 is 0.99 (m, 8H), 1.32 to to 1.38 (m, 9H), 1,76 (l,J=4,1 Hz, 1H), 1,82 is 1.91 (m, 3H), 1.93 and-2,02 (m, 3H), 2,11-of 2.20 (m, 1H), 2,69 (s, 4H), 3,17 (l,J=5,2 Hz, 2H), 3,54 (s, 3H), 3,63 (l,J=9,3 Hz, 1H), 3,78 (DD,J=9,6, 6.4 Hz, 2H), 4,11 (l,J=5,2 Hz, 1H), 4,21 (l,J=9,0 Hz, 1H), 4,37 (DD,J=7,9, 3.1 Hz, 1H), of 4.44 (DD,J=8,1, 5.3 Hz, 1H), 4,59 (s, 4H), to 6.57 (t,J=7.2 Hz, 1H), 6,66 (l,J=8,1 Hz, 2H),? 7.04 baby mortality-7,11 (m, 3H), 7,18 (DD,J=8,5, and 3.2 Hz, 4H), 7,34-7,40 (m, 4H), 7,52 (DD,J=9,9, to 8.7 Hz, 4H), 10,00 (s, 1H); MS (ECI) m/z 902,8 (M+H)+.

Example 75

Methyl [(1R)-2-{(2S)-2-[(4-{[{4-[({(2S)-1-[(2R)-2-(diethylamino)-2-phenylacetyl]pyrrolidin-2-the l}carbonyl)amino]benzyl}(phenyl)amino]methyl}phenyl)carbarnoyl]-pyrrolidin-1-yl}-2-oxo-1-phenylethyl]carbamate

The product from Example 69A (0,033 g 0,048 mmol) was subjected to the procedure described in Example 10B, substituting (R)-2-(dimethylamino)-2-phenylacetic acid for (R)-2-(diethylamino)-2-phenylacetic acid, to obtain specified in the connection header (0,0238 g, 57%).1H NMR (500 MHz, DMSO-d6) δ memorial plaques to 0.89 (t,J=6,9 Hz, 3H), of 1.07 (t,J=7.2 Hz, 3H), of 1.21 and 1.33 (m, 4H), 1,74-2,03 (m, 8H), 2.05 is-are 2.19 (m, 2H), 3,53 (s, 3H), 3,76-a-3.84 (m, 1H), 3,97-Android 4.04 (m, 1H), 4,35-of 4.44 (m, 2H), br4.61 (s, 4H), 5,43-5,52 (m, 2H), return of 6.58 (t,J=7.2 Hz, 1H), 6,67 (l,J=8,1 Hz, 2H), 7,05-7,11 (m, 2H), 7,20 (m,J=8,3 Hz, 4H), 7,33-7,42 (m, 6H), 7,49-7,58 (m, 6H), 7,66-7,71 (m, 2H), 9,84 (s, 1H), 10,16 (s, 1H); MS m/z 878,3 (M+H)+.

Example 76

Methyl {(1R)-2-oxo-1-phenyl-2-[(2S)-2-({4-[(phenyl{4-[({(2S)-1-[(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-2-yl}carbonyl)amino]benzyl}amino)methyl]phenyl}carbarnoyl)pyrrolidin-1-yl]ethyl}carbamate

The product from Example 69A (0,032 g, 0.046 mmol) was subjected to the procedure described in Example 10B, substituting (R)-2-(dimethylamino)-2-phenylacetic acid for (S)-tetrahydrofuran-2-carboxylic acid, to obtain specified in the connection header (0,0244 g, 66%).1H NMR (400 MHz, DMSO-d6) δ M. D. 1,72-of 2.16 (m, 12H), 3,53 (s, 3H), to 3.58-a-3.84 (m, 4H), or 4.31 is 4.45 (m, 2H), 6,57 (t,J=7.2 Hz, 1H), 6,66 (l,J=8,2 Hz, 2H), 7.03 is for 7.12 (m, 2H), 7,18 (DD,J=8,3, 4.6 Hz, 4H), 7,32-7,42 (m, 5H), 7,47-7,58 (m, 4H), 7,68 (l,J=7.9 Hz, 1H), 9,83 (s, 1H), 9,96 (s, 1H); MS m/z 787,2 (M+H)+.

Example 77

N-(Meloxicam who yl)-3-methyl-L-poured-N-[4-({[4-({1-[(2R)-2-amino-2-phenylacetyl]-L-prolyl}amino)benzyl](phenyl)amino}methyl)phenyl]-L-prolinamide

To a solution of the product from Example 74 (136,1 mg, 0,151 mmol) in CH2Cl2(0.2 ml) was added triperoxonane acid (0,20 ml). The mixture was stirred at room temperature and concentrated in vacuum. The crude product was distributed between CH2Cl2and saturated aqueous NaHCO3and the organic layer was dried (Na2SO4), filtered and concentrated in vacuum to obtain specified in the title compound (115 mg, 94%).1H NMR (400 MHz, DMSO-d6) δ memorial plaques to 0.96 (s, 8H), 1,53 (s, 1H), 1,74 (s, 1H), 1,82 is 1.91 (m, 3H), 1,99 (s, 2H), 2,15 (s, 1H), 2,69 (s, 2H), 2,84 (s, 1H), 3,54 (s, 3H), 3,63 (s, 1H), 3,79 (s, 2H), 4,21 (l,J=a 8.9 Hz, 1H), to 4.41-4,47 (m, 2H), 4,60 (s, 4H), from 5.29 (s, 1H), 6,57 (t,J=7.2 Hz, 1H), 6,66 (l,J=8,2 Hz, 2H), 7,05-7,11 (m, 3H), 7,19 (t,J=8,3 Hz, 4H), 7,42-7,49 (m, 4H), 7,53 (DD,J=12,8, 8,5 Hz, 5H), 10,00 (s, 1H), to 10.09 (s, 1H); MS (ECI) m/z 802,5 (M+H)+.

Example 78

Dimethyl {(phenylimino)bis[meander-1H-benzimidazole-5,2-diyl(2S)pyrrolidin-2.1-diyl{(1S)-2-oxo-1-[(3R)-tetrahydrofuran-3-yl]ethane-2,1-diyl}]}bicarbonat

The product from Example 7E (17 mg, 0.035 mmol) was subjected to the procedure described in Example 2, substituting (R)-2-(dimethylamino)-2-phenylacetic acid for (S)-2-(methoxycarbonylamino)-2-((R)-tetrahydrofuran-3-yl)acetic acid (14,75 mg, 0,073 mmol), to obtain the specified title compound (10 mg, 34%).1H NMR (400 MHz, DMSO-d6) δ memorial plaques to 0.80-0.87 (m, 1H), 1,19-of 1.30 (m, 6H), and 1.63 (s, 2H), 1,73 (d,i> J=12.9 Hz, 2H), 1,96 (s, 3H), 2,10 (s, 2H), 2,17 (s, 1H), 3,39-3,47 (m, 3H), 3,52 is 3.57 (m, 7H), 3,61 (t,J=7.9 Hz, 2H), 3,70 (l,J=8.0 Hz, 2H), 3,81 (s, 3H), 4,29 (s, 2H), 4.75 in (q,J=10.1 Hz, 3H), 5,12 (s, 2H), is 6.54 (s, 1H), 6,72 (l,J=8,3 Hz, 2H), 7,01-to 7.09 (m, 4H), 7,26 (s, 1H), 7,34-7,38 (m, 2H), 7,44 (l,J=8,2 Hz, 1H), EUR 7.57 (s, 1H), 12,00 (s, 2H); MS (ECI) m/z 862,4 (M+H)+.

Example 79

(2S,2'S)-N,N'-[(Phenylimino)bis(metandienon-4,1-diyl)]bis{1-[(2S)-2-(acetylamino)-3,3-dimethylbutanol]pyrrolidin-2-carboxamide}

Example 79A

tert-Butyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(pyrrolidin-2.1-diyl))bis(3,3-dimethyl-1-oxobutyl-2.1-diyl)dicarbamate

The product of Example 1D (1.0 g, a 2.01 mmol) and (S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanol acid (1,02 g, was 4.42 mmol) were processed as in Example 25B, with the receipt of 1.46 g (76%) indicated in the title compound in the form of not-quite-white solid.

Example 79B

(S,2S,2'S)-N,N'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene))bis(1-((S)-2-amino-3,3-dimethylbutanol)pyrrolidin-2-carboxamid)

The product from Example 79A (1.44 g, 1.56 mmol) was dissolved in dichloromethane (10 ml) at ambient temperature and were processed using triperoxonane acid (5 ml). After 3 hours the solution was concentrated, was transferred into a 25% solution of isopropanol is chloroform and washed with 10% sodium bicarbonate solution. Organics were dried over sodium sulfate, filtered and concentrated to dryness to obtain specified in the title compound as a white solid.

Example 79 ° C

(2S,2'S)-N,N'-[(phenylimino)bis(metandienon-4,1-diyl)]bis{1-[(2S)-2-(acetylamino)-3,3-dimethylbutanol]pyrrolidin-2-carboxamide}

The product of Example 79B (0.03 g, 0,041 mmol) was dissolved in dichloromethane (1.5 ml) at ambient temperature and were processed using DMAP (0,012 g, 0.10 mmol), followed by treatment with acetic anhydride (0,009 ml, 0,091 mmol) and was stirred for 2 hours. The solution was concentrated and was purified on a column of combi-flash 12g, elwira mixture of 0-4% methanol in dichloromethane, to obtain 0.025 g (75%) indicated in the title compound as a white solid.1H NMR (500 MHz, DMSO-d6) δ memorial plaques of 0.95 (s, 18H) 1,79-1,90 (m, 10H) 1,90-2,00 (m, 2H) 2,07-2,19 (m, 2H) 3,59-to 3.67 (m, 2H) of 3.73-3,82 (m, 2H) to 4.41 (DD, J=8,32, 5,26 Hz, 2H) 4,51 (d, J=9,00 Hz, 2H) of 4.57 (s, 4H) 6,55 (t, J=7,25 Hz, 1H) 6,64 (d, J=8,09 Hz, 2H) 7.03 is-7,10 (m, 2H) 7,16 (d, J=8.54 in Hz, 4H) 7,50 (d, J=8.54 in Hz, 4H) 7,87 (d, J=9,00 Hz, 2H) becomes 9.97 (s, 2H); MS ECI - m/z 806,6.

Example 80

(2S,2'S)-N,N'-[(Phenylimino)bis(metandienon-4,1-diyl)]bis(1-{(2S)-2-[(dimethylcarbamoyl)amino]-3,3-dimethylbutanol}pyrrolidin-2-carboxamid)

The product of Example 79B (0,045 g, 0,062 mmol) was dissolved in dichloromethane (2 ml) at ambient temperature and treated with Diisopropylamine(0,065 ml, of 0.37 mmol), followed by processing dimethylcarbamodithioato (of 0.013 ml, 0.14 mmol) and was stirred for 3 days. The solution was concentrated to dryness and purified on a column of combi-flash 12g with silicon dioxide, elwira mixture of 0-10% methanol in dichloromethane, to obtain the 0,031 g (58%) indicated in the title compound as a white solid.1H NMR (400 MHz, DMSO-d6) δ memorial plaques of 0.95 (s, 18H) 1,79-1,90 (m, 4H) 1,92-2,04 (m, 2H) 2,08-to 2.18 (m, 2H) and 2.79 (s, 12H) 3,55-3,66 (m, 2H) of 3.77-3,86 (m, 2H) 4,35 (d, J=9,11 Hz, 2H) and 4.40 (DD, J=8,08, 5,69 Hz, 2H) of 4.57 (s, 4H) are 5.36 (d, J=9,11 Hz, 2H) 6,55 (t, J=7,26 Hz, 1H) 6,64 (d, J=8.35 Hz, 2H) 7,05 (t, J=a 7.92 Hz, 2H) 7,16 (d, J=8,46 Hz, 4H) 7,49 (d, J=8,46 Hz, 4H) 9,98 (s, 2H); MS ECI - m/z 864,6.

Example 81

Methyl {(1S)-2-{(2S)-2-[(4-{[{4-[({(2S)-1-[(2R)-2-(diethylamino)-2-phenylacetyl]pyrrolidin-2-yl}carbonyl)amino]benzyl}(4-forfinal)amino]methyl}phenyl)carbarnoyl]pyrrolidin-1-yl}-2-oxo-1-[(3R)-tetrahydrofuran-3-yl]ethyl}carbamate

Example 81A

(S)-1-((R)-2-(diethylamino)-2-phenylacetyl)-N-(4-(((4-forfinal)(4-((S)-pyrrolidin-2-carboxamido)benzyl)amino)methyl)phenyl)pyrrolidin-2-carboxamide

The product from Example 13D (0,428 g, 0.83 mmol) and (R)-2-(diethylamino)-2-phenylacetic acid (was 0.138 g, 0,664 mmol) were combined in dimethyl sulfoxide (8 ml) at ambient temperature and treated with diisopropylethylamine (of 0.26 ml, 1,49 mmol), followed by treatment HATU (0,252 g, 0,664 mmol). After one hour the solution p is bavlyali water and the product was filtered and purified on a column of combi-flash 24g, elwira mixture of 0-10% methanol in dichloromethane, to obtain the strength of 0.159 g (27%) indicated in the title compound as a white solid.

Example 81B

Methyl {(1S)-2-{(2S)-2-[(4-{[{4-[({(2S)-1-[(2R)-2-(diethylamino)-2-phenylacetyl]pyrrolidin-2-yl}carbonyl)amino]benzyl}(4-forfinal)amino]methyl}phenyl)carbarnoyl]pyrrolidin-1-yl}-2-oxo-1-[(3R)-tetrahydrofuran-3-yl]ethyl}carbamate

The product from Example 81A (0,042 g to 0.060 mmol) and (S)-2-(methoxycarbonylamino)-2-((R)-tetrahydrofuran-3-yl)acetic acid (0,013 g, 0 066 mmol) were processed as in Example 81A, obtaining 0,033 g (62%) indicated in the title compound in the form of not-quite-white solid. MS (AA, ELSD+) m/z 890 (M+H)+.

Example 82

N-(Methoxycarbonyl)-3-methyl-L-poured-N-[4-({[4-({1-[(2R)-2-(diethylamino)-2-phenylacetyl]-L-prolyl}amino)benzyl](4-forfinal)amino}methyl)phenyl]-L-prolinamide

The product from Example 81A (0,042 g to 0.060 mmol) and (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid (0,013 g of 0.066 mmol) were processed as in Example 81A, obtaining 0,031 g (59%) indicated in the title compound in the form of not-quite-white solid.1H NMR (500 MHz, DMSO-d6) δ memorial plaques to 0.88 (t, J=7,10 Hz, 6H) of 0.95 (s, 9H) 1,76-1,89 (m, 4H) 1,93 is 2.00 (m, 2H) 2,02 is 2.10 (m, 1H) 2,10-to 2.18 (m, 1H) 2,40-2,47 (m, 2H) 2,56-to 2.65 (m, 2H) to 3.52 (s, 3H) 3,61 (DD, J=17,24, of 7.48 Hz, 2H) of 3.73-of 3.80 (m, 2H) 4,20 (d, J=9,00 Hz, 1H) 4,37 (DD, J=7,93, 4,27 Hz, 1H) was 4.42 (DD, J=7,78, 5,19 Hz, 1H) 4,54 (s, 4H) 4,66 (s, 1H) 6,63 (DD, J=9,31, 4,43 Hz, 2H) 6,90 (t, J=cent to 8.85 is C, 2H) 7,07 (d, J=cent to 8.85 Hz, 1H) 7,17 (DD, J=of 8.47, to 3.89 Hz, 4H) 7,26 (t, J=7,17 Hz, 1H) to 7.32 (t, J=7,40 Hz, 2H) 7,39 (d, J=7,17 Hz, 2H) 7,50 (DD, J=8,39, 6,10 Hz, 4H) 9,95 (s, 1H) 9,99 (s, 1H); MS ECI+ m/z 876,5.

Example 83

(2S)-1-[(2R)-2-(Diethylamino)-2-phenylacetyl]-N-(4-{[(4-forfinal){4-[({(2S)-1-[(2R)-2-phenyl-2-pyrrolidin-1-ylacetic]pyrrolidin-2-yl}carbonyl)amino]benzyl}amino]methyl}phenyl)pyrrolidin-2-carboxamide

The product from Example 81A (0 032 g, 0.045 mmol) and (R)-2-phenyl-2-(pyrrolidin-1-yl)acetic acid (0,010 g, 0.05 mmol) was treated as in Example 81A, obtaining 0.015 g (37%) indicated in the title compound in the form of not-quite-white solid.1H NMR (500 MHz, DMSO-d6) δ memorial plaques to 0.89 (t, J=7,10 Hz, 6H) 1,56-of 1.66 (m, 4H) 1,74-of 1.88 (m, 4H) 1,94-of 2.09 (m, 4H) 2,29-of 2.34 (m, 2H) 2.57 m-2,62 (m, 4H) 3,36-to 3.50 (m, 4H) 3.75 to 3,88 (m, 2H) is 4.21 (s, 1H) or 4.31 (DD, J=7,93, 4,27 Hz, 1H) to 4.38 (DD, J=8,16, 4,50 Hz, 1H) 4,57 (s, 4H) and 4.68 (s, 1H) 6,65 (DD, J=9,31, 4,43 Hz, 2H) 6,92 (t, J=8,93 Hz, 2H) 7,19 (d, J=8,24 Hz, 4H) 7,26-7,30 (m, 2H) 7,31 and 7.36 (m, 4H) 7,40 (d, J=7,17 Hz, 2H) 7,46 (d, J=6.87 in Hz, 2H) 7,53 (d, J=8,24 Hz, 4H) 9,96 (d, J=5,34 Hz, 2H); MS ECI-m/z 890,5.

Example 84

N-(Methoxycarbonyl)-O-methyl-L-threonyl-N-[4-({[4-({1-[(2R)-2-(diethylamino)-2-phenylacetyl]-L-prolyl}amino)benzyl](4-forfinal)amino}methyl)phenyl]-L-prolinamide

The product from Example 81A (0,038 g, 0,054 mmol) and (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butane acid (0,011 g, 0,059 mmol) were processed as in Example 81A, obtaining 0,019 g (40%) specified in the header of soedineniya as not quite white solid. 1H NMR (500 MHz, DMSO-d6) δ memorial plaques to 0.89 (t, J=7,10 Hz, 3H) 1,07 (t, J=7,17 Hz, 2H) of 1.13 (d, J=6,26 Hz, 3H) of 1.28 (t, J=7,25 Hz, 1H) 1,76-of 1.92 (m, 4H) 1,94-2,05 (m, 2H) 2,07-of 2.23 (m, 2H) 2,39 is 2.46 (m, 2H) 2.57 m) 2.63 in (m, 2H) 3,24 (s, 3H) 3,34-of 3.42 (m, 1H) 3,43-to 3.50 (m, 1H) 3,53 (s, 3H) 3,63-3,70 (m, 1H) 3.75 to a 3.87 (m, 2H) 3,97-a 4.03 (m, 1H) 4.26 deaths (t, J=7,78 Hz, 1H) 4,36-to 4.46 (m, 2H) 4,56 (s, 4H) 4,67 (s, 1H) 6,64 (DD, J=9,31, 4,43 Hz, 2H) 6,89-to 6.95 (m, 2H) 7,16-7,22 (m, 4H) 7,28 (t, J=7,17 Hz, 1H) 7,33 (t, J=7,40 Hz, 2H) 7,40 (d, J=7,17 Hz, 1H) 7,49-EUR 7.57 (m, 4H) 7,66-of 7.70 (m, 1H) 9,96 (d, J=7,02 Hz, 2H); MS ECI-m/z 876,5.

Example 85

(2S,2'S)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis{1-[(2R)-2-phenyl-2-pyrrolidin-1-ylacetic]pyrrolidin-2-carboxamide}

The product from Example 13D (0.10 g, 0,19 mmol) and (R)-2-phenyl-2-(pyrrolidin-1-yl)acetic acid (0,088 g, 0.43 mmol) were processed as in Example 25B, obtaining 0,098 g (57%) indicated in the title compound in the form of not-quite-white solid.1H NMR (500 MHz, DMSO - d6) δ memorial plaques of 1.62 (s, 8H) 1,76 is 1.86 (m, 6H) 1,94-to 2.06 (m, 6H) 2,28 is 2.43 (m, 4H) 3,42-to 3.49 (m, 2H) 3,81-to 3.89 (m, 2H) is 4.21 (s, 2H) or 4.31 (DD, J=7,86, 4,20 Hz, 2H) of 4.57 (s, 4H) of 6.65 (DD, J=9,31, 4,43 Hz, 2H) 6,92 (t, J=cent to 8.85 Hz, 2H) 7,19 (d, J=8.54 in Hz, 4H) 7,26-7,37 (m, 6H) 7,46 (d, J=7,02 Hz, 4H) 7,52 (d, J=8.54 in Hz, 4H) 9,96 (s, 2H); MS ECI-m/z 888,6 (M-H)-.

Example 86

Dimethyl {[(4-forfinal)imino]bis[metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl{(1S)-2-oxo-1-[(3R)-tetrahydrofuran-3-yl]ethane-2,1-diyl}]}bicarbonat

The product from Example 13D (0.03 g, 0,058 mmol) and (S)-2-(methoxycarbonylamino-2-((R)-tetrahydrofuran-3-yl)acetic acid (0,026 g, 0,128 mmol) were processed as in Example 25B, obtaining 0,040 g (78%) indicated in the title compound in the form of not-quite-white solid.1H NMR (500 MHz, DMSO - d6) δ M. D. 1,71 (dt, J=20,07, 7,21 Hz, 2H) 1,82-of 1.94 (m, 6H) 1,96-2,05 (m, 2H) 2,10-of 2.21 (m, 2H) 2,37 at 2.45 (m, 2H) 3,41-3,47 (m, 2H) 3,53 (s, 6H) to 3.58-3,70 (m, 6H) 3,71-with 3.79 (m, 2H) 3,85 (DDD, J=to 9.57, of 6.71, 6,60 Hz, 2H) 4,20-4.26 deaths (m, 2H) 4,43 (DD, J=8,16 and 4.65 Hz, 2H) 4,55 (s, 4H) 6,63 (DD, J=9,31, 4,43 Hz, 2H) 6,91 (t, J=8,93 Hz, 2H) 7,17 (d, J=8,70 Hz, 4H) 7,51 (d, J=8.54 in Hz, 4H) to 7.61 (d, J=to 7.93 Hz, 2H) 9,98 (s, 2H); MS ECI - m/z 884 (M-H)-.

Example 87

N-(Methoxycarbonyl)-3-methyl-L-poured-N-[4-({phenyl[4-({1-[(2R)-2-phenyl-2-{[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}acetyl]-L-prolyl}amino)benzyl]amino}methyl)phenyl]-L-prolinamide

The product from Example 77 (20 mg, of 0.025 mmol) was subjected to the procedure described in Example 10B, substituting (R)-2- (dimethylamino)-2-phenylacetic acid for (S)-(-)-2-tetrahydropyrazolo acid (3 μl, 0,031 mmol), to obtain the specified title compound (21 mg, 94%).1H NMR (500 MHz, DMSO-d6) δ memorial plaques to 0.96 (s, 8H), 1,22-of 1.27 (m, 3H), 1,73-to 1.82 (m, 3H), 1,82-1,90 (m, 3H), 1,94-2,03 (m, 2H), 2,09 (s, 2H), 2,69 (s, 3H), of 3.54 (s, 3H), 3,71-of 3.80 (m, 2H), 3,82-to 3.89 (m, 2H), 4,19-of 4.25 (m, 2H), to 4.38 (DD,J=8,5, 3.1 Hz, 1H), of 4.44 (DD,J=8,0, 5.3 Hz, 1H), 4,60 (s, 4H), 5,65 (l,J=7.2 Hz, 1H), 6,57 (t,J=7.2 Hz, 1H), 6,66 (l,J=8,1 Hz, 2H), 7,05-7,11 (m, 3H), 7,18 (DD,J=8,5, and 5.2 Hz, 4H), 7,33 (DD,J=5,7, 3.0 Hz, 1H), 7,37-7,41 (m, 3H), 7,49-7,56 (m, 4H), 8,08 (l,J=7,3 Hz, 1H), 8,31 (s, 1H), 9,88 (s, 1H), 10,00 (s, 1H); MS (ECI) m/z 900,4 (M+H)+ .

Example 88

N-(Methoxycarbonyl)-3-methyl-L-poured-N-[4-({phenyl[4-({1-[(2R)-2-phenyl-2-{[(2R)-tetrahydrofuran-2-ylcarbonyl]amino} acetyl]-L-prolyl}amino)benzyl]amino}methyl)phenyl]-L-prolinamide

The product from Example 77 (20 mg, of 0.025 mmol) was subjected to the procedure described in Example 10B, substituting (R)-2-(dimethylamino)-2-phenylacetic acid for (R)-(+)-2-tetrahydropyrazolo acid (2,6 μl, or 0.027 mmol), to obtain the specified title compound (17 mg, 76%).1H NMR (500 MHz, DMSO-d6) δ memorial plaques to 0.96 (s, 9H), 1,24 (s, 4H), of 1.66 (s, 2H), 1,74 (s, 1H), 1,78 (s, 1H), 1,86 (DD,J=5,6, 2,8 Hz, 3H), 1,99 (s, 2H), 2.06 to (s, 1H), and 2.14 (s, 1H), 2,69 (s, 3H), of 3.54 (s, 3H), 3.72 points-with 3.79 (m, 2H), 3,82 (l,J=7.9 Hz, 2H), 4,21 (l,J=9,0 Hz, 1H), 4,27 (DD,J=8,2, 5,1 Hz, 1H), 4,37 (s, 1H), of 4.44 (s, 1H), 4,60 (s, 4H), 5,64 (l,J=7,0 Hz, 1H), to 6.57 (s, 1H), 6,66 (l,J=8,1 Hz, 2H),? 7.04 baby mortality-7,10 (m, 3H), 7,18 (DD,J=to 8.5, 5.0 Hz, 4H), 7,37-7,40 (m, 3H), 7,49-of 7.55 (m, 4H), 8,14 (l,J=7,0 Hz, 1H), 9,90 (s, 1H), 10,00 (s, 1H); MS (ECI) m/z 900,5 (M+H)+.

Example 89

(2S,2'S)-N,N'-{[(3,4-Differenl)imino]bis(metandienon-4,1-diyl)}bis{1-[(2R)-2-(diethylamino)-2-phenylacetyl]pyrrolidin-2-carboxamide}

Example 89A

3,4-debtor-Ν,Ν-bis(4-nitrobenzyl)aniline

3,4-Diptiranjan and 4-nitrobenzylamine were processed using the method described in Example 32A, obtaining specified in the connection header. LC/MS Rt 2,15 m/z 400 (M+H)+.

<>

Example 89B

N,N-bis(4-aminobenzyl)-3,4-diptiranjan

The product from Example 89A were processed using the method described in Example 1B, with the receipt specified in the connection header.

Example 89C

2S,2'S)-tert-Butyl 2,2'-(4,4'-(3,4-differentiatiedoel)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)dipyrrole-1-carboxylate

The product of Example 89B were processed using the method described in Example 1C, substituting DMSO in dichloromethane, to obtain specified in the connection header.1H NMR (400 MHz, DMSO) δ 0,89-0,80 (m, 1H), 1.26 in (s, 12H), of 1.39 (s, 6H), 1.93 and-of 1.74 (m, 6H), 2,23-of 2.08 (m, 2H), 3,41 (m,J=9,6, 8,9, 6,4, 3H), 4,17 (DD,J=8,0, 4,4, 1H), 4,24 (DD,J=8,1, 2,6, 1H), 4,60 (s, 4H), 6,41 (l,J=9,4, 1H), 6,68-6,55 (m, 1H), 7,11 (DD,J=19,7, 9,7, 1H), 7,18 (l,J=8,0, 4H), 7,54 (e,J=8,5, 4H), 9,94 (s, 2H), MS (ECI)m/z734 (M+H)+, 732 (M-H)+.

Example 89D

(2S,2'S)-N,N'-(4,4'-(3,4-differentiatiedoel)bis(methylene)bis(4,1-phenylene))dipyrrole-2-carboxamide

The product from Example 89C were processed using the method described in Example 1D, obtaining specified in the connection header. MS (ESI) m/z 534 (M+H+, 60%), 532 (M-H)+.

Example 89E

(2S,2'S)-N,N'-{[(3,4-differenl)imino]bis(metandienon-4,1-diyl)}bis{1-[(2R)-2-(diethylamino)-2-phenylacetyl]pyrrolidin-2-carbox the MFA}

The product from Example 89D were processed using the method described in Example 12, replacing DMSO in dichloromethane, to obtain specified in the connection header (68,5 mg, 52%).1H NMR (500 MHz, DMSO) δ 0.95 to-0,83 (m, 14H), 1,23 (s, 2H), is 1.81 (m, 5H), 2,10 is 1.91 (m, 5H), 2,61 (dt,J=14,1, 3,5, 3H), 3,84-to 3.73 (m, 2H), 4,39 (DD,J=8,2, 4,5, 2H), 4,60 (s, 4H), and 4.68 (s, 2H), 6,46-6,36 (m, 1H), only 6.64 (DDD,J=17,5, 6,8, 3,0, 1H), 7,16-7,06 (m, 2H), 7,19 (l,J=8,6, 4H), 7,30-7,25 (m, 2H), 7,33 (t,J=7,4, 4H), 7,40 (l,J=7,1, 4H), 7,54 (e,J=8,5, 4H), 9,98 (s, 2H), MS (ECI)m/z912 (M+H+, 40%) 457 (0.5 M+H+, 100%), 910 (M-H)+.

Example 90

Dimethyl ([(3,4-differenl)imino]bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]})bicarbonate

The product from Example 89D were processed using the method described in Example 6, replacing DMSO in dichloromethane, and purified using flash chromatography (silica gel, MeOH/dichloromethane) to obtain the specified title compound (0.14 g, 35%).1H NMR (500 MHz, DMSO) δ of 0.96 (s, 18H), 1,93 is 1.75 (m, 4H), 2.05 is-of 1.93 (m, 2H), 2,22-of 2.08 (m, 2H), 3,54 (s, 6H), 3,63 (DD,J=16,0, 6,8, 2H), 3,84-3,71 (m, 2H), 4,21 (l,J=8,9, 2H), of 4.44 (DD,J=7,9, 5,3, 2H), 4,58 (s, 4H), 6,40 (l,J=9,1, 1H), 6,62 (DDD,J=14,5, 6,8, 3,0, 1H), 7,10 (m, 3H), 7,17 (l,J=8,5, 4H), 7,52 (d,J=8,5, 4H), 10,00 (s, 2H), MS (ECI)m/z876 (M+H)+, 874 (M-H)+.

Example 91

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrole the in-2,1-diyl[(2S)-1-oxo-4-phenylbutane-1,2-diyl]}]bicarbonate

Example 91A

(S)-2-(methoxycarbonylamino)-4-phenylbutanoate acid

(S)-2-Amino-4-phenylbutane acid (0.50 g, 2.8 mmol) suspended in 1M solution of Na2CO3(of 8.4 ml, 8.4 mmol) and then added to the solution of methylchloroform (0,32 ml, 4.2 mmol) in THF (4.0 ml) and the mixture vigorously stirred at room temperature for 4 hours. The mixture was then concentrated under reduced pressure, and the residue was dissolved in water and made acidic by means of 0.1 n HCl solution. The mixture was extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain specified in the title compound (0.64 g, 97% yield).

Example 91B

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-1-oxo-4-phenylbutane-1,2-diyl]}]bicarbonate

Specified in the title compound was obtained using the methods of Example 2, substituting (R)-2-(dimethylamino)-2-phenylacetic acid the product from Example 91A, obtaining specified in the title compound (103 mg, 55% yield).1H NMR (500 MHz, DMSO) δ becomes 9.97 (s, 2H), 7,53-7,46 (m, 6H), 7,31-7,26 (m, 4H), 7.23 percent (l,J=7,0, 4H), 7,18 (t,J=of 7.3, 2H), 7,15 (l,J=8,6, 4H), 7,05 (DD,J=7,3, to 8.7, 2H), only 6.64 (d,J=8,1, 2H), 6,56 (t,J=7,2, 1H), 4,58 (s, 4H), 4,42 (DD,J=from 4.5 to 8.3, 2H), 4,22 (DD,J=8,1, 13,5, 2H), 3,61-of 3.54 (m, 2H), 3,54 (s, 6H), 3,45-3,37 (m, 2H), 2,73-to 2.57 (m, 4H), 2,18-to 2.06 (m, 2H), 1,99-of 1.74 (m, 10H), M is (ECI; M+H) m/z=937.

Example 92

(2S,2'S)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis{1-[(2R)-2-phenyl-2-piperidine-1-ylacetic]pyrrolidin-2-carboxamide}

Example 92A

(R)-tert-butyl 2-phenyl-2-(piperidine-1-yl)acetate

To a suspension of (R)-tert-butyl 2-amino-2-phenylacetate HCL (Chem-Impex, 0,200 g, 0,821 mmol), MP-cyanoborohydride (2,44 mmol/g; 500 mg) and acetic acid (0,141 ml, 2,462 mmol) in MeOH (2.00 ml) and CH2Cl2(2 ml) at room temperature was added glutaraldehyde (0,155 ml, 0,821 mmol) in 50% solution in water. The reaction mixture was stirred for 30 minutes, the reaction mixture was filtered, washed using MeOH and concentrated. The residue was transferred into a CH2Cl2off , washed with a saturated solution of NaHCO3, dried (Na2SO4) and concentrated to obtain specified in the connection header. MS (DCI; (M+H) m/z=276.

Example 92B

(R)-2-phenyl-2-(piperidine-1-yl)acetic acid

The product from Example 92A were processed using TFOC (1.5 ml) at room temperature for 3 hours. Volatile components were removed under vacuum, the residue was concentrated from toluene (×2) and dried in a vacuum oven to obtain specified in the title compound, which was used without further purification. MS (DCI; (M+H) m/z=220.

Example 92C

(2S,2'S)-N,N'-{[(4-forfinal)imino]bis(metandienon-4,1-diyl)}bis{1-[(2R)-2-phenyl-2-piperidine-1-ylacetic]pyrrolidin-2-carboxamide}

The product from Example 13D and the product from Example 92B were processed using the method described in Example 41, to obtain 30 mg (11%) specified in the connection header.1H NMR (500 MHz, methanol-D4) δ 1,40-1,45 (m, 4H) 1,50 is 1.58 (m, 8H) 1,79-of 1.88 (m, 2H) 1,92-2,02 (m, 2H) 2,05 with 2.14 (m, 4H) 2,30-to 2.40 (m, 4H) 2,35-2,48 (m, 4H) 3,43-3,51 (m, 2H) a 3.87-3,93 (m, 2H) to 4.15 (m, 2H) was 4.42 (DD, J=7,78, 4,43 Hz, 2H) of 4.54 (s, 4H) 6,69 to 6.75 (m, 2H) for 6.81-to 6.88 (m, 2H) 7,17-of 7.23 (m, 4H) 7,30-7,38 (m, 8H) 7,46-7,53 (m, 8H).

Example 93

Methyl [(1S)-1-{[(4R)-4-{[4-({[4-({[(4R)-3-{(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanol}-5,5-dimethyl-1,3-thiazolidin-4-yl]carbonyl}amino)benzyl](phenyl)amino}methyl)phenyl]carbarnoyl}-5,5-dimethyl-1,3-thiazolidin-3-yl]carbonyl}-2.2-dimethylpropyl]carbamate

Example 93A

(4R,4'R)-tert-butyl 4,4'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(5,5-dimethylthiazolidine-3-carboxylate)

Specified in the title compound was obtained using the methods from Example 1C, substituting N-(tert-butoxycarbonyl)-L-Proline (R)-3-(tert-butoxycarbonyl)-5,5-dimethylthiazolidine-4-carboxylic acid, to obtain the specified title compound (0.32 g, 61% yield).

Example 93B

(4R,4'R)-N,N'-(4,4'-(phenyl is anevil)bis(methylene)bis(4,1-phenylene))bis(5,5-dimethylthiazolidine-4-carboxamide)

Specified in the title compound was obtained using the methods from Example 1D, substituting the product from Example 1C for the product from Example 93A, obtaining specified in the connection header (0,23 g, 97% yield).

Example 93C

Methyl [(1S)-1-{[(4R)-4-{[4-({[4-({[(4R)-3-{(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanol}-5,5-dimethyl-1,3-thiazolidin-4-yl]carbonyl}amino)benzyl](phenyl)amino}methyl)phenyl]carbarnoyl}-5,5-dimethyl-1,3-thiazolidin-3-yl]carbonyl}-2.2-dimethylpropyl]carbamate

Specified in the title compound was obtained using the methods of Example 13E, substituting the product from Example 13D product from Example 93B, obtaining specified in the connection header.1H NMR (500 MHz, DMSO) δ 10,02 (s, 2H), 7,51 (l,J=8,6, 4H), 7,28 (l,J=8,1, 2H), 7,19 (l,J=8,6, 4H), was 7.08 (DD,J=7,3, to 8.7, 2H), 6,66 (l,J=8,1, 2H), 6,57 (t,J=7,2, 1H), 5,07 (l,J=the 8.6, 2H), 4,85 (l,J=the 8.6, 2H), 4,65-4,56 (m, 6H), 4,22 (l,J=8,0, 2H), 3,55 (s, 6H), of 1.50 (s, 6H), of 1.36 (s, 6H), of 0.97 (s, 18H); MS (ECI; M+H) m/z=933.

Example 94

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba[(2S,4S)-4-ftorpirimidinu-2.1-diyl][(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]}]bicarbonate

Example 94A

(3S,3'S,5S,5'S)-tert-butyl 5,5'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(3-ftorpirimidinu-1-carboxylate)

Specified in the title compound was obtained with use is by way of Example 1C, substituting N-(tert-butoxycarbonyl)-L-Proline (2S,4S)-1-(tert-butoxycarbonyl)-4-ftorpirimidinu-2-carboxylic acid, to obtain specified in the connection header (0,42 g, 87% yield).

Example 94B

(2S,2'S,4S,4'S)-N,N'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene))bis(4-ftorpirimidinu-2-carboxamide)

Specified in the title compound was obtained using the methods from Example 1D, substituting the product from Example 1C for the product from Example 94A, obtaining specified in the connection header (0,29 g, 93% yield).

Example 94C

Dimethyl [(phenylimino)bis{metandienon-4,1-Vilcabamba[(2S,4S)-4-ftorpirimidinu-2.1-diyl][(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]}]bicarbonate

Specified in the title compound was obtained using the methods of Example 13E, substituting the product from Example 13D of the product of Example 94B, obtaining specified in the title compound (89 mg, 57% yield).1H NMR (500 MHz, DMSO) δ 9,88 (s, 2H), 7,49 (l,J=to 8.5, 4H), 7,22-7,14 (m, 6H), 7,06 (DD,J=7,3, to 8.7, 2H), 6,65 (l,J=8,1, 2H), 6,56 (t,J=7,2, 1H), are 5.36 (d,J=53,5, 2H) and 4.65 (DD,J=2,1, 10,0, 2H), 4,59 (s, 4H), 4.16 the (l,J=of 8.7, 2H), 4,12-Android 4.04 (m, 1H), 4.04 the-3,86 (m, 3H), of 3.54 (s, 6H), 2,29-2,19 (m, 2H), and 0.98 (s, 18H); MS (ECI; M+H) m/z=877.

Example 95

N,N-bis[(2-{(2S)-1-[(2R)-2-(Diethylamino)-2-phenylacetyl]pyrrolidin-2-yl}-1H-benzimidazole-5-yl)methyl]-4-ftoranila

Note the R 95A

(S)-tert-butyl 2-(5-formyl-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-carboxylate

The product of Example 7B (1.0 g, 3,15 mmol) and MnO2(of 1.37 g of 15.75 mmol) in tetrahydrofuran (20 ml) was heated to boiling point under reflux for 24 hours. The mixture was filtered and concentrated to obtain specified in the connection header (0,99 g, 100%). MS (ESI) m/z 316 (M+H)+.

Example 95B

(S)-tert-butyl 2-(5-((4-forgenerating)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-carboxylate

To a mixture of the product from Example 95A (1.0 g, 3,17 mmol), 4-foronline (304 μl, 3,17 mmol) and AcOH (150 μl) in MeOH (30 ml) was added cyanoborohydride sodium (199 mg, 3,17 mmol). The mixture was stirred at room temperature over night and then put water 1 N. HCl solution with subsequent stirring for 5 minutes. Added a few drops of aqueous solution of NH4OH and the mixture was diluted using EtOAc and washed with saturated aqueous NaHCO3H2O and saturated salt solution. The organic layer was dried (MgSO4), filtered and concentrated to obtain specified in the title compound (1.3 g, 100%). MS (ESI) m/z 411 (M+H)+.

Example 95C

(2S,2'S)-tert-butyl 2,2'-(5,5'-(4-ftorhinolonovy)bis(methylene)bis(1H-benzo[d]imidazole-5,2-diyl))dipyrrole-1-carboxylate

The product of Example 95B (1.29 g, 3.14 mmol), PR is a measure 7C (1.2 g, 3.14 mmol) and K2CO3(1.3 g, 9.43 mmol) in dimethylformamide (25 ml) were processed using the method described in Example 7D, obtaining specified in the title compound (1.3 g, 58%). MS (ESI) m/z 710 (M+H)+.

Example 95D

4-fluoro-N,N-bis((2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)methyl)aniline

The product of Example 95C (1.3 g, to 1.83 mmol) were processed using the method described in Example 7E, obtaining specified in the connection header (0,46 g, 50%). MS (ESI) m/z 510 (M+H)+.

Example 95E

N,N-bis[(2-{(2S)-1-[(2R)-2-(diethylamino)-2-phenylacetyl]pyrrolidin-2-yl}-1H-benzimidazole-5-yl)methyl]-4-ftoranila

The product from Example 95D (20 mg, 0,039 mmol) was subjected to the procedure described in Example 7F, substituting (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid the hydrochloride of (R)-2-(diethylamino)-2-phenylacetic acid (23.9 mg, 0,098 mmol), to obtain specified in the connection header in the form of a salt TFOC (8.5 mg).1H NMR (500 MHz, DMSO-d6) δ M. D. 0,76 (t,J=7,0 Hz, 1H), 0,99 (t,J=7,0 Hz, 2H), 1,07 is 1.16 (m, 11H), to 1.22 to 1.31 (m, 4H), 1.91 a (s, 3H), 1,99-of 2.08 (m, 5H), 2,17 was 2.25 (m, 3H), 3,05 is 3.15 (m, 10H), 4,11-4,18 (m, 2H), a 4.83 (s, 3H), to 5.21 (DD,J=to 8.5, 2.7 Hz, 2H), of 5.45 (s, 2H), 6,68-6,77 (m, 2H), 6,93 (t,J=a 8.9 Hz, 2H), 7,27 (l,J=8,2 Hz, 2H), 7,47 (s, 2H), 7,52-to 7.61 (m, 8H), 7,63-of 7.70 (m, 4H); MS (ECI) m/z 888,6 (M+H)+.

Example 96

Methyl [(1S)-1-{[(2S)-2-(5-{[(4-forfinal)({2-[(2S)-1-{(2S)-2-[(methods is dicarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazole-5-yl}methyl)amino]methyl}-1H-benzimidazole-2-yl)pyrrolidin-1-yl]carbonyl}-2-methylpropyl]carbamate

The product from Example 95D (20 mg, 0,039 mmol) was subjected to the procedure described in Example 7F, substituting (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid to (S)-2-(methoxycarbonylamino)-3-methylbutanoyl acid (17,2 mg, 0,098 mmol), to obtain specified in the connection header in the form of a salt TFOC (8 mg).1H NMR (500 MHz, DMSO-d6) δ M. D. 0,75-0,84 (m, 11H), 1,20 of 1.28 (m, 2H), 1,97 (DD,J=13,8 that 6.8 Hz, 3H), 2.05 is with 2.14 (m, 4H), to 2.18 (DD,J=11,9, 6.4 Hz, 2H), 3,54 (s, 14H), 3,81-3,90 (m, 4H), 4,12 (t,J=7.9 Hz, 2H), 4,87 (s, 3H), 5,20 (DD,J=7,9, and 5.5 Hz, 2H), 6,69 to 6.75 (m, 2H), 6,94 (t,J=a 8.9 Hz, 2H), 7,33 (l,J=8,4 Hz, 2H), 7,41 (l,J=8,4 Hz, 2H), 7,55 (s, 2H), 7,71 (l,J=8,4 Hz, 2H); MS (ECI) m/z 824,4 (M+H)+.

Example 97

Dimethyl ([(3R)-tetrahydrofuran-3-elimina]bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S,3R)-3-hydroxy-1-oxobutyl-1,2-diyl]})bicarbonate

To a solution of the product from Example 44D (0.05 g, is 0.102 mmol) in DMSO (1.0 ml) at room temperature was added the product from Example 25A (0,040 g, 0,224 mmol), HATU (of 0.085 g, 0,244 mmol) and base Hunya (0,089 ml, 0,509 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated solution of NaHCO3, water and saturated NaCl solution. The organic layer was dried over MgSO4, was filtered and was evaporated. The product was purified using chromatography on silica gel with poluchenierazreshenija in the connection header. 1H NMR (400 MHz, DMSO-d6) δ memorial plaques to 1.14 (d,J=6,40 Hz, 6H) 1,80-2,03 (m, 8H) 2,10-2,22 (m, 2H) 3,33-3,44 (m, 3H) 3,47-of 3.53 (m, 2H) 3,53 (s, 6H) 3,56-to 3.64 (m, 2H) 3,66 of 3.75 (m, 2H) 3,76-a 3.87 (m, 4H) 4,21 (t,J=7,37 Hz, 2H) 4,43 (DD,J=8,29, 4,72 Hz, 2H) to 4.81 (d,J=5,64 Hz, 2H) 7,09 (l,J=of 7.48 Hz, 2H) 7,24 (l,J=8,46 Hz, 4H) 7,52 (d,J=8,46 Hz, 4H) 9,83 (s, 2H), MS (ECI) m/z 810,4 (M+H)+.

Example 98

Dimethyl ([(4-forfinal)imino]bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3-hydroxy-3-methyl-1-oxobutyl-1,2-diyl]})bicarbonate

The product from Example 13D (0.03 g, 0,058 mmol) and (S)-3-hydroxy-2-(methoxycarbonylamino)-3-methylbutanoyl acid (0.025 g, 0,128 mmol) were processed as in Example 25B, obtaining 0,010 g (82%) indicated in the title compound in the form of not-quite-white solid.1H NMR (400 MHz, DMSO - d6) δ memorial plaques to 1.15 (s, 6H) 1,22 (s, 6H) 1,86-to 1.98 (m, 6H) 2,11-of 2.23 (m, 2H) 3,55 (s, 6H) 3,65-3,74 (m, 2H) 3,83-of 3.94 (m, 2H) to 4.38 (d, J=8,67 Hz, 2H) of 4.44-4,51 (m, 2H) 4,56 (s, 4H) 5,09 (s, 2H) 6,63 (DD, J=which 9.22, of 4.45 Hz, 2H) 6,91 (t, J=8,89 Hz, 2H) 7,11-7,21 (m, 6H) 7,52 (d, J=8,46 Hz, 4H) to 9.66 (s, 2H); MS ECI+m/z 862 (M+H)+; m/z 879 (M+NH4)+.

Example 99

3-Hydroxy-N-(methoxycarbonyl)-L-poured-N-[4-({(4-forfinal)[(2-{(2S)-1-[3-hydroxy-N-(methoxycarbonyl)-L-valil]pyrrolidin-2-yl}-1H-benzimidazole-5-yl)methyl]amino}methyl)phenyl]-L-prolinamide

Example 99A

(S)-tert-butyl 2-(5-formyl-1H-benzo[d]imidazol-2-yl)pyrrolidin-carboxylat

The product from Example 7B (0.50 g, was 1.58 mmol) was dissolved in tetrahydrofuran (8 ml) was heated to 70°C and treated with manganese dioxide, adding it to the number (0.27 g, 3.5 mmol) every two hours to complete the reaction in a total amount of 10 equivalents. The solution was filtered through celite and concentrated to dryness to obtain specified in the connection header.

Example 99B

(S)-tert-butyl 2-(5-((4-forgenerating)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-carboxylate

The product from Example 99A (0.50 g, to 1.59 mmol), 4-ftoranila (0.15 g, to 1.59 mmol) and acetic acid (0,09 ml of 1.59 mmol) were combined at ambient temperature in methanol (15 ml) and treated with cyanoborohydride sodium (0.10 g, to 1.59 mmol) and stirred 17 hours. The mixture was poured into ice water, extracted into ethyl acetate, dried over sodium sulfate, filtered and concentrated to obtain 0.65 g (100%) specified in the connection header.

Example 99C

(S)-tert-butyl 2-(5-(((4-forfinal)(4-nitrobenzyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-carboxylate

The product from Example 99B (0.65 g, was 1.58 mmol), 1-(methyl bromide)-4-nitrobenzene (0,479 g, 2.22 mmol) and potassium carbonate (0,547 g of 3.96 mmol) were combined in dimethylformamide (15 ml) and heated at 40°C for 3 hours, then was diluted with water and filtered. The product was purified in the column on the combi-flash with 24 g of silicon dioxide, elwira mixture of 0-5% methanol in dichloromethane, to obtain the 0,805 g (93%) specified in the connection header.

Example 99D

(S)-tert-butyl 2-(5-(((4-aminobenzyl)(4-forfinal)amino)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-carboxylate

The product from Example 99C (0,67 g of 1.23 mmol) was dissolved in ethanol (15 ml) and cooled in an ice bath. Added trichloride bismuth (0,245 ml, 3,68 mmol) and formed a suspension, to which portions was added sodium borohydride (0,743 g of 19.7 mmol), which led to the formation of a black precipitate. This mixture was stirred at ambient temperature for 20 minutes, then cooled and extinguished by methanol (2 ml) was stirred for 10 minutes before filtering through celite. The filtered substance was concentrated to obtain specified in the connection header.

Example 99E

(R)-(9H-fluoren-9-yl)methyl 2-(4-((((2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)methyl)(4-forfinal)amino)methyl)phenylcarbamoyl)pyrrolidin-1-carboxylate

The product from Example 99D (0,251 g, 0.75 mmol), FMOC-PRO-OH (0.32 g, 0,621 mmol) and diisopropylethylamine (with 0.27 ml, 1.55 mmol) were combined in dimethyl sulfoxide (8 ml) at ambient temperature and were processed using HATU (0.26 g, 0,683 mmol). The solution was stirred for 40 minutes, then was diluted with water, filter the Wali and was purified on a column of combi-flash with 24 g of silicon dioxide, elwira mixture of 0-5% methanol in dichloromethane, to obtain 0,38 g (55%) specified in the connection header.

Example 99F

(R)-(9H-fluoren-9-yl)methyl 2-(4-(((4-forfinal)((2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)methyl)amino)methyl)phenylcarbamoyl)pyrrolidin-1-carboxylate

The product from Example 99E (0,38 g, 0,455 mmol) was dissolved in dichloromethane (4 ml) and were processed using triperoxonane acid (3 ml) at ambient temperature for 3 hours, then concentrated to dryness, transferred into ethyl acetate and washed with a solution of sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated to obtain 0,092 g (28%) specified in the connection header.

Example 99G

(R)-(9H-fluoren-9-yl)methyl 2-(4-(((4-forfinal)((2-((S)-1-((S)-3-hydroxy-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)methyl)amino)methyl)phenylcarbamoyl)pyrrolidin-1-carboxylate

The product from Example 99F (0,092 g, 0.125 mmol), (S)-3-hydroxy-2-(methoxycarbonylamino)-3-methylbutanoyl acid (0,029 g, 0.15 mmol) was treated as in Example 99E, obtaining 0,115 g (100%) specified in the connection header.

Example 99H

Methyl (S)-1-((S)-2-(5-(((4-forfinal)(4-((R)-pyrrolidin-2-carboxamido)benzyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)pyrrol the DIN-1-yl)-3-hydroxy-3-methyl-1-oxobutyl-2-ylcarbamate

The product from Example 99G (0,115 g to 0.127 mmol) was dissolved in acetonitrile (2 ml) at ambient temperature and treated with diethylamine (1 ml) for 1 hour. The solution was concentrated to dryness to obtain the crude specified in the connection header.

Example 99I

3-hydroxy-N-(methoxycarbonyl)-L-poured-N-[4-({(4-forfinal)[(2-{(2S)-1-[3-hydroxy-N-(methoxycarbonyl)-L-valil]pyrrolidin-2-yl}-1H-benzimidazole-5-yl)methyl]amino}methyl)phenyl]-L-prolinamide

The product from Example 99H (0,087 g to 0.127 mmol) were processed as in Example 99G, obtaining 0,048 g (44%) not quite white solid.1H NMR (400 MHz, DMSO-d6) δ memorial plaques of 1.06 (d, J=7,05 Hz, 3H) to 1.15 (s, 3H) 1,17 (s, 3H) of 1.23 (s, 3H) 1,87-2,05 (m, 6H) 2,13-of 2.20 (m, 1H) 2,23-of 2.30 (m, 1H) 3,55 (s, 6H) of 3.69 (DDD, J=16,13, 8,00, 7,86 Hz, 2H) 3,84-to 3.92 (m, 1H) 4,08-to 4.15 (m, 1H) and 4.40 (DD, J=14,42, 8,78 Hz, 2H) 4,47 (DD, J=8,35, to 3.36 Hz, 1H) 4,59 (d, J=2,93 Hz, 2H) 4,70 (d, J=8,67 Hz, 2H) 5,09 (d, J=2,49 Hz, 1H) 5,22 is 5.28 (m, 1H) of 5.84 (d, J=5,64 Hz, 1H) 6,64-6,70 (m, 2H) 6,90 (TD, J=8,84, of 4.77 Hz, 2H) 7,03-to 7.09 (m, 2H) 7,14 (d, J=8,67 Hz, 1H) 7,19 (d, J=to 7.59 Hz, 2H) 7,30 (d, J=to 20.28 Hz, 1H) 7,39 (DD, J=11,66, 8,29 Hz, 1H) 7,52 (DD, J=8,51, of 1.57 Hz, 2H) 9,67 (d, J=2,39 Hz, 1H) 12,11 (d, J=13,34 Hz, 1H); MS ECI+m/z 859 (M+H)+.

Example 100

Methyl [(1S)-1-{[(2S)-2-{[4-({(4-forfinal)[4-({[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanol}azetidin-2-yl]carbonyl}amino)benzyl]amino}methyl)phenyl]carbarnoyl}azetidin-1-yl]carbonyl}-2,2-dimethylpropyl]carbamate

Example 100

(2S,2'S)-tert-butyl 2,2'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)diazetidine-1-carboxylate

The product of Example 13B and (S)-N-Boc-azetidinone acid were processed using the method described in Example 1C, substituting DMSO in dichloromethane, to obtain specified in the connection header. LC/MS Rt 2,04 m/z 688 (M+H)+.

Example 100B

(2S,2'S)-N,N'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene))diazetidine-2-carboxamide

The product from Example 100A were processed using the method described in Example 1D, obtaining specified in the connection header. MS (ESI) m/z 488 (M+H)+, 486 (M-H)+.

Example 100C

Methyl [(1S)-1-{[(2S)-2-{[4-({(4-forfinal)[4-({[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanol}azetidin-2-yl]carbonyl}amino)benzyl]amino}methyl)phenyl]carbarnoyl}azetidin-1-yl]carbonyl}-2,2-dimethylpropyl]carbamate

The product from Example 100B were processed using the method described in Example 13E, obtaining specified in the connection header (93,9 mg, 21%).1H NMR (400 MHz, DMSO) δ of 0.96 (s, 18H), 2,28-2,11 (m, 2H), 2,48-of 2.36 (m, 2H), 3,55 (s, 6H), 3,85 (l,J=8,6, 2H), 4,30-to 4.14 (m, 4H), of 4.57 (s, 4H), 4,79 (DD,J=8,9, 5,7, 2H), only 6.64 (DD,J=9,2, 4,4, 2H), 6,91 (t,J=8,9, 2H), 7,20 (m,J=7,9, 6H), 7,53 (l,J=8,4, 4H), of 10.05 (s, 2H), MS (ECI) m/z 830 (M+H)+, 828 (M-H)+.

Example 101

Methyl[(1)-1-{[(2S)-2-{[4-({(4-forfinal)[4-({[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanol}piperidine-2-yl]carbonyl}amino)benzyl]amino}methyl)phenyl]carbarnoyl}-piperidine-1-yl]carbonyl}-2,2-dimethylpropyl]carbamate

Example 101A

(2S,2'S)-tert-butyl 2,2'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)piperidin-1-carboxylate

The product from Example 13B and Boc-L-pipecolinic acid were processed using the method described in Example 1C, substituting DMSO in dichloromethane, to obtain specified in the connection header. LC/MS Rt 2,31 m/z 744 (M+H)+.

Example 101B

(2S,2'S)-N,N'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene))piperidin-2-carboxamide

The product from Example 101A were processed using the method described in Example 1D, obtaining specified in the connection header. MS (DCI) m/z 544 (M+H)+.

Example 101C

Methyl [(1S)-1-{[(2S)-2-{[4-({(4-forfinal)[4-({[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanol}piperidine-2-yl]carbonyl}amino)benzyl]amino}methyl)phenyl]carbarnoyl}-piperidine-1-yl]carbonyl}-2,2-dimethylpropyl]carbamate

The product from Example 101B were processed using the method described in Example 13E, substituting DMF in dichloromethane, to obtain specified in the connection header (0,23 g, 57%).1H NMR (400 MHz, DMSO) δ of 0.95 (s, 13H), 0,97 (l,J=10,6, 5H), 1,80-a 1.08 (m, 12H), 2,10 (l,J=13,1, ,51H), and 2.27 (d,J=10,5, 0.5 H), of 3.54 (s, 6H), is 4.03 (d,J=12,2, 1H), of 4.44 (DD,J=12,9, and 6.5, 1H), 4,56 (l,J=5,9, 6H), 5,10 (s, 0.5 H), 5,20 (s, 1.5 H), only 6.64 (DD,J=9,1, 4,4, 2H), 6,91 (t,J=8,9, 2H), 7,05 (l, =9,1, 1H), 7,20 (DD,J=18,9, 9,9, 5H), 7,50 (d,J=8,5, 3H), 7,60 (l,J=8,3, 1H), 9,83 (s, 0.5 H), 9,88 (s, 1.5 H), MS (ECI)m/z886 (M+H+, 20%) 944 (M+CH3CN+NH4, 100%), 884 (M-H)+.

Example 102

(2S,4R,2'S,4'R)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis{4-fluoro-1-[(2R)-2-phenyl-2-piperidine-1-ylacetic]pyrrolidin-2-carboxamide}

Example 102 A

(3R,3'R,5S,5'S)-tert-butyl 5,5'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(3-ftorpirimidinu-1-carboxylate)

The product from Example 13D and (2S,4R)-1-(tert-butoxycarbonyl)-4-ftorpirimidinu-2-carboxylic acid (Aldrich) were processed using the method described in Example 41, with the receipt of 1.05 g (90%) specified in the connection header. MS (DCI; (M+H) m/z=752.

Example 102B

(2S,2'S,4R,4'R)-N,N'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene))bis(4-ftorpirimidinu-2-carboxamide)

The product from Example 102A were processed using the method described in Example 47B, to obtain 540 mg (70%) specified in the connection header. MS (ESI, M+H) m/z=552.

Example 102

(2S,4R,2'S,4'R)-N,N'-{[(4-forfinal)imino]bis(metandienon-4,1-diyl)}bis{4-fluoro-1-[(2R)-2-phenyl-2-piperidine-1-ylacetic]pyrrolidin-2-carboxamide}

The product of Example 102B and the product from Example 92B were processed using the method described in Example 41, the receiving 25 mg (8%) specified in the connection header. 1H NMR (400 MHz, methanol-D4) δ 1,45-1,55 (m, 4H) 1,58 is 1.70 (m, 8H) 2,09-of 2.27 (m, 2H) 2,39-2,90 (m, 10H) 3.75 to Android 4.04 (m, 4H) 4,22-4,70 (m, 4H) 4,55 (s, 4H) 5,22 (s, 1H) to 5.35 (s, 1H) 6,69-6,76 (m, 2H) for 6.81-6.89 in (m, 2H) 7,22 (d, J=8,46 Hz, 4H) 7,42 (s, 6H) 7,50 (d, J=8,46 Hz, 4H) rate of 7.54 (d,J=4,23 Hz, 4H).

Example 103

Dimethyl ([(4-forfinal)imino]bis{metandienon-4,1-Vilcabamba[(2S,4R)-4-ftorpirimidinu-2.1-diyl][(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]})bicarbonate

Example 103A

(3S,3'S,5S,5'S)-tert-butyl 5,5'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(3-ftorpirimidinu-1-carboxylate)

Specified in the title compound was obtained using the methods from Example 13C, substituting N-(tert-butoxycarbonyl)-L-Proline (2S,4R)-1-(tert-butoxycarbonyl)-4-ftorpirimidinu-2-carboxylic acid, to obtain specified in the connection header (to 0.29 g, 83% yield).

Example 103B

(2S,2'S,4S,4'S)-N,N'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene))bis(4-ftorpirimidinu-2-carboxamide)

Specified in the title compound was obtained using the methods from Example 13D substituting the product from Example 13C to the product from Example 103A, obtaining specified in the connection header.

Example 103C

Dimethyl ([(4-forfinal)imino]bis{metandienon-4,1-Vilcabamba[(2S,4R)-4-ftorpirimidinu-2.1-diyl][(2S)-3,3-dimethyl-1-oxo is utan-1,2-diyl]})bicarbonate

Specified in the title compound was obtained using the methods of Example 13E, substituting the product from Example 13D of the product of Example 103B, obtaining specified in the title compound (89 mg, 57% yield).1H NMR (400 MHz, DMSO) δ 10,11 (Shir. s, 2H), 7,51 (l,J=to 8.5, 4H), 7,21-to 7.15 (m, 6H), 6,91 (t,J=8,9, 2H), only 6.64 (DD,J=4,4, 9,1, 2H), 5,46 (Shir. s, 1H), 5,32 (Shir. s, 1H), 4,57-4,48 (m, 6H), 4,20-4,06 (m, 4H), 3,88-3,71 (m, 2H), 3,54 (s, 6H), 3,17 (l,J=5,2, 2H), 2.21 are of 1.97 (m, 2H), of 0.96 (s, 18H); MS (ECI; M+H) m/z=895.

Example 104

Dimethyl ([(4-forfinal)imino]bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(1S)-1-cyclohexyl-2-oxetan-2.1-diyl]})bicarbonate

The product from Example 13D and (S)-2-cyclohexyl-2-(methoxycarbonylamino)acetic acid were processed using the method described in Example 13E, substituting DMF in dichloromethane, to obtain specified in the connection header (74,4 mg, 16%).1H NMR (400 MHz, DMSO) δ 1,29-0,83 (m, 10H), was 1.69 (DD, J=14,2, 61,5, 12H), 1.93 and-is 1.81 (m, 4H), 2.06 to of 1.93 (m, 2H), 2,19-to 2.06 (m, 2H), 3,51 (s, 6H), 3,66-3,55 (m, 2H), 3,88-to 3.73 (m, 2H), 4,07 (t, J=8,6, 2H), to 4.41 (DD, J=4,8, 8,1, 2H), 4,55 (s, 4H), 6,69-6,56 (m, 2H), 6,97-6,83 (m, 2H), 7,17 (d, J=8,5, 4H), 7,30 (d, J=8,4, 2H), 7,50 (d, J=8,5, 4H), 9,96 (s, 2H), MS (ECI) m/z 910 (M+H)+, 908 (M-H)+.

Example 105

(2S,2'S)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis[1-(3-ethyl-3-hydroxy-2-phenylpentane)pyrrolidin-2-carboxamid]

The product from Example 13D (30 mg, 0,058 mmol) machining the RGALI procedure, described in Example 24E, substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoyl acid 3-ethyl-3-hydroxy-2-phenylpentane acid (27 mg, 0,122 mmol), to obtain specified in the connection header in the form of a salt TFOC (11 mg).1H NMR (400 MHz, DMSO-d6) δ M. D. 0,66-0,74 (m, 7H), 0,84 (t,J=7,4 Hz, 6H), 1.00 m (e,J=7.9 Hz, 4H), 1,52-to 1.63 (m, 3H), 1,86 (l,J=7,3 Hz, 4H), 2.05 is (l,J=16.6 Hz, 2H), 3,30 (s, 2H), 3,34-of 3.42 (m, 2H), 3,83 (l,J=13.3 Hz, 3H), 4,32-4,39 (m, 1H), 4,50 (s, 1H), 4.53-in-br4.61 (m, 5H), of 6.65 (DDD,J=9,3, 4,9, 4,7 Hz, 2H), 6,88-of 6.96 (m, 3H), 7,14-7,22 (m, 4H), 7.24 to 7,33 (m, 7H), 7,39 (l,J=6,7 Hz, 2H), 7,42-to 7.50 (m, 5H), 7,55 (DDD,J=15,8, to 8.6, 2.3 Hz, 3H), 9,94 (s, 1H), 10,00 (s, 1H); MS (ECI) m/z 924,5 (M+H)+.

Example 106

(2S,2'S)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis{1-[(1-hydroxycyclopent)(phenyl)acetyl]pyrrolidin-2-carboxamide}

The product from Example 13D (30 mg, 0,058 mmol) was subjected to the procedure described in Example 24E, substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoyl acid 2-(1-hydroxycyclopent)-2-phenylacetic acid (27 mg, 0,122 mmol), to obtain specified in the connection header in the form of a salt TFOC (13 mg).1H NMR (400 MHz, DMSO-d6) δ memorial plaques of 1.09 (s, 2H), 1,50 (l,J=5,9 Hz, 6H), 1.61 of (s, 4H), 1,67 (l,J=4,7 Hz, 6H), 1.77 in (s, 1H), 1,81-to 1.87 (m, 3H), 1.91 a (s, 1H), 2,02 (s, 1H), 2,07 (s, 1H), 3,14 (s, 1H), 3,22 (l,J=10.0 Hz, 1H), 3,71 (l,J=10.1 Hz, 2H), 3,80 (s, 1H), 3,91 (l,J=to 12.8 Hz, 2H), to 4.38 (DD,J=8,2, a 4.1 Hz, 1H), 4,49 (l,J=3.8 Hz, 1H), 4,57 (l,J=2,9 Hz, 4H), 6,62-6,69 (m,J=4,6, and 2.3 Hz, 2H), 6,92 (t,J=8,8 Hz, 2H), 7,16-7,22 (m, 4H), 7.24 to 7,31 (m, 6H), 7,34-7,37 (m, 2H), 7,47 (DD,J=16,2, 7,6 Hz, 4H), 7,54 (e,J=8,3 Hz, 3H), becomes 9.97 (d,J=1.7 Hz, 2H); MS (ECI) m/z 920,2 (M+H)+.

Example 107

(2S,2'S)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis{1-[cyclopentyl(phenyl)acetyl]pyrrolidin-2-carboxamide}

The product from Example 13D (30 mg, 0,058 mmol) was subjected to the procedure described in Example 24E, substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoyl acid 2-cyclopentyl-2-phenylacetic acid (25 mg, 0,122 mmol), to obtain specified in the connection header in the form of a salt TFOC (12 mg).1H NMR (400 MHz, DMSO-d6) δ memorial plaques of 1.03 (s, 2H), 1,16 (l,J=4,2 Hz, 3H), 1,25 (l,J=13.1 Hz, 3H), 1,38 (l,J=3.3 Hz, 3H), 1,48 is 1.60 (m, 4H), 1,74 (s, 2H), 1,79 (s, 2H), 1,81 is 1.91 (m, 4H), 1,99 (s, 2H), 2,07 (s, 1H), 3,32 (l,J=9.7 Hz, 2H), 3,42 (s, 1H), 3,70 (s, 2H), 3,81 (s, 1H), 4,29 is 4.35 (m, 1H), 4,45 (DD,J=8,2, 3.6 Hz, 1H), to 4.52-to 4.62 (m, 4H), 6,60-6,70 (m, 2H), 6,88-6,98 (m, 2H), 7,14-7,26 (m, 6H), 7,27-7,38 (m, 8H), 7,44 (DD,J=to 8.6, 2.6 Hz, 2H), 7,51-7,56 (m, 2H), 7,58 (DD,J=to 8.6, 2.6 Hz, 1H), 9,88 (s, 1H), to 9.93 (s, 1H); MS (ECI) m/z 888,3 (M+H)+.

Example 108

(2S,2'S)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis[l-(3-methyl-2-phenylbutane)pyrrolidin-2-carboxamid]

The product from Example 13D (30 mg, 0,058 mmol) was subjected to the procedure described in Example 24E, substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoyl acid 3-METI the-2-phenylbutanoate acid (22 mg, 0,122 mmol), to obtain specified in the connection header in the form of a salt TFOC (24 mg).1H NMR (400 MHz, DMSO-d6) δ M. D. 0,41 (DD,J=6,7, 1.5 Hz, 2H), 0,56 (DD,J=6,6, and 4.5 Hz, 4H), 0,75-0,84 (m, 2H), were 0.94 (DD,J=8,4, 6,7 Hz, 4H), of 1.20 (s, 3H), 1,73-of 1.88 (m, 5H), to 1.96 (s, 3H), 2,10-of 2.24 (m, 4H), 3,37 (l,J=10,2 Hz, 2H), 4,27 (l,J=7.7 Hz, 1H), 4,43 (DD,J=8,3, 3,4 Hz, 2H), 4.53-in (DD,J=16,5, 8,3 Hz, 4H), of 6.61 (s, 3H), 6,83-6,93 (m, 3H), 7,08-7,34 (m, 11H), 7,35-7,44 (m, 2H), 7,46-7,53 (m, 2H), 7,53-to 7.59 (m, 1H), 9,84 (s, 1H), 9,92 (s, 1H); MS (ECI) m/z 836,8 (M+H)+.

Example 109

Methyl [(1S)-1-{[{1S,2S,5R)-2-{[4-({(4-forfinal)[4-({[(1S,2S,5R)-3-{(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanol}-3-azabicyclo[3.1.0]Gex-2-yl]carbonyl}amino)benzyl]amino}methyl)phenyl]carbarnoyl}-3-azabicyclo[3.1.0]Gex-3-yl]carbonyl}-2,2-dimethylpropyl]carbamate

Example 109A

(1S,1'S,2S,2'S,5R,5'R)-tert-butyl 2,2'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(3-azabicyclo[3.1.0]hexane-3-carboxylate)

The product from Example 13D and (1S,2S,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (Tensiid) were processed using the method described in Example 41, with getting 685 mg (96%) specified in the connection header. MS (ESI, M+H) m/z=740.

Example 109B

(1S,1'S,2S,2'S,5R,5'R)-N,N'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene))bis(3-azabicyclo[3.1.0]hexane-2-ka is boxlid)

The product from Example 109A were processed using the method described in Example 47B, with the receipt of 458 mg (92%) specified in the connection header. MS (ESI, M+H) m/z=540.

Example 109C

Methyl [(1S)-1-{[(lS,2S,5R)-2-{[4-({(4-forfinal)[4-({[(1S,2S,5R)-3-{(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanol}-3-azabicyclo[3.1.0]Gex-2-yl]carbonyl}amino)benzyl]amino}methyl)phenyl]carbarnoyl}-3-azabicyclo[3.1.0]Gex-3-yl]carbonyl}-2,2-dimethylpropyl]carbamate

The product from Example 109B and (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid were processed using the method described in Example 41, to obtain 237 mg (73%) specified in the connection header.1H NMR (400 MHz, methanol-D4) δ 0,20-0,30 (m, 2H) 0,81-of 0.91 (m, 2H) 0,92-of 1.03 (m, 18H) 1,67-to 1.79 (m, 4H) to 3.64 (s, 6H) and 3.72 (m, 2H) to 3.92 (DD, J=9,81, 4,07 Hz, 2H) 4,03 is 4.13 (m, 2H) is 4.21 (s, 2H) 4,53 (s, 4H) 4.72 in (s, 2H) 6,67-of 6.73 (m, 2H) 6,79-6,86 (m, 2H) 7,20 (d, J=8,46 Hz, 4H) of 7.48 (d, J=8,46 Hz, 4H).

Example 110

(2S,2'S)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis{1-[(2R)-2-hydroxy-2-phenylacetyl]pyrrolidin-2-carboxamide}

The product from Example 13D (0,045 g, 0,087 mmol) and (R)-2-hydroxy-2-phenylacetic acid (0,095 g, 0,192 mmol) were processed as in Example 25B, obtaining specified in the connection header in the form of not-quite-white solid.1H NMR (400 MHz, DMSO-d6) δ M. D. 1,71-of 1.88 (m, 4H) 1,88-to 2.06 (m, 4H) 3,09-3,18 (m, 2H) 3,62-to 3.73 (m, 2H) and 4.40 (DD, J=8,13 at 3.25 Hz, 2H) of 4.57 (s, 4H) of 5.26 (d, J=to 3.58 Hz, 2H) 5.5 (l, J=5,64 Hz, 2H) 6,65 (DD, J=9,27, 4,39 Hz, 2H) 6,92 (t, J=8,89 Hz, 2H) 7,13-of 7.23 (m, 6H) 7,27-7,33 (m, 2H) 7,33-7,42 (m, 6H) 7,53 (d, J=8,57 Hz, 4H) 10,00 (s, 2H); MS ECI - m/z 782 (M-H)-.

Example 111

(2S,2'S)-N,N'-[(Phenylimino)bis(metandienon-4,1-diyl)]bis{1-[(2S)-3,3-dimethyl-2-(pyrimidine-2-ylamino)butanoyl]pyrrolidin-2-carboxamide}

The product of Example 79B (0.05 g, 0,069 mmol) and 2-bromopyrimidine (of 0.066 g, 0,414 mmol) was dissolved in dimethyl sulfoxide (1.5 ml), was treated with diisopropylethylamine (0,072 ml, 0,414 mmol) and was heated at 100°C in a sealed tube in a microwave reactor for 1.5 hours. The solution was poured into ice water, extracted into ethyl acetate, concentrated and purified on a column of combi-flash 12g, elwira mixture of 0-5% methanol in dichloromethane, to obtain the 0,004 grams (7%) specified in the connection header in the form of not-quite-white solid.1H NMR (400 MHz, DMSO-d6) δ memorial plaques was 1.04 (s, 18H) 1,81-of 1.94 (m, 4H) 1,97-2,07 (m, 2H) 2,07-to 2.18 (m, 2H) 3,63-and 3.72 (m, 2H) 3,96-Android 4.04 (m, 2H) and 4.40 (DD, J=7,92, of 5.75 Hz, 2H) 4,59 (s, 4H) and 4.68 (d, J=9,00 Hz, 2H) 6,51 (d, J=9,00 Hz, 2H) to 6.57 (t, J=7,16 Hz, 1H) 6,62 (t, J=4,77 Hz, 2H) 6,66 (d, J=8,13 Hz, 2H)? 7.04 baby mortality-7,11 (m, 2H) 7,17 (d, J=8,57 Hz, 4H) 7,51 (d, J=8,57 Hz, 4H) 8,29 (d, J=4,77 Hz, 4H) 9,98 (s, 2H); MS ECI - m/z 878,6 (M-H)-.

Example 112

Dimethyl ([(4-forfinal)imino]bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-1-oxobutyl-1,2-diyl]})bicarbonate

The product from Example 13D (0,030 g 0,058 mmol) and (S)-2-(methoxy is bonellie)butane acid (0,021 g, 0,128 mmol) were processed as in Example 25B, obtaining specified in the connection header in the form of not-quite-white solid.1H NMR (400 MHz, DMSO-d6) δ memorial plaques of 0.90 (t, J=7,37 Hz, 6H) 1,52 (TD, J=14,07, 6,89 Hz, 2H) 1,65 (TD, J=13,61, is 6.61 Hz, 2H) 1,81-of 1.93 (m, 4H) 1,95-2,05 (m, 2H) 2,08-of 2.20 (m, 2H) 3,52 (s, 6H) 3,56-to 3.67 (m, 2H) 3,68-3,81 (m, 2H) 4,12-to 4.23 (m, 2H) was 4.42 (DD, J=8,02, 4,55 Hz, 2H) 4,55 (s, 4H) 6,63 (DD, J=which 9.22, of 4.45 Hz, 2H) 6,91 (t, J=8,89 Hz, 2H) 7,16 (d, J=8,46 Hz, 4H) 7,30 (d, J=of 7.70 Hz, 2H) 7,50 (d, J=8,46 Hz, 4H) 9,94 (s, 2H); MS ECI - m/z 800 (M-H)-.

Example 113

[(4-Forfinal)imino]bis[metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl(1R)-2-oxo-1-Penilaian-2.1-diyl]diacetate

The product from Example 13D (0,030 g 0,058 mmol) and (R)-2-acetoxy-2-phenylacetic acid (0.025 g, 0,128 mmol) were processed as in Example 25B, obtaining specified in the connection header in the form of not-quite-white solid.1H NMR (400 MHz, DMSO-d6) δ M. D. 1,74 is 2.01 (m, 8H) 2,02-of 2.09 (m, 6H) of 3.07-3.15 in (m, 2H) 3,79-3,88 (m, 2H) to 4.38 (DD, J=7,75, 2,87 Hz, 2H) of 4.57 (s, 4H) 5,98-6,23 (m, 2H) 6,65 (DDD, J=of 9.30, 4,36, 2,49 Hz, 2H) 6,92 (TD, J=8,95, totaling 3.04 Hz, 2H) 7,11-of 7.23 (m, 6H) 7,28 and 7.36 (m, 2H) 7,40-7,47 (m, 6H) of 7.48-7,52 (m, 2H) rate of 7.54 (d, J=to 8.57 Hz, 2H) 9,73-10,02 (m, 2H); MS ECI - m/z 866 (M-H)-.

Example 114

Methyl {(1S)-2-{(2S)-2-[(4-{[(4-forfinal){4-[({(2S)-1-[(2R)-2-phenyl-2-piperidine-1-ylacetic]pyrrolidin-2-yl}carbonyl)amino]benzyl}amino]methyl}phenyl)carbarnoyl]pyrrolidin-1-yl}-2-oxo-1-[(3R)-tetrahydrofuran-3-yl]ethyl}CT the Amat

Example 114A

(S)-tert-butyl 2-(4-(((4-forfinal)(4-((S)-pyrrolidin-2 - carboxamido)benzyl)amino)methyl)phenylcarbamoyl)pyrrolidin-1-carboxylate

The solution from Example 13C (2.25 g, 3.14 mmol) in dichloromethane (20 ml) was treated triperoxonane acid at ambient temperature by adding 1 ml every 30 minutes in a total amount of 4 ml of the Reaction mixture is carefully tracked in order to achieve good distribution of the bis-BOC, mono-Vos and unreacted compounds. The mixture was washed with sodium bicarbonate solution, extracted into dichloromethane, concentrated and purified on a column of combi-flash 40 g silica, with a mixture of 0-40% methanol in dichloromethane to obtain 0,632 g (33%) specified in the connection header containing a single Re-group.

Example 114B

(S)-tert-butyl 2-(4-(((4-forfinal)(4-((S)-1-((R)-2-phenyl-2-(piperidine-1-yl)acetyl)pyrrolidin-2-carboxamido)benzyl)amino)methyl)phenylcarbamoyl)pyrrolidin-1-carboxylate

The product from Example 114A (0.26 g, 0.42 mmol) and (R)-2-phenyl-2-(piperidine-1-yl)acetic acid (0.12 g, 0.55 mmol) was treated as in Example 81A, to obtain 0.20 g (58%) indicated in the title compound as a white solid.

Example 114C

(S)-N-(4-(((4-forfinal)(4-((S)-pyrrolidin-2-carboxamido)benzyl)amino)METI is)phenyl)-1-((R)-2-phenyl-2-(piperidine-1-yl)acetyl)pyrrolidin-2-carboxamide

The product from Example 114B (0.20 g, 0.24 mmol) was dissolved in dichloromethane (3 ml) and treated triperoxonane acid (2 ml) at ambient temperature for 2 hours. The solution was concentrated, was transferred into a 25% solution of isopropanol in chloroform, washed with sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated to obtain 0.16 g (91%) specified in the connection header.

Example 114D

Methyl {(1S)-2-{(2S)-2-[(4-{[(4-forfinal){4-[({(2S)-1-[(2R)-2-phenyl-2-piperidine-1-ylacetic]pyrrolidin-2-yl}carbonyl)amino]benzyl}amino]methyl}phenyl)carbarnoyl]pyrrolidin-1-yl}-2-oxo-1-[(3R)-tetrahydrofuran-3-yl]ethyl}carbamate

The product from Example 114C (0,040 g 0,056 mmol) and (S)-2-(methoxycarbonylamino)-2-((R)-tetrahydrofuran-3-yl)acetic acid (0,014 g 0,067 mmol) were processed as in Example 81A, obtaining specified in the connection header.1H NMR (400 MHz, DMSO-d6) δ M. D. 1,29-to 1.38 (m, 2H) of 1.39 to 1.47 (m, 4H) 1,68-of 1.78 (m, 1H) 1,79-1,90 (m, 4H) 1,93-to 2.06 (m, 4H) 2,10-2,22 (m, 1H) 3,14-of 3.25 (m, 1H) 3,41-to 3.50 (m, 4H) 3,53 (s, 3H) to 3.58-3,70 (m, 4H) 3,71-with 3.79 (m, 2H) 3,80-3,90 (m, 2H) 4,20-to 4.28 (m, 2H) or 4.31 (DD, J=of 7.64, 4,07 Hz, 1H) of 4.44 (DD, J=7,97, is 4.93 Hz, 1H) 4,56 (s, 4H) only 6.64 (DD, J=which 9.22, 4,34 Hz, 2H) 6,91 (t, J=8,95 Hz, 2H) to 7.18 (d, J=8,13 Hz, 4H) 7,25-7,37 (m, 3H) 7,42 (d, J=6,83 Hz, 2H) 7,51 (DD, J=8,57, of 1.84 Hz, 4H) 7,60 (d, J=8,02 Hz, 1H) 9,96 (s, 1H) 9,98 (s, 1H); MS ECI - m/z 900,6 (M-H)-.

Example 115

Methyl [(1S)-1-({(2S)-2-[(4-{[(4-forfinal){4-[({(2S)-1-[(2R)-2-phenyl-2-piperidine-1-ilace the Il]pyrrolidin-2-yl}carbonyl)amino]benzyl}amino]methyl}phenyl)carbarnoyl]pyrrolidin-1-yl}carbonyl)propyl]carbamate

The product from Example 114C (0,040 g 0,056 mmol) and (S)-2- (methoxycarbonylamino)butane acid (0,011 g 0,067 mmol) were processed as in Example 81A, obtaining specified in the connection header.1H NMR (400 MHz, DMSO-d6) δ memorial plaques of 0.90 (t, J=7,37 Hz, 3H) of 1.29 to 1.37 (m, 2H) of 1.39 to 1.47 (m, 4H) 1,47 is 1.58 (m, 1H) 1,61-1,72 (m, 1H) 1,75-to 2.06 (m, 6H) 2,08-of 2.20 (m, 1H) 3,39-to 3.50 (m, 1H) 3,52 (s, 3H) 3,56-to 3.64 (m, 1H) 3,69-of 3.77 (m, 1H) 3,79-3,90 (m, 1H) 4,14-is 4.21 (m, 1H) 4,24 (s, 1H) or 4.31 (DD, J=7,81, to 4.23 Hz, 1H) 4,43 (DD, J=7,92, 4,34 Hz, 1H) 4,56 (s, 4H) only 6.64 (DD, J=9,27, 4,39 Hz, 2H) 6,91 (t, J=8,89 Hz, 2H) 7,17 (DD, J=8,51, 2.55 Hz, 4H) 7,27 was 7.36 (m, 3H) 7,42 (d, J=6,94 Hz, 2H) 7,51 (DD, J=8,51, 3,74 Hz, 4H) 9,95 (d, J=2,93 Hz, 2H); MS ECI - m/z 858,6 (M-H)-.

Example 116

(2S,2'S)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis(1-{[(3R)-3-ftorpirimidinu-1-yl](phenyl)acetyl}pyrrolidin-2-carboxamid)

The product from Example 13D and 2-((R)-3-ftorpirimidinu-1-yl)-2-phenylacetic acid were processed using the method described in Example 13E, substituting DMF in dichloromethane, to obtain a mixture of three stereoisomers. Specified in the title compound of Example 116 was the first isomer, which was swirbul in the chromatography.1H NMR (400 MHz, DMSO) δ 1,90 by 1.68 (m, 6H), 2,15-1,90 (m, 6H), 2,45 to 2.35 (m, 2H), 2,65-of 2.58 (m, 3H), 2,70 (DD, J=4,1, 10,7, 1H), 2,77 (d, J=11,2, 1H), 2,84 (d, J=11,4, 1H), 3.45 points-to 3.34 (m, 2H), 3,90 is 3.76 (m, 2H), 4,36-the 4.29 (m, 2H), to 4.38 (s, 2H), 4,57 (s, 4H), 5,07 (t, J=5,6, 1H), total of 5.21 (t, J=5,6, 1H), 6,70-6,60 (m, 2H), of 6.96-6.87 in (m, 2H), 7,19 (d, J=8,5, 4H), 7,38-7,27 (m, 6H), 7,46 (d, J=6,8, 4H), 7,53 (d, J=8,5, 4H), becomes 9.97 (s, 2H),MS (ECI) m/z 926 (M+H)+, 924 (M-H)+.

Example 117

(2S,2'S)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis(1-{[(3R)-3-ftorpirimidinu-1-yl](phenyl)acetyl}pyrrolidin-2-carboxamid)

Specified in the title compound of Example 117 was isolated from the cleaning product of Example 116 as isomer, which was swirbul second.1H NMR (400 MHz, DMSO) δ 1,91 is 1.70 (m, 7H), 2,14-of 1.93 (m, 6H), 2,46 to 2.35 (m, 3H), 2,66-to 2.57 (m, 2H), 2,88-2,69 (m, 4H), 3,39 (DD, J=8,4, 17,4, 1H), 3,68 (TD, J=5,5, 9,6, 1H), 3,86-of 3.78 (m, 1H), 4,36-4,30 (m, 1H), to 4.38 (s, 1H), 4,46 (DD, J=4,3, and 8.4, 1H), 4,49 (s, 1H), 4,57 (d, J=10,2, 3H), 5,07 (t, J=5,5, 1H), total of 5.21 (t, J=5,3, 1H), 6,65 (dt, J=4,4, 9,2, 2H), 6,92 (TD, J=2,8, 9,1, 2H), 7,26-7,13 (m, 4H), 7,39-7,26 (m, 6H), to 7.59-7,39 (m, 8H), 10,34-9,87 (m, 2H), MS (ECI) m/z926 (M+H)+, 924 (M-H)+.

Example 118

(2S,2'S)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis(1-{[(3R)-3-ftorpirimidinu-1-yl](phenyl)acetyl}pyrrolidin-2-carboxamid)

Specified in the title compound of Example 118 was isolated from the cleaning product of Example 116 as isomer, which was swirbul third.1H NMR (400 MHz, DMSO) δ 1.00 and was 0.77 (m, 8H), 1,94 was 1.69 (m, 6H), 2,15-of 1.94 (m, 6H), 2,87-2,69 (m, 2H), of 3.73-to 3.52 (m, 2H), br4.61-and 4.40 (m, 7H), is 5.06 (t, J=5,5, 1H), total of 5.21 (t, J=5,3, 1H), only 6.64 (dt, J=4,4, 8,9, 2H), 6,91 (TD, J=2,9, 8,9, 2H), 7,60 for 7.12 (m, 19H), 10,31-9,90 (m, 2H), MS (ECI)m/z926 (M+H)+, 924 (M-H)+.

Example 119

(2S,2'S)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis(1-{[(3S)-3-ftorpirimidinu-1-yl](phenyl)acetyl}pyrrole the Jn-2-carboxamide)

The product from Example 13D and 2-((S)-3-ftorpirimidinu-1-yl)-2-phenylacetic acid were processed using the method described in Example 13E, substituting DMF in dichloromethane, to obtain a mixture of stereoisomers. Specified in the title compound of Example 119 was the first isomer, which was swirbul in the chromatography.1H NMR (400 MHz, DMSO) δ 2,15 is 1.70 (m, 13H), 2,66-to 2.57 (m, 2H), 2,81-a 2.71 (m, 3H), 3.43 points-to 3.34 (m, 2H), 3,90-of 3.78 (m, 2H), 4,32 (DD, J=4.2, and is 7.9, 2H), 4,36 (s, 2H), 4,57 (s, 4H), of 5.06 (s, 1H), 5,20 (s, 1H), 6,70-6,60 (m, 2H), 6,97-6,86 (m, 2H), 7,19 (d, J=8,5, 5H), 7,39-7,24 (m, 7H), 7,46 (d, J=6,9, 4H), 7,53 (d, J=8,5, 4H), 9,96 (s, 2H), MS (ECI)m/z925 (M+H)+.

Example 120

(2S,2'S)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis(1-{[(3S)-3-ftorpirimidinu-1-yl](phenyl)acetyl}pyrrolidin-2-carboxamid)

Specified in the title compound of Example 120 was isolated from the cleaning product of Example 119 as isomer, which was swirbul second.1H NMR (400 MHz, DMSO) δ 2,16-to 1.67 (m, 12H), 2,39 (DD, J=11.8 in, 19,9, 2H), 2,65 is 2.55 (m, 2H), 2.91 in-2,70 (m, 4H), 3,44-to 3.33 (m, 2H), 3,66 (dt, J=6,1, 14,0, 1H), 3,92-of 3.78 (m, 1H), 4,32 (DD, J=4.2, and is 7.9, 1H), 4,36 (s, 1H), of 4.45 (DD, J=3,9, 8,2, 1H), 4,49 (s, 1H), 4,57 (d, J=10,0, 4H), of 5.06 (DD, J=3,5, 9,6, 1H), 5.25 to further 5.15 (m, 1H), 6,65 (dt, J=4,4, 9,2, 2H), 6,92 (TD, J=2,9, 9,1, 2H), to 7.59 for 7.12 (m, 18H), 10,32-9,86 (m, 2H), MS (ECI) m/z 926 (M+H)+, 924 (M-H)+.

Example 121

(2S,2'S)-N,N'-[(Phenylimino)bis(metandienon-4,1-diyl)]bis{1-[(2S)-3,3-dimethyl-2-(1,3-thiazol-2-ylamino)butanoyl]pyrrolidin-2-carboxym the D.}

Example 121A

(S,2S,2'S)-N,N'-(4,4'-(phenylaziridine)bis(methylene)bis(4,1-phenylene))bis(1-((S)-3,3-dimethyl-2-youreincontrol)pyrrolidin-2-carboxamid)

The product of Example 79B (0.075 g, in 0.104 mmol) was dissolved in dichloromethane (2 ml) at ambient temperature and treated fluorenylmethoxycarbonyl (0,061 g, 0,218 mmol) and was stirred for 4 hours. Was added dropwise diethylamine (0,50 ml) and the resulting solution was stirred for 1 hour, then concentrated to dryness to obtain specified in the connection header.

Example 121B

(2S,2'S)-N,N'-[(phenylimino)bis(metandienon-4,1-diyl)]bis{1-[(2S)-3,3-dimethyl-2-(1,3-thiazol-2-ylamino)butanoyl]pyrrolidin-2-carboxamide}

The product from Example 121A (0,087 g, 0,103 mmol) was dissolved in ethanol (1 ml) and treated with chloroacetaldehyde (0,040 ml, 0,310 mmol) and the solution was heated at 70°C for 18 hours, during which time was added 0.04 ml of chloroacetaldehyde to accelerate completion of the reaction. The solution was concentrated and was purified on a column of combi-flash with 12 g of silicon dioxide, elwira mixture of 0-5% methanol in dichloromethane, followed by purification in the second column, elwira mixture 0-15% ethyl acetate in dichloromethane, to obtain 3.5 mg specified in the connection header.1H NMR (400 MHz, DMSO-d6) δ memorial plaques of 1.02 (s, 18H) a 1.46-of 1.65 (m, 4H) 1,67-to 1.77 (m, 1H) 1,79 is 1.91 (m, 4H) 2,08-of 2.20 (m, 1H) 3,63-3,71 (m, 2H) 4,43 (DD, J=7,92, 5,64 Hz, 2H) 4,56-4,63 (m, 6H) 6,54-of 6.61 (m, 3H) 6,66 (d, J=8,24 Hz, 2H) of 6.96 (d, J=3,69 Hz, 2H) 7,07 (t, J=7,97 Hz, 2H) 7,17 (d, J=8,46 Hz, 4H) 7,51 (d, J=8,57 Hz, 4H) to 7.64 (d, J=9,11 Hz, 2H) 9,99 (s, 2H); MS ECI - m/z 888,5 (M-H)-.

Example 122

(2S,2'S)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis(1-{(2R)-2-[acetyl(ethyl)amino]-2-phenylacetyl}pyrrolidin-2-carboxamid)

Example 122A

(R)-tert-butyl 2-(ethylamino)-2-phenylacetate

To a solution of (R)-tert-butyl 2-amino-2-phenylacetaldehyde (0.25 g, 1,026 mmol) in MeOH (10,26 ml) was added 10% Pd/C (0,080 g, 1,026 mmol). The resulting mixture was cooled to 0°C was added acetaldehyde (0,576 ml, 10,26 mmol). The resulting mixture was stirred at 0°C for 10-15 minutes, the ice bath was removed and the mixture was placed under a balloon with hydrogen and stirred at room temperature for 45 minutes. The mixture was filtered through celite, washed with methanol, and the filtrate was concentrated in vacuum to obtain specified in the connection header (0,267 g).

Example 122B

(R)-tert-butyl 2-(N-ethylacetamide)-2-phenylacetate

A solution of the product from Example 122A (0,267 g 1,135 mmol) in acetic anhydride (1,073 ml, 11,35 mmol) and pyridine (0,918 ml, 11,35 mmol) was stirred at 98°C for 2 hours. The mixture was distributed between CH2Cl21 N. HCl solution, and the organic extract was separated, dried over besttranslator sodium, was filtered and concentrated in vacuum. The crude product was purified using column chromatography on silica gel using a gradient solvent 1-35% ethyl acetate in hexane, to obtain specified in the title compound (0.083 g, 27%).

Example 122C

(R)-2-(N-ethylacetamide)-2-phenylacetic acid

To a solution of the product from Example 122B (81 mg, 0,293 mmol) in CH2Cl2(3 ml) was added 2,2,2-triperoxonane acid (1.5 ml, 0,293 mmol) and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuum to obtain specified in the title compound (50 mg, 77%).

Example 122D

(2S,2'S)-N,N'-{[(4-forfinal)imino]bis(metandienon-4,1-diyl)}bis(1-{(2R)-2-[acetyl(ethyl)amino]-2-phenylacetyl}pyrrolidin-2-carboxamid)

The product from Example 13D (0,024 g 0,047 mmol) was subjected to the procedure described in Example 24E, substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoyl acid the product from Example 122C, obtaining specified in the connection header in the form of a salt TFOC (7 mg).1H NMR (400 MHz, DMSO-d6) δ memorial plaques of 0.49 to 0.63 (m, 4H), 0,69-0,78 (m, 2H), 1,24 (s, 2H), 1.70 to 2,04 (m, 8H), 2.05 is-of 2.16 (m, 4H), 2,84-of 3.27 (m, 4H), 3,42 at 3.69 (m, 3H), 4,42-4,48 (m, 2H), 4,58 (s, 4H), 6,63 of 6.68 (m, 2H), 6,92 (t,J=a 8.9 Hz, 2H), 7,20 (DD,J=8,3, 3.8 Hz, 4H), 7,31-to 7.50 (m, 11H), 7,51-to 7.64 (m, 6H), 9,62 (s, 1H), of 10.05 (s, 1H); MS m/z 923,6 (M+H)+.

Example 13

Dimethyl ([(4-forfinal)imino]bis{metandienon-4,1-Vilcabamba(2S,3aS,6aS)hexahydrotriazine[b]pyrrol-2,1(2H)-diyl[(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]})bicarbonate

Example 123A

(2S,3aS,6aS)-2-benzyl 1-tert-butylacrylate[b]pyrrole-1,2(2H), in primary forms

To a solution of benzyl ether (S,S,S)-2-azabicyclo[3,3,0]-octane-3-carboxylic acid, hydrochloride (0.50 g, 1.8 mmol) in CH2Cl2(8,9 ml) at room temperature was added di-tert-BUTYLCARBAMATE (0.45 ml, 2.0 mmol) and base Hunya (of 0.77 ml, 4.4 mmol) to obtain the bronze solution. The mixture was stirred for 2 hours at room temperature, then was diluted with the help of CH2Cl2off , washed with a saturated sodium bicarbonate solution and saturated saline solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain specified in the title compound (0.56 g, 91% yield).

Example 123B

(2S,3aS,6aS)-1-(tert-butoxycarbonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid

To a solution of the product from Example 123A (0.56 g, 1.6 mmol) in MeOH (8.0 ml) was added Pd(OH)2/carbon. Of the mixture was pumped the air and through the balloon entered the atmosphere of H2. The mixture was stirred overnight, then filtered and the solvent was removed when eigendom pressure obtaining specified in the connection header (0,42 g, 102% yield).

Example 123C

(2S,2'S,3aS,3a'S,6aS,6A's)-tert-butyl 2,2'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis-(hexahydrotriazine[b]pyrrol-1(2H)-carboxylate)

Specified in the title compound was obtained using the methods from Example 13C, substituting N-(tert-butoxycarbonyl)-L-Proline for the product of Example 123B, obtaining specified in the title compound (0.95 g, 100% yield).

Example 123D

(2S,2'S,3aS,3a'S,6aS,6A's)-N,N'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene))bis(octahydrocyclopenta[b]pyrrole-2-carboxamido)

Specified in the title compound was obtained using the methods from Example 13D substituting the product from Example 13C of the product of Example 123C, obtaining specified in the title compound (0.17 g, 81%).

Example 123E

Dimethyl ([(4-forfinal)imino]bis{metandienon-4,1-Vilcabamba(2S,3aS,6S)hexahydrotriazine[b]pyrrol-2,1(2H)-diyl[(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]})bicarbonate

Specified in the title compound was obtained using the methods of Example 13E, substituting the product from Example 13D of the product of Example 123D, obtaining specified in the title compound (75 mg, 41% yield).1H NMR (400 MHz, METHANOL-D4) δ 7,52-the 7.43 (m, 4H), 7,22-to 7.15 (m, 4H), 6,83 (t,J=the 8.6, 2H), 6,74 is 6.67 (m, 2H), 4,73 with 4.65 (m, 2H), 4,59-4,50 (m, 6H), 4,39 (Shir. s, 2H), 3,65 (who, 6H), 2,85-to 2.74 (m, 2H), 2,39 (m, 2H), 2,19 (l,J=8,0, 2H), 2,09-1,90 (m, 4H), 1,89-of 1.56 (m, 8H), of 1.03 (s, 18H); MS (ECI; M+H) m/z=939.

Example 124

(2S,3aS,6aS,2'S,3a'S,6A's)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis{1-[(2R)-2-phenyl-2-piperidine-1-ylacetic]octahydrocyclopenta[b]pyrrole-2-carboxamide}

To a mixture of the product from Example 123D (0.17 g, 0.29 mmol), (R)-2-phenyl-2-(piperidine-1-yl)acetic acid - salt TFOC (0.21 g, 0.67 mmol) and HATU (0.24 g, 0.64 mmol) in CH2Cl2(2.9 ml) was added to the base Hunya (0,41 ml, 2.3 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure and purified using column chromatography, elwira a mixture of 30-70% ethyl acetate in hexane, to obtain specified in the title compound (39 mg, 13% yield).1H NMR (400 MHz, METHANOL-D4) δ 7,54-the 7.43 (m, 8H), 7,38-7,30 (m, 6H), 7.23 percent-7,17 (m, 4H), at 6.84 (t,J=the 8.6, 2H), 6,72 (DD,J=4,2, 9,2, 2H), 4,54 (Shir. s, 4H), 4,46 (t,J=of 8.3, 2H), or 4.31 (DD,J=8,1, 13,9, 2H), 4,12 (s, 2H), 2,73-2,60 (m, 2H), 2,53 is 2.44 (m, 3H), 2,42-of 2.24 (m, 8H), 2,17-2,04 (m, 2H), 2,03-of 1.88 (m, 2H), 1,83-of 1.64 (m, 7H), of 1.55 (s, 10H), USD 1.43 (s, 4H), MS (ECI; M+H) m/z=999.

Example 125

Methyl [(1S)-1-{[(2S)-2-{[4-({(4-forfinal)[4-({[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanol}-2,5-dihydro-1H-pyrrol-2-yl]carbonyl}amino)benzyl]amino}methyl)phenyl]carbarnoyl}-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}-2.2-dimethylpropyl]carbama the

Example 125A

(2S,2'S)-tert-butyl 2,2'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(2,5-dihydro-1H-pyrrol-1-carboxylate)

Specified in the title compound was obtained using the methods from Example 13C, substituting N-(tert-butoxycarbonyl)-L-Proline (S)-1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid, to obtain the specified title compound (0.64 g, 96% yield).

Example 125B

(2S,2'S)-N,N'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene))bis(2,5-dihydro-1H-pyrrol-2-carboxamide)

Specified in the title compound was obtained using the methods from Example 13D substituting the product from Example 13C of the product of Example 125A, obtaining specified in the title compound (0.50 g, 109% yield).

Example 125C

Methyl [(1S)-1-{[(2S)-2-{[4-({(4-forfinal)[4-({[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanol}-2,5-dihydro-1H-pyrrol-2-yl]carbonyl}amino)benzyl]amino}methyl) phenyl]carbarnoyl}-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}-2.2-dimethylpropyl]carbamate

Specified in the title compound was obtained using the methods of Example 13E, substituting the product from Example 13D of the product of Example 125B, obtaining specified in the title compound (0.15 g, 45% yield).1H NMR (400 MHz, DMSO) δ 10,13 (s, 2H), 7,51 (l,J=8,5, 4H), 7.23 percent (l,J=8,7, H), to 7.18 (d,J=8,5, 4H), 6,91 (t,J=8,9, 2H), 6,63 (DD,J=9,2, 4,4, 2H), the 6.06 (DD,J=6,3, 1,8, 2H), 5,88 (DD,J=6,2, 2,1, 2H), 5,20-5,13 (m, 2H), br4.61-4,51 (m, 6H), 4,49-4,39 (m, 2H), 4,15 (l,J=8,7, 2H), 3,54 (s, 6H), 0,99 (s, 18H); MS (ECI; M+H) m/z=855.

Example 126

Dibenzyl (4S,4'S)-4,4'-{[(4-forfinal)imino]bis(meander-benzene-4,1-Vilcabamba)}bis(1,3-oxazolidin-3-carboxylate)

The product from Example 13B (100 mg, 0,311 mmol) and (S)-3-(benzyloxycarbonyl)oxazolidin-4-carboxylic acid (195 mg, 0,778 mmol) were processed using the method described in Example 43, to obtain 215 mg (88%) specified in the connection header.1H NMR (400 MHz, DMSO-d6) δ memorial plaques to 10.09 (s, 2H), 7,51 (l,J=7,1 Hz, 4H), of 7.36 (m, 4H), 7,18 (m, 10H) 6,91 (l,J=a 8.9 Hz, 2H), only 6.64 (m, 2H), 5,13 (m, 2H), to 5.03 (m, 2H), is 4.93 (m, 4H), 4,58 (Shir. s, 4H), 4,48 (m, 2H), 4,28 (m, 2H), 4,01 (m, 2H).

Example 127

(2S,4S,2'S,4'S)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis{4-hydroxy-1-[(2R)-2-phenyl-2-piperidine-1-ylacetic]pyrrolidin-2-carboxamide}

Example 127A

(2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid

To a solution of (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid (3.9 g, 29.7 mmol) in THF (26,7 ml) and water (13.3 ml) was added di-tert-BUTYLCARBAMATE (7,14 g, to 32.7 mmol) and sodium hydroxide (2,0 N., 22.9 ml, with 45.8 mmol) and the mixture was stirred at room temperature overnight. To the mixture was then added 10% rastvorennoi acid (50 ml) followed by addition of EtOAc and extraction with water and saturated salt solution. The organic extract was dried, filtered and concentrated to obtain 5.31g (77%) specified in the connection header. MS (ESI) m/z 232 (M+H)+.

Example 127B

(2S,4S)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)pyrrolidin-2-carboxylic acid

To a solution of Example 127A (5.31g, 22,96 mmol) and imidazole (of 7.82 g, 115 mmol) in dichloromethane (106 ml) and DMF (21,3 ml) was added tert-butyldimethylsilyl (to 7.61 g, and 50.5 mmol) and the mixture was stirred at room temperature overnight. To the mixture was then added water (425 ml) and the solution was extracted using EtOAc, and the organic extract was concentrated to obtain residue, which was dissolved in 25% solution of EtOAc and 75% hexane solution and then was extracted with saturated brine and the organic extract was concentrated to obtain a solid substance. The obtained solid substance was dissolved in methanol (65 ml) and water (85 ml), then was added lithium hydroxide, monohydrate (1,93 g, 46 mmol) and the solution was stirred at room temperature for 2 hours. Then added water (106 ml) and aqueous 1 n hydrochloric acid solution until it reached pH 2. The mixture then was extracted using a mixture of 25% EtOAc and 75% hexane, the organic extract was dried, filtered and concentrated to obtain specified in the title compound as a colourless solid. MS (ESI) m/z 346 (M+H)+./p>

Example 127C

(3S,3'S,5S,5'S)-tert-butyl 5,5'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-carboxylate)

The product of Example 127B (161 mg, 0,467 mmol) and the product from Example 13B (50 mg, 0,156 mmol) were processed using the method described in Example 43, to obtain 110 mg (72%) specified in the connection header. MS (ESI) m/z 977 (M+H)+.

Example 127D

(2S,2'S,4S,4'S)-N,N'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene))bis(4-hydroxypyrrolidine-2-carboxamido)

The product of Example 127C (110 mg, 0,113 mmol) was dissolved in triperoxonane acid (6 ml), water (0.2 ml) and dichloromethane (0.3 ml) and the mixture was stirred at room temperature for 2 hours. After that, the mixture was concentrated to obtain oil, which was dissolved in 75% solution CHCl3and 25% isopropyl alcohol solution, and then was extracted with saturated aqueous sodium bicarbonate, the organic extract was separated, dried, filtered and concentrated to obtain specified in the title compound as a colourless solid. MS (ESI) m/z 548 (M+H)+.

Example 127E

(25,4'S,2'S,4'S)-N,N'-{[(4-forfinal)imino]bis(metandienon-4,1-diyl)}bis{4-hydroxy-1-[(2R)-2-phenyl-2-piperidine-1-ylacetic]pyrrolidin-2-carboxamide}

The product of Example the 127D (30 mg, by 0.055 mmol) and (R)-2-phenyl-2-(piperidine-1-yl)acetic acid (36 mg, 0,164 mmol) were processed using the method described in Example 43, receiving 8 mg (15%) specified in the connection header.1H NMR (400 MHz, DMSO-d6) δ memorial plaques becomes 9.97 (s, 2H), 7,51 (l,J=8,4 Hz, 4H), 7,40 (m, 4H), 7,30 (m, 6H), 7,19 (l,J=8.6 Hz, 4H), 6,91 (l,J=9,0 Hz, 2H), 6,63 (m, 2H), 5,27 (l,J=6,6 Hz, 2H), 4,56 (Shir. s, 4H), 4,24 (m, 2H), 4,,07 (m, 2H), 3,68 (m, 2H), 3,61 (m, 2H), 3,32 (m, 8H), of 1.74 (m, 2H), of 1.42 (m, 8H), of 1.35 (m, 4H).

Example 128

(25,2'S)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis{1-[(2-oxopyrrolidin-1-yl)(phenyl)acetyl]pyrrolidin-2-carboxamide}

Example 128A

(R)-ethyl 4-(2-tert-butoxy-2-oxo-1-phenylethylamine)butanoate

A mixture of (R)-tert-butyl 2-amino-2-phenylacetaldehyde (0.5 g, 2,051 mmol), ethyl 4-bromobutyrate (0,44 g of 2.26 mmol) and K2CO3(1.13 g, 8,21 mmol) in CH3CN (10 ml) was heated to 50°C for 40 hours. The mixture was diluted using EtOAc and then washed with H2O and saturated salt solution. The organic layer was then dried (MgSO4), filtered and concentrated. Purification via chromatography (silica gel, 40% EtOAc in hexane) to give 486 mg (74%) specified in the connection header. MS (ESI) m/z 322 (M+H)+.

Example 128B

(R)-4-(2-tert-butoxy-2-oxo-1-phenylethylamine)butane acid

PR is the product of Example 128A (480 mg, for 1.49 mmol) and NaOH (299 mg, 7,47 mmol) in MeOH (10 ml) was stirred at ambient temperature for 1 hour. To the mixture was added HCl (1M solution) and was extracted using EtOAc. The organic layer was washed with saturated saline solution, dried (MgSO4), filtered and concentrated to obtain 310 mg (71%) specified in the connection header. MS (ESI) m/z 294 (M+H)+.

Example 128C

(R)-tert-butyl 2-(2-oxopyrrolidin-1-yl)-2-phenylacetate

The product of Example 128B (307 mg, 1.05 mmol) and N1-((ethylimino)methylene)-N3,N3-DIMETHYLPROPANE-1,3-dimenhydrinate (602 mg, 3.14 mmol) in pyridine (5 ml) and dimethylformamide (5 ml) was stirred at ambient temperature for 16 hours. The mixture was diluted using EtOAc and washed with H2O and saturated salt solution. The organic layer was dried (MgSO4), filtered and concentrated. Purification via chromatography (silica gel, 60% EtOAc in hexane) to give 249 mg (86%) specified in the connection header. MS (ESI) m/z 276 (M+H)+.

Example 128D

(R)-2-(2-oxopyrrolidin-1-yl)-2-phenylacetic acid

The product of Example 128C (245 mg, 0.89 mmol) in triperoxonane acid (5 ml) was stirred at ambient temperature for 2 hours. The mixture was concentrated to obtain 201 mg (100%) specified in the connection header. MS (ESI) m/z 276 (M+H)+.

P the emer 128E

(2S,2'S)-N,N'-{[(4-forfinal)imino]bis(metandienon-4,1-diyl)}bis{1-[(2S)-2-(2-oxopyrrolidin-1-yl)-2-phenylacetyl]pyrrolidin-2-carboxamide}

The product of Example 128D (42,5 mg, 0,194 mmol) and Example 13E (50 mg, 0,087 mmol) were processed using the method described in Example 7F, after receiving three stereoisomers. Specified in the title compound was first isomer, which was swirbul, and the HPLC fractions were neutralized with saturated aqueous solution of NaHCO3followed by extraction with a mixture of isopropyl alcohol/CH2Cl2(ratio 1:3; 3×100 ml) and the allocation specified in the connection header. Specified in the header of Example 129 connection was buyrevia second, and specified in the header of Example 130 connection was buyrevia third.1H NMR (400 MHz, DMSO-d6) δ M. D. 1,72 is 2.00 (m, 5H), 2,03 with 2.14 (m, 2H), 2,27-of 2.34 (m, 6H), to 2.94 (dt,J=8,81, 5,80 Hz, 2H), and 3.16 (s, 6H), 3,50-to 3.58 (m, 2H), 3,65 (TD,J=8,67, 6,07 Hz, 2H), 4,08 (s, 2H), of 4.44 (DD,J=8,29, 4,39 Hz, 2H), 4,55 (s, 4H), 6,59-of 6.65 (m, 2H), 6.90 to (t,J=8,89 Hz, 2H), 7,17 (l,J=to 8.57 Hz, 4H), 7.23 percent (l,J=6,94 Hz, 4H), 7,30-7,41 (m, 6H), 7,53 (l,J=8,46 Hz, 4H), 9,94 (s, 2H), MS (ECI) m/z 919 (M+H)+.

Example 129

(2S,2'S)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis{1-[(2-oxopyrrolidin-1-yl)(phenyl)acetyl]pyrrolidin-2-carboxamide}

Specified in the header of Example 129 connection was the second eluting compound, described in the procedures on the I example 128E. Neutralization fractions HPLC saturated aqueous NaHCO3followed by extraction with a mixture of isopropyl alcohol/CH2Cl2(ratio 1:3; 3×100 ml) and the selection resulted in the receipt of 26 mg (25%) specified in the connection header.1H NMR (400 MHz, DMSO-d6) δ M. D. 1,73 is 2.00 (m, 10H), 2,04-of 2.21 (m, 2H), 2,23-of 2.36 (m, 4H), 2,63-2,70 (m, 2H), 2,90-3,03 (m, 2H), and 3.16 (s, 6H), 3,47-3,61 (m, 4H), 3,60-and 3.72 (m, 1H), 4.09 to (s, 2H), 4,46 (TD,J=8,13, 4,88 Hz, 2H), 4,56 (s, 4H), 5,94 (l,J=3.04 from Hz, 2H), only 6.64 (DD,J=9,27, 4,39 Hz, 2H), 6,91 (t,J=8,89 Hz, 2H), 7,18 (DD,J=8,40, 5,15 Hz, 6H), 7.23 percent (l,J=6,94 Hz, 1H), 7,32-the 7.43 (m, 8H), 7,54 (e,J=8,46 Hz, 4H), 9,94 (s, 1H), 10,08 (s, 1H), MS (ECI) m/z 919 (M+H)+.

Example 130

(2S,2'S)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis{1-[(2-oxopyrrolidin-1-yl)(phenyl)acetyl]pyrrolidin-2-carboxamide}

Specified in the title compound, Example 130, was the third eluting compound, described in the procedures for example 128E. Neutralization fractions HPLC saturated aqueous NaHCO3followed by extraction with a mixture of isopropyl alcohol/CH2Cl2(ratio 1:3; 3×100 ml) and the selection resulted in the receipt of 13 mg (12%) specified in the connection header.1H NMR (400 MHz, DMSO-d6) δ M. D. 1,73-of 1.92 (m, 10H), 2,11-of 2.34 (m, 7H), 2,64-of 2.72 (m, 4H), 2.95 and totaling 3.04 (m, 2H), 3,47-3,63 (m, 6H), 4,43-4,51 (m, 2H), 4,57 (s, 4H), 5,94 (s, 2H), 6,65 (DD,J=which 9.22, of 4.45 Hz, 2H), 6,91 (t,J=8,89 Hz, 2H), 7,20 (m,J=8,57 G is, 4H), 7,34-the 7.43 (m, 10H), 7,55 (l,J=8,46 Hz, 4H), to 10.09 (s, 2H), MS (ECI) m/z 919 (M+H)+.

Example 131

(2S,2'S)-N,N'-{[(4-forfinal)imino]bis(metandienon-4,1-diyl)}bis{1-[(2R)-2-(ethylamino)-2-phenylacetyl]pyrrolidin-2-carboxamide}

Example 131A

(R)-2-(ethylamino)-2-phenylacetic acid

The product from Example 122A was subjected to the procedure described in Example 122C, obtaining specified in the connection header.

Example 131B

(R)-2-(tert-butoxycarbonyl(ethyl)amino)-2-phenylacetic acid

To a solution of the product from Example 131A (0,23 g, 1.28 mmol) in MeOH (5 ml) was added to the base Hunya (0,90 ml, 5,13 mmol) and di-tert-BUTYLCARBAMATE (0.56 g, 2.57 mmol). The mixture was stirred at room temperature for 22 hours and was divided between CH2Cl21 N. HCl solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The crude product was purified using column chromatography on silica gel using a gradient solvent 0-4% MeOH in CH2Cl2with obtaining specified in the connection header (0,086 g, 24%).

Example 131C

tert-butyl (1R,1'R)-2,2'-((2S,2'S)-2,2'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene)bis(ethanediyl)) bis(octamethylene)bis(pyrrolidin-2.1-diyl))bis(-oxo-1-Penilaian-2.1-diyl)bis(ethylcarbamate)

The product from Example 13D (0,062 g, 0,120 mmol) was subjected to the procedure described in Example 2, substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoyl acid the product from Example 131B, obtaining specified in the connection header (0,0427 g, 34%).

Example 131D

(2S,2'S)-N,N'-{[(4-forfinal)imino]bis(metandienon-4,1-diyl)}bis{1-[(2R)-2-(ethylamino)-2-phenylacetyl]pyrrolidin-2-carboxamide}

To a solution of the product from Example 131C (0,043 g 0,041 mmol) in CH2Cl2(1.5 ml) was added 2,2,2-triperoxonane acid (0.75 ml, 0,041 mmol) and the solution was stirred at room temperature for 45 minutes. The mixture was distributed between CH2Cl2and saturated aqueous NaHCO3and the organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered, and the solvent was removed in vacuum to obtain specified in the title compound (18 mg, 51%).1H NMR (400 MHz, DMSO-d6) δ M. D. 0,98 (sq,J=6.9 Hz, 6H), 1.70 to and 2.26 (m, 10H), 3,18-of 3.27 (m, 2H), 3,82 (s, 2H), 4,37 (DD,J=7,9, and 3.7 Hz, 2H), 4,56 (l,J=3,9 Hz, 4H), 6,61-6,69 (m, 2H), 6,88-of 6.96 (m, 2H), 7,14-7,22 (m, 4H), 7.24 to 7,42 (m, 10H), 7,46-7,58 (m, 4H), becomes 9.97 (d,J=9.7 Hz, 2H); MS m/z 838,3 (M+H)+.

Example 132

(2S,2'S)-N,N'-{[(4-forfinal)imino]bis(metandienon-4,1-diyl)}bis(1-{(2R)-2-[ethyl(1-methylethyl)amino]-2-phenylacetyl}pyrrolidin-2-carboxamid)

Example 132A

(R)-tert-butyl 2-(ethyl(from ropyl)amino)-2-phenylacetate

To a solution of the product from Example 122A (0,098 g 0 416 mmol) in EtOH (5 ml) was added acetone (0,031 ml, 0,416 mmol), acetic acid (0,024 ml, 0,416 mmol) and cyanoborohydride sodium (0,039 g of 0.625 mmol) and the resulting mixture was stirred at room temperature for 8 hours. The mixture was distributed between CH2Cl2and saturated aqueous NaHCO3and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The crude product was purified using column chromatography on silica gel using a gradient solvent 0-1% MeOH in CH2Cl2with obtaining specified in the connection header (0,0352 g, 31%).

Example 132B

(R)-2-(ethyl(isopropyl)amino)-2-phenylacetic acid

The product of Example 132A (0.035 g, 0.13 mmol) was subjected to the procedure described in Example 122C, obtaining specified in the connection header (0,027 g).

Example 132C

(2S,2'S)-N,N'-{[(4-forfinal)imino]bis(metandienon-4,1-diyl)}bis(1-{(2R)-2-[ethyl(1-methylethyl)amino]-2-phenylacetyl}pyrrolidin-2-carboxamid)

The product from Example 13D (0,030 g 0,058 mmol) was subjected to the procedure described in Example 13E, substituting (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid the product from Example 132B, obtaining specified in the connection header (0,011 g, 21%).1H NMR (400 MHz, DMSO-d6) δ M. D. 0,78-of 1.02 (m, 6H), 1.14 in (q, =6,4 Hz, 2H), 1,21-of 1.35 (m, 12H), 1.39 in (q,J=6,4 Hz, 4H), 1,73-to 2.18 (m, 8H), 2,74-is 3.21 (m, 6H), to 4.41 (DD,J=8,3, 3,4 Hz, 2H), 4,59 (s, 4H), 5,43-5,52 (m, 2H), 6,59-6,69 (m, 2H), 6,92 (t,J=8,8 Hz, 2H), 7,21 (l,J=8,3 Hz, 4H), 7,47-of 7.82 (m, 12H), to 9.32 (s, 1H), 10,14 (s, 1H); MS m/z= 922,6 (M+H)+.

Example 133

Dimethyl ([(4-forfinal)imino]bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(1S)-1-cyclopentyl-2-oxetan-2.1-diyl]})bicarbonate

The product from Example 13D (0.035 g, 0,068 mmol) and (S)-2-cyclopentyl-2-(methoxycarbonylamino)acetic acid (0,030 g, 0,149 mmol) were processed as in Example 25B, obtaining specified in the connection header in the form of not-quite-white solid.1H NMR (400 MHz, DMSO-d6) δ M. D. 1,20-of 1.36 (m, 4H) 1,41 of 1.50 (m, 4H) 1,51-of 1.74 (m, 8H) 1,82-of 1.92 (m, 4H) 1,95-2,04 (m, 2H) 2,08-2,19 (m, 4H) to 3.52 (s, 6H) 3,57-the 3.65 (m, 2H) 3,79-to 3.89 (m, 2H) 4,10 (t, J=8,73 Hz, 2H) was 4.42 (DD, J=8,13, of 4.77 Hz, 2H) 4,55 (s, 4H) only 6.64 (DD, J=which 9.22, of 4.45 Hz, 2H) 6,91 (t, J=8,84 Hz, 2H) 7,17 (d, J=8,46 Hz, 4H) 7,41 (d, J=a 7.92 Hz, 2H) 7,51 (d, J=8,57 Hz, 4H) 9,95 (s, 2H); MS ECI - m/z 880,6 (M-H)-.

Example 134

Dimethyl ([(4-forfinal)imino]bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-4-hydroxy-1-oxobutyl-1,2-diyl]})bicarbonate

The product from Example 13D (0.035 g, 0,068 mmol) and (S)-4-hydroxy-2-(methoxycarbonylamino)butane acid (0,027 g, 0,149 mmol) were processed as in Example 25B, obtaining specified in the connection header as not quite white is solid substances. 1H NMR (400 MHz, DMSO-d6) δ M. D. 1,58 is 1.70 (m, 2H) 1,75-to 1.82 (m, 2H) 1,84-2,04 (m, 6H) 2,07-2,17 (m, 2H) 3,42-to 3.50 (m, 4H) 3,50-of 3.54 (m, 6H) 3,68 (t, J=6,45 Hz, 4H) 4,37-4,47 (m, 4H) 4,55 (s, 4H) br4.61 (t, J=4,93 Hz, 2H) 6,63 (DD, J=which 9.22, 4,34 Hz, 2H) 6,91 (t, J=8,89 Hz, 2H) 7,16 (d, J=8,46 Hz, 4H) 7,34 (d, J=of 7.70 Hz, 2H) 7,50 (d, J=8,46 Hz, 4H) 9,94 (s, 2H); MS ECI+ m/z 834,4 (M+H)+.

Example 135

Dimethyl ([(4-forfinal)imino]bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3-ethyl-1-oxopent-1,2-diyl]})bicarbonate

Example 135A

(S)-3-ethyl-2-(methoxycarbonylamino)pentane acid

(S)-2-Amino-3-ethylpentane acid (1.0 g, 6,89 mmol) were processed as in Example 25A, with the receipt of 1.02 g (73%) indicated in the title compound in the form of a waxy solid.

Example 135B

Dimethyl ([(4-forfinal)imino]bis{metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3-ethyl-1-oxopent-1,2-diyl]})bicarbonate

The product from Example 13D (0,040 g 0,078 mmol) and the product from Example 135A (0.035 g, 0,171 mmol) were processed as in Example 25B, obtaining specified in the connection header in the form of not-quite-white solid.1H NMR (400 MHz, DMSO-d6) δ M. D. 0,59 with 0.93 (m, 12H) of 1.05 to 1.36 (m, 6H) 1,37 of 1.50 (m, 2H) 1,54 is 1.70 (m, 2H) 1,78-of 1.97 (m, 3H) 2,08-of 2.21 (m, 2H) 3,41-to 3.49 (m, 2H) 3,51-to 3.64 (m, 9H) 3,74-of 3.85 (m, 2H) 4,27-4,48 (m, 4H) 4,55 (s, 4H) 6,63 (DD, J=which 9.22, 4,34 Hz, 2H) 6,90 (t, J=8,89 Hz, 2H) 7,17 (d, J=8,24 Hz, 4H) 7,20-7,38 (m, 2H) 7,47-of 7.55 (m, 4H) 9,71-10,24 (m, 2H); MS ECI - m/z 88,6 (M-H) -.

Example 136

Dimethyl ([(4-forfinal)imino]bis{metandienon-4,1-Vilcabamba[(2S,4S)-4-hydroxypyrrolidine-2.1-diyl][(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]})bicarbonate

The product from Example 127D (30 mg, 0,057 mmol) and (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid (to 26.8 mg, 0,142 mmol) were processed using the method described in Example 43, to obtain 8.5 mg (15%) specified in the connection header.1H NMR (400 MHz, DMSO-d6) δ memorial plaques becomes 9.97 (s, 2H), 7,49 (l,J=7,6 Hz, 4H), 7,17 (d, J=7,6 Hz, 4H), 7,10 (m, 2H), 6.90 to (m, 4H), 6,62 (m, 2H), from 5.29 (d,J=5.5 Hz, 2H), 4,54 (Shir. s, 4H), to 4.38 (m, 2H), 4,22 (m, 2H), 4,15 (m, 2H), 3.96 points (m, 2H), 3,52 (s, 6H), 2,53 (s, 4H), of 2.38 (m, 2H), 1,65 (m, 2H), 0,95 (s, 18H).

Example 137

(2S,2'S)-N,N'-{[(3,4-Differenl)imino]bis(metandienon-4,1-diyl)}bis{1-[(2R)-2-phenyl-2-piperidine-1-ylacetic] pyrrolidin-2-carboxamide}

The product from Example 89D hydrochloride and (R)-2-phenyl-2-(piperidine-1-yl)acetic acid were processed using the method described in Example 13E, substituting DMF in dichloromethane, to obtain specified in the connection header (of 55.5 mg, 25%).1H NMR (400 MHz, DMSO) δ 1,51 is 1.20 (m, 14H), 1,90-of 1.74 (m, 5H), 2,10 is 1.91 (m, 5H), 2,40-of 2.34 (m, 4H), 3,54-to 3.41 (m, 2H), 3,90-of 3.78 (m, 2H), 4,24 (s, 2H), 4,36-the 4.29 (m, 2H), 4,60 (s, 4H), 6,46-6,37 (m, 1H), 6,68-to 6.57 (m, 1H), 7,14-7,07 (m, 2H), 7,19 (l,J=8,4, 4H), of 7.36-7,25 (m, 5H), 7,42 (l,J=7,2, 4H), 7,53 (l,J=8,5, 4H), becomes 9.97 (s, 2H), MS (ECI)m/z936 (M+H+, 30%) 69 (0.5 M+H +, 100%).

Example 138

(2S,2'S)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis{1-[(4,4-deformability-1-yl)(phenyl)acetyl]pyrrolidin-2-carboxamide}

Example 138A

(S)-1-phenylethyl 2-bromo-2-phenylacetate

To a mixture of α-bromoferrocene acid (11,20 g of 52.1 mmol), (S)-(-)-1-phenylethanol (8.2 ml, with 67.9 mmol) and DMAP (to 0.63 g, 5.2 mmol) in CH2Cl2(100 ml) was added EDAC (13,80 g, 72.0 mmol). The resulting mixture was stirred at room temperature for 3 hours, then was diluted with ethyl acetate (200 ml), washed with water (2×100 ml) and saturated saline (100 ml). The organic layer was dried (MgSO4), filtered and concentrated, then purified by using column chromatography to obtain specified in the connection header (of 12.6 g, 76% yield).

Example 138B

(S)-1-phenylethyl 2-(4,4-deformability-1-yl)-2-phenylacetate

To a solution of the product from Example 138A (1,00 g of 3.13 mmol) in tetrahydrofuran (20 ml) at room temperature was added triethylamine (1.75 ml, 12.5 mmol) and tetrabutylammonium (0,46 g, 1.25 mmol). The mixture was stirred for 5 minutes and then was added 4,4-deltocephalinae (0.74 g, 4,70 mmol) in the form of the free base in THF. The mixture was stirred for 1 hour at room temperature and then was heated to 55°C in accordance with is their night. The cooled mixture was washed with saturated brine, concentrated, and then purified using column chromatography (EtOAc-hexane) to obtain the specified title compound (1.04 g, 92% yield).

Example 138C

2-(4,4-deformability-1-yl)-2-phenylacetic acid

To a solution of the product from Example 138B (1.04 g, 2.89 mmol) in CH2Cl2(6 ml) at room temperature was added triperoxonane acid (2.0 ml) and the mixture was stirred for 48 hours. The mixture was concentrated under reduced pressure, and the residue was transferred into toluene. The mixture was concentrated under reduced pressure and dried in a vacuum oven at 50°C with obtaining specified in the connection header (in the form of a salt TFUC) as a pale yellow solid (1.07 g, 100%).

Example 138D

(2S,2'S)-N,N'-{[(4-forfinal)imino]bis(metandienon-4,1-diyl)}bis{1-[(4,4-deformability-1-yl)(phenyl)acetyl]pyrrolidin-2-carboxamide}

Specified in the title compound was obtained using the methods of Example 13E, substituting (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid the product from Example 138C, with a mixture of three diastereomers. Specified in the title compound (176 mg, 31% yield) was isolated via column chromatography as the first eluting diastereoisomer of.1H NMR (400 MHz, METHANOL-D4) δ 7,52-7,46 (m, 8H), 7,41-7,31 m, 6H), 7,21 (l,J=8,4, 4H), 6,85 (t,J=8,8, 2H), 6,72 (DD,J=of 9.2, 4.3, 2H), of 4.54 (s, 4H), 4,42 (DD,J=7,8, 4,8, 2H), or 4.31 (s, 2H), 3,94-of 3.85 (m, 2H), 3,52 is 3.40 (m, 2H), 2,66 is 2.44 (m, 8H), 2,19-to 1.79 (m, 16H), MS (ECI; M+H) m/z=990.

Example 139

(2S,2'S)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis{1-[(4,4-deformability-1-yl)(phenyl)acetyl]pyrrolidin-2-carboxamide}

Specified in the title compound (77 mg, 14% yield) was isolated in the column chromatography in Example 138D as the second eluting diastereoisomer of.1H NMR (400 MHz, METHANOL-D4) δ EUR 7.57-7,44 (m, 6H), 7,43-7,30 (m, 8H), 7,28-to 7.15 (m, 4H), 6,88-for 6.81 (m, 2H), 6,77 of 6.68 (m, 2H), 4.63 to-4,51 (m, 5H), 4,48 (s, 1H), 4,42 (DD,J=7,4, 4,6, 1H), or 4.31 (s, 1H), 3,94-3,86 (m, 1H), 3,81-3,71 (m, 1H), 3,54-3,39 (m, 2H), 2,69 to 2.35 (m, 8H), 2,23-to 1.77 (m, 16H), MS (ECI; M+H) m/z=990.

Example 140

(2S,2'S)-N,N'-{[(4-Forfinal)imino]bis(metandienon-4,1-diyl)}bis{1-[(4,4-deformability-1-yl)(phenyl)acetyl]pyrrolidin-2-carboxamide}

Specified in the title compound (49 mg, 9% yield) was isolated in the column chromatography in Example 138D, elwira as a third of eluting diastereoisomer.1H NMR (400 MHz, METHANOL-D4) δ EUR 7.57-to 7.15 (m, 18H), 6,88-for 6.81 (m, 2H), 6,76 of 6.68 (m, 2H), 4,62-4,51 (m, 4H), 4,50-and 4.40 (m, 2H), 3,81-to 3.67 (m, 2H), 3,53-to 3.33 (m, 2H), 2,70 to 2.35 (m, 8H), 2,29-of 1.81 (m, 18H); MS (ECI; M+H) m/z=990.

Example 141

Dimethyl ([(4-forfinal)imino]bis{meander(6-methoxybenzo-3,1-diyl)carb is oil(2S)pyrrolidin-2.1-diyl[(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]})bicarbonate

Dimethyl ([(4-forfinal)imino]bis{metandienon-4,1-Vilcabamba[(2S,3S)-3-hydroxypyrrolidine-2.1-diyl][(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]})bicarbonate

Example 141A

(2S,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid

To a solution of (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid (0.50 g, 3.8 mmol) in CH2Cl2(19 ml) at room temperature was added di-tert-BUTYLCARBAMATE (of 0.96 ml, 4.2 mmol) and the base Hunya (1,32 ml, 7.6 mmol) to obtain the bronze solution. The reaction mixture was stirred over night at room temperature and then diluted with the help of CH2Cl2and washed with a saturated solution of sodium bicarbonate. The aqueous layer was concentrated under reduced pressure and then suspended in methanol and filtered. The solvent was then removed under reduced pressure to obtain specified in the connection header (0,91 g, 103% yield).

Example 141B

(2S,2'S,3S,3'S)-tert-butyl 2,2'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(3-hydroxypyrrolidine-1-carboxylate)

Specified in the title compound was obtained using the methods from Example 13C, substituting N-(tert-butoxycarbonyl)-L-Proline for the product of Example 141A, obtaining specified in the title compound (0.51 g, 77 output).

Example 141C

(2S,2'S,3S,3'S)-N,N'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene))bis(3-hydroxypyrrolidine-2-carboxamido)

Specified in the title compound was obtained using the methods from Example 13D substituting the product from Example 13C of the product of Example 141B, obtaining specified in the title compound (0.28 g, 76% yield).

Example 141D

Dimethyl ([(4-forfinal)imino]bis{meander(6-methoxybenzo-3,1-diyl)carbarnoyl(2S)pyrrolidin-2.1-diyl[(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]})bicarbonate

Dimethyl ([(4-forfinal)imino]bis{metandienon-4,1-Vilcabamba[(2S,3S)-3-hydroxypyrrolidine-2.1-diyl][(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]})bicarbonate

Specified in the title compound was obtained using the methods of Example 13E, substituting the product from Example 13D of the product of Example 141C, obtaining specified in the title compound (0.15 g, 45% yield).1H NMR (400 MHz, DMSO) δ 10,14 (s, 2H), 7,52 (d,J=to 8.5, 4H), to 7.15 (d,J=to 8.5, 4H), was 7.08 (d,J=9,3, 2H), 6.89 in (t,J=the 8.6, 2H), 6,62 (DD,J=4,4, 9,2, 2H), of 5.39 (s, 2H), 4.53-in (lat. s, 4H), 4,30-4,16 (m, 6H), 3,82 at 3.69 (m, 4H), 3,53 (s, 6H), 2,15-2,02 (m, 2H), 1,88-of 1.78 (m, 2H), 0,96-to 0.88 (m, 18H); MS (ECI; M+H) m/z=891.

Example 142

Methyl [(1R)-1-{[(2S)-2-{[4-({(4-forfinal)[4-({[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanol}-5-methylpyrrolidine-2-yl]carbonyl}amino)benzyl]amino}methyl)phenyl]carbarnoyl}-5-methyl who irreligion-1-yl]carbonyl}-2,2-dimethylpropyl]carbamate

Example 142A

(2S)-1-tert-butyl-2-ethyl-5-methylpyrrolidine-1,2, in primary forms

Specified in the title compound was obtained from (2S)-1-tert-butyl 2-ethyl 5-hydroxypyrrolidine-1,2-in primary forms, following the method described by Collado et al. J. Org. Chem. 1995, 60, 5011-5015.

Example 142B

(2S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid

To a solution of the product from Example 142A (0,068 g, 0,264 mmol) in MeOH (2,64 ml) was added NaOH (10,57 mg, 0,264 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was distributed between CH2Cl2and water 1 N. HCl solution, and the organic layer was separated and dried over anhydrous sodium sulfate. The desiccant was filtered, and the solvent was removed in vacuum to obtain specified in the connection header (0,050 g, 83%).

Example 142C

Methyl [(1R)-1-{[(2S)-2-{[4-({(4-forfinal)[4-({[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanol}-5-methylpyrrolidine-2-yl]carbonyl}amino)benzyl]amino}methyl)phenyl]carbarnoyl}-5-methylpyrrolidine-1-yl]carbonyl}-2,2-dimethylpropyl]carbamate

Specified in the title compound was obtained from the product of Example 13B, using the procedures described in Examples 1C-1E, substituting N-(tert-butoxycarbonyl)-L-Proline for the product from Example 142B and substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoyl acid to (S)-2-(metaxya is benjamina)-3,3-dimethylbutanol acid, and the final product was purified using chromatography on silica gel with gradient elution 0-3% methanol in dichloromethane.1H NMR (400 MHz, DMSO-d6) δ memorial plaques to 0.96 (s, 18H), 1,25 (l,J=6,0 Hz, 6H), to 1.61 (DD,J=11,4, 6,1 Hz, 2H), 1,78-of 2.30 (m, 6H), 3,53 (s, 6H), to 3.58-to 3.67 (m, 2H), 4,27-to 4.38 (m, 3H), 4,43 (l,J=9.4 Hz, 2H), of 4.54 (s, 4H), 6,60 is 6.67 (m, 2H), 6,85-to 6.95 (m, 2H), 7,16 (l,J=8,5 Hz, 4H), 7,49 (l,J=8.6 Hz, 4H), becomes 9.97 (s, 2H); MS m/z 886,7 (M+H)+.

Example 143

Dimethyl ([(4-forfinal)imino]bis{metandienon-3,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]})bicarbonate

Example 143A

4-fluoro-N,N-bis(3-nitrobenzyl)aniline

4-Ftoranila and 3-nitrobenzylamine were processed using the method described in Example 1A, with the receipt of 1.46 g (87%) specified in the connection header.1H NMR (400 MHz, DMSO-d6) δ 4,88 (s, 4H) 6,69 to 6.75 (m, 2H) 6,97 (t, J=8,89 Hz, 2H) to 7.64 (t, J=7,81 Hz, 2H) 7,70-7,74 (m, 2H) 8,08-8,13 (m, 4H).

Example 143B

N,N-bis(3-aminobenzyl)-4-ftoranila

To a suspension of the product from Example 143A (0,450 g, 1,180 mmol) in THF (4 ml), ethanol (1,00 ml) and water (4,00 ml) at room temperature was added ammonium chloride (0,189 g, 3.54 mmol) followed by addition of iron (0,329 g 5,90 mmol) and the mixture was heated to 80°C. After 3 hours the mixture was filtered through celite, concentrated, and the residue was distributed m is waiting for water and 25% solution of isopropyl alcohol-CHCl 3. The organic phase was dried (Na2SO4) and concentrated. The solid was dried in a vacuum oven to obtain 321 mg (85%) specified in the connection header. MS (ESI, M+H) m/z=322.

Example 143C

(2S,2'S)-tert-butyl 2,2'-(3,3'-(4-ftorhinolonovy)bis(methylene)bis(3,1-phenylene)bis(ethanediyl))bis(octamethylene)dipyrrole-1-carboxylate

The product from Example 143B and (S)-1-(tert-butoxycarbonyl)pyrrolidin-2-carboxylic acid (Aldrich) were processed using the method described in Example 41, to obtain 495 mg (69%) specified in the connection header. MS (ESI, M+H) m/z=716.

Example 143D

(2S,2'S)-N,N'-(3,3'-(4-ftorhinolonovy)bis(methylene)bis(3,1-phenylene))dipyrrole-2-carboxamide

The product from Example 143C were processed using the method described in Example 47B, to obtain 341 mg (96%) specified in the connection header.1H NMR (400 MHz, DMSO-d6) δ 1,60 by 1.68 (m, 4H) 1,71 and 1.80 (m, 2H) 1,98-of 2.08 (m, 2H) 2,69 (s, 6H) is 2.88 (t, J=6,56 Hz, 4H) to 3.67 (DD, J=8,73, 5,69 Hz, 2H) 4,63 (s, 4H) of 6.61 (DD, J=9,27, 4,39 Hz, 2H) 6,89-6,97 (m, 4H) to 7.25 (DD, J=7,81 Hz, 2H) of 7.55 (s, 4H) 9,92 (s, 2H).

Example 143E

Dimethyl ([(4-forfinal)imino]bis{metandienon-3,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]})bicarbonate

The product from Example 143D and (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid was treated with used the eat method, described in Example 41, to obtain 460 mg (81%) specified in the connection header.1H NMR (400 MHz, DMSO-d6) δ of 0.96 (s, 18H) 1,80-1,90 (m, 4H) 1,93-2,03 (m, 2H) 2,09-2,19 (m, 2H) 3,54 (s, 6H) 3,60-3,68 (m, 2H) 3,71-3,82 (m, 2H) is 4.21 (d, J=8,89 Hz, 2H) 4,43 (DD, J=8,02, 5,31 Hz, 2H) 4,63 (s, 4H) 6,57 of 6.66 (m, 2H) 6,89-of 6.96 (m, 4H) was 7.08 (d, J=8,78 Hz, 2H) 7,24 (t, J=7,86 Hz, 2H) 7,38 (s, 2H) to 7.59 (d, J=8,13 Hz, 2H) 10,00 (s, 2H).

Example 144

Dimethyl (3S,3'S)-3,3'-{[(4-forfinal)imino]bis[metandienon-4,1-Vilcabamba(2S)pyrrolidin-2.1-vylcarbenes]}dimorpholino-4-carboxylate

The product from Example 13D and (S)-4-(methoxycarbonyl)morpholine-3-carboxylic acid were processed using the method described in Example 13E, substituting DMF in dichloromethane, to obtain specified in the title compound (0.21 g, 52%).1H NMR (400 MHz, DMSO) δ 1,95 to 1.76 (m, 4H), 2,08-of 1.95 (m, 2H), 2,23-of 2.08 (m, 2H), 3,90-to 3.36 (m, 20H), 4,15 (l,J=11,6, 2H), 4,50-to 4.38 (m, 2H), 4,55 (s, 6H), 6,63 (DD,J=9,2, 4,4, 2H), 6,91 (t,J=8,9, 2H), 7,17 (l,J=8,5, 4H), 7,51 (l,J=8,4, 4H), for 9.90 (s, 2H), MS (ECI)m/z858 (M+H)+.

Example 145

Dimethyl ([(4-forfinal)imino]bis{metandienon-4,1-Vilcabamba[(2S,3S)-3-methylpyrrolidine-2.1-diyl][(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]})bicarbonate

Example 145A

(2S,3S)-1-(tert-butoxycarbonyl)-3-methylpyrrolidine-2-carboxylic acid

Specified in the title compound was obtained using esprimere 141A, replacing (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid (2S,3S)-3-methylpyrrolidine-2-carboxylic acid, to obtain the specified title compound (0.31 g, 74% yield).

Example 145B

(2S,2'S,3S,3'S)-tert-butyl 2,2'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene)bis(ethanediyl))bis(octamethylene)bis(3-methylpyrrolidine-1-carboxylate)

Specified in the title compound was obtained using the methods from Example 13C, substituting N-(tert-butoxycarbonyl)-L-Proline for the product from Example 145A, obtaining specified in the title compound (0.32 g, 70% yield).

Example 145C

(2S,2'S,3S,3'S)-N,N'-(4,4'-(4-ftorhinolonovy)bis(methylene)bis(4,1-phenylene))bis(3-methylpyrrolidine-2-carboxamide)

Specified in the title compound was obtained using the methods from Example 13D substituting the product from Example 13C of the product of Example 145B, obtaining specified in the title compound (0.20 g, 86% yield).

Example 145D

Dimethyl ([(4-forfinal)imino]bis{meander(6-methoxybenzo-3,1-diyl)carbarnoyl(2S)pyrrolidin-2.1-diyl[(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]})bicarbonate

Dimethyl ([(4-forfinal)imino]bis{metandienon-4,1-Vilcabamba[(2S,3S)-3-hydroxypyrrolidine-2.1-diyl][(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]})bicarbonate

Specified in the title compound was obtained using esprimere 13E, substituting the product from Example 13D of the product of Example 145C, obtaining specified in the title compound (55 mg, 33% yield).1H NMR (400 MHz, DMSO) δ 10,01 (Shir. s, 2H), 7,53 (l,J=to 8.5, 4H), 7,17 (l,J=8,5, 5H), 7,07 (l,J=the 8.6, 2H), 6,91 (t,J=of 8.7, 2H), only 6.64 (DD,J=4,4, 9,2, 2H), 4,55 (Shir. s, 4H), 4.16 the (l,J=to 8.5, 2H), 3,97(l,J=to 6.8, 2H), 3,90 (s, 2H), 3,62-3,55 (m, 2H), 3,54 (s, 6H), 2,28-of 2.16 (m, 2H), 2,15-2,03 (m, 2H), 1,62-1,49 (m, 2H), 1,09 (l,J=6,7, 6H), of 0.95 (s, 18H); MS (ECI; M+H) m/z=887.

Example 146

Dimethyl ([(4-forfinal)imino]bis{metandienon-3,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3-methyl-1-oxobutyl-1,2-diyl]})bicarbonate

Example 146A

4-fluoro-N,N-bis(3-nitrobenzyl)aniline

4-Ftoranila and 3-nitrobenzylamine were processed using the method described in Example 32A, obtaining specified in the connection header. LC/MS Rt 2,15 m/z 423 (M+CH3CN)+.

Example 146B

N,N-bis(3-aminobenzyl)-4-ftoranila

The product from Example 146A (1 g, 2,62 mmol), ammonium chloride (0,4965 g, 9.28 are mmol) and iron (0,7849 g 14,05 mmol) were combined in a mixture of THF (12 ml)/ethanol (12,00 ml)/water (3,00 ml) and heated to 80°C. After 18 hours was added an additional amount of ammonium chloride (0,5162 g, 9,65 mmol) and iron (0,8541 g, 15,29 mmol), and heating was continued for 3 days. The reaction mixture was filtered through a cake of celite and koncentrira the Lee. The residue was transferred into EtOAc and washed with water (2x), saturated brine (1x), dried (MgSO4) and concentrated. Specified in the title compound was used without purification. MS (DCI) m/z 322 (M+H)+.

Example 146C

(2S,2'S)-tert-butyl 2,2'-(3,3'-(4-ftorhinolonovy)bis(methylene)bis(3,1-phenylene)bis(ethanediyl))bis(octamethylene)dipyrrole-1-carboxylate

The product from Example 146B were processed using the method described in Example 1C, substituting DMSO in dichloromethane, to obtain specified in the connection header (1,34 g, 71%). MS (ESI) m/z 716 (M+H)+.

Example 146D

(2S,2'S)-N,N'-(3,3'-(4-ftorhinolonovy)bis(methylene)bis(3,1-phenylene))dipyrrole-2-carboxamide

The product from Example 146C were processed using the method described in Example 1D, obtaining specified in the connection header. LC/MS Rt 1,26 m/z 516 (M+H)+.

Example 146E

dimethyl ([(4-forfinal)imino]bis{metandienon-3,1-Vilcabamba(2S)pyrrolidin-2.1-diyl[(2S)-3-methyl-1-oxobutyl-1,2-diyl]})bicarbonate

The product from Example 146D were processed using the method described in Example 1E, and was purified using flash chromatography (silica gel, MeOH/dichloromethane) to obtain specified in the connection header.1H NMR (400 MHz, DMSO) δ 0,97-of 0.82 (m, 12H), 2,19-to 1.79 (m, 10H), 3,52 (s, 6H), 3,67 is 3.57 (m, 2H), 3,85 of 3.75 (m, 2), as 4.02 (t, J=8,5, 2H), 4,43 (DD, J=4,7, 8,1, 2H), 4,63 (s, 4H), 6,63-6,56 (m, 2H), 6,92 (DD, J=5,6, 12,0, 4H), 7,24 (t, J=7,9, 2H), 7,31 (d, J=8,4, 2H), 7,40 (s, 2H), 7,58 (d, J=8,1, 2H), 10,00 (s, 2H), MS (ECI)m/z831 (M+H)+, 828 (M-H)+.

Example 147

Dimethyl ([(4-forfinal)imino]bis{meander(6-methoxybenzo-3,1-diyl)carbarnoyl(2S)pyrrolidin-2.1-diyl[(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]})bicarbonate

Example 147A

4-fluoro-N,N-bis(4-methoxy-3-nitrobenzyl)aniline

4-Ftoranila and 4-methoxy-3-nitrobenzylamine were processed using the method described in Example 1A, with the receipt of 2.33 g (91%) specified in the connection header. MS (ESI, M+H) m/z=442.

Example 147B

N,N-bis(3-amino-4-methoxybenzyl)-4-ftoranila

The product from Example 147A were processed using the method described in Example 143B, to obtain 1.64 g (81%) specified in the connection header. MS (ESI, M+H) m/z=382.

Example 147C

(2S,2'S)-tert-butyl 2,2'-(5,5'-(4-ftorhinolonovy)bis(methylene)bis(2-methoxy-5,1-phenylene))bis(ethanediyl)bis(octamethylene)dipyrrole-1-carboxylate

The product from Example 147B and (S)-1-(tert-butoxycarbonyl)pyrrolidin-2-carboxylic acid (Aldrich) were processed using the method described in Example 41, obtaining 2,49 g (75%) specified in the connection header. MS (ESI, M+H) m/z=776.

Example 147D

(2S,2'S)-N,N'-(5,5'-(4-ftorhinolonovy)bis(methylene)bis(2-methoxy-5,1-phenylene))dipyrrole-2-carboxamide

The product from Example 147C were processed using the method described in Example 47B, obtaining 1,82 g (99%) specified in the connection header. LC/MS (M+H) m/z=576; retention time 1.13 minutes.

Example 147E

dimethyl ([(4-forfinal)imino]bis{meander(6-methoxybenzo-3,1-diyl)carbarnoyl(2S)pyrrolidin-2.1-diyl[(2S)-3,3-dimethyl-1-oxobutyl-1,2-diyl]})bicarbonate

The product from Example 147D and (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid were processed using the method described in Example 41, to obtain 250 mg (48%) specified in the connection header.1H NMR (400 MHz, DMSO-d6) δ 0,97 (s, 18H) 1,88-1,95-2,03 (m, 8H) of 3.54 (s, 6H) 3,61-to 3.67 (m, 2H) of 3.73-3,82 (m, 2H) 3,79 (s, 6H) is 4.21 (d, J=8,78 Hz, 2H) 4,51 (s, 4H) 4,67 (DD, J=6,89, 5,15 Hz, 2H) 6,58 of 6.68 (m, 2H) 6,86-of 6.96 (m, 6H) 7,16 (d, J=8,67 Hz, 2H) 8,05 (Shir. s, 2H) 9,20 (Shir. s, 2H).

Example 148

Methyl [(1S)-1-{[(2S)-2-(5-{[({2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1,3-benzoxazol-5-yl}methyl)(phenyl)amino]methyl}-1,3-benzoxazol-2-yl)pyrrolidin-1-yl]carbonyl}-2-methylpropyl]carbamate

Example 148AA

4-(methyl bromide)-1-chloro-2-nitrobenzene

To a solution of (4-chloro-3-nitrophenyl)methanol (5.0 g, to 26.6 mmol) in toluene (100 ml) was added tribromide phosphorus (0,879 ml, to 9.32 mmol) at 40°C. the Reaction mixture was paramesh the Wali at 100°C for 15 minutes and was distributed between water and ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated in vacuum to obtain specified in the connection header.

Example 148BB

N-(4-chloro-3-nitrobenzyl)aniline

To a solution of 4-chloro-3-nitrobenzaldehyde (10.0 g, 53,9 mmol) and aniline (2,34 ml of 25.7 mmol) in ethanol (200 ml) was added acetic acid (7,35 ml, 128 mmol), followed by the addition of portions of an additional amount cyanoborohydride sodium (4,84 g, 77 mmol). The resulting mixture was stirred at room temperature for 2.5 hours and concentrated in vacuum. The residue was distributed between ethyl acetate and saturated aqueous NaHCO3and the organic layer was dried over anhydrous Na2SO4. The desiccant was filtered, and the solvent was removed in vacuum to obtain the crude product, which was purified using column chromatography on silica gel using a gradient solvent 0-1% methanol in dichloromethane to obtain specified in the title compound (5.7 g, 85%).

Example 148C

N,N-bis (4-chloro-3-nitrobenzyl)aniline

To a solution of the product from Example 148A (4.0 g, 15,23 mmol) and the product from Example 148B (7,63 g of 30.5 mmol) in DMF (150 ml) was added to the base Hunya (8.0 ml of 45.7 mmol) and the resulting mixture was stirred at 90°C during the night. The mixture was cooled to room is temperature and distributed between CH 2Cl2and H2O, and the organic layer was dried over anhydrous Na2SO4. The desiccant was filtered, and the solvent was removed in vacuum to obtain the crude product, which was purified using column chromatography on silica gel using a gradient solvent 0-5% methanol in dichloromethane, to obtain specified in the connection header.

Example 148D

N,N-bis(3-amino-4-Chlorobenzyl)aniline

To a solution of the product from Example 148C (0,304 g, 0,703 mmol) in EtOH (10 ml), THF (10 ml) and H2O (2.5 ml) was added iron powder (0,393 g, 7.03 mmol) followed by the addition of ammonium chloride (0,188 g to 3.52 mmol). The resulting mixture was stirred at 90°C for 2 hours and then filtered through celite and washed with ethanol. The filtrate was concentrated in vacuo, and the residue was distributed between CH2Cl2and H2O, and the organic layer was dried over anhydrous Na2SO4. The desiccant was filtered, and the solvent was removed in vacuum to obtain the crude product, which was purified using column chromatography on silica gel using a gradient solvent 0-0,1% MeOH in CH2Cl2with obtaining specified in the connection header (0,259 g, 99%).

Example 148E

(2S,2'S)-tert-butyl 2,2'-(5,5'-(phenylaziridine)bis(methylene)bis(2-chloro-5,1-phenylene))bystander)bis (octamethylene)dipyrrole-1-carboxylate

To a solution of the product from Example 148D (0.50 g, up 1.343 mmol) in DMF (6,7 ml) and pyridine (6,7 ml) was added (S)-1-(tert-butoxycarbonyl)pyrrolidin-2-carboxylic acid (0.723 g, to 3.36 mmol) and 1-[3-(dimethylaminopropyl]-3-ethylcarbodiimide (to 2.57 g, 13,43 mmol). The resulting mixture was stirred at room temperature overnight and then distributed among ethylacetat and 1 N. aqueous solution of HCl. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude product, which was purified using column chromatography on silica gel using a gradient solvent 0-2% MeOH in CH2Cl2obtaining specified in the connection header (0,875 g, 85%).

Example 148F

(2S,2'S)-tert-butyl 2,2'-(5,5'-(phenylaziridine)bis(methylene)bis(benzo[d]oxazole-5,2-diyl))dipyrrole-1-carboxylate

To a solution of the product from Example 148E (0,366 g, 0,477 mmol) in 1,4-dioxane (5 ml) was added 1,10-phenanthroline (0,086 g, 0,477 mmol), cesium carbonate (0,933 g of 2.86 mmol) and copper iodide(I) (0,045 g, 0,239 mmol). The resulting mixture was stirred at 110°C for 3.5 days. The cooled mixture was distributed between CH2Cl2and H2O, and the organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered, and the solvent was removed in vacuum to obtain the crude product, which is first purified using column chromatography on silica gel, using a gradient solvent 0-5% MeOH in CH2Cl2with obtaining specified in the connection header (0,150 g, 45%).

Example 148G

N,N-bis((2-((S)-pyrrolidin-2-yl)benzo[d]oxazol-5-yl)methyl)aniline

To a solution of the product from Example 148F (0,150 g, 0,216 mmol) in CH2Cl2(2 ml) was added 2,2,2-triperoxonane acid (1 ml, 0,216 mmol). The resulting mixture was stirred at room temperature for 30 minutes and concentrated in vacuum. The mixture was distributed between CH2Cl2and saturated aqueous NaHCO3and the organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered, and the solvent was removed in vacuum to obtain the crude product, which was purified using column chromatography on silica gel using a gradient solvent 0-14% MeOH in CH2Cl2with obtaining specified in the connection header (44,3 mg, 42%).

Example 148H

methyl [(1S)-1-{[(2S)-2-(5-{[({2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1,3-benzoxazol-5-yl}methyl)(phenyl)amino]methyl}-1,3-benzoxazol-2-yl)pyrrolidin-1-yl]carbonyl}-2-methylpropyl]carbamate

The product from Example 148G (0,019 g of 0.038 mmol) was subjected to the procedure described in Example 24E, obtaining specified in the connection header in the form of a salt TFOC (6 mg).1H NMR (500 MHz, DMSO-d6) δ M. D. 0,84 with 0.93 (m, 12H, 1,85-of 2.34 (m, 12H), 3,53 (s, 6H), a 3.87-of 3.97 (m, 3H), 4,05-to 4.14 (m, 2H), 4,79-a 4.86 (m, 4H), 5,12 (DD, 1H), 5,16 (DD,J=7,7, 3.1 Hz, 1H), return of 6.58 (t,J=7.2 Hz, 1H), of 6.71 (d,J=8,1 Hz, 2H),? 7.04 baby mortality-7,11 (m, 2H), 7,28 (l,J=8.5 Hz, 2H), 7,32-7,39 (m, 1H), 7,50 (s, 2H), 7,56-to 7.64 (m, 2H); MS m/z 808,3 (M+H)+.

Example 149

N-(Methoxycarbonyl)-3-methyl-L-poured-N-(4-{[{4-[((E)-2-{(2S)-1-[N-(methoxycarbonyl)-3-methyl-L-valil]pyrrolidin-2-yl}ethynyl]benzyl}(phenyl)amino]methyl}phenyl)-L-prolinamide

Example 149A

methyl 4-((diethoxyphosphoryl)methyl)benzoate

A solution of methyl 4-(methyl bromide)benzoate (12.5 g, the 54.6 mmol) in triethylphosphite (20 ml, 114 mmol) was heated at 150°C for 2 hours. After cooling, the solution was concentrated under vacuum. Purification via chromatography (silica gel, 0-2% methanol in dichloromethane) gave specified in the header connection. MS (ESI) m/z 287 (M+H)+.

Example 149B

(S,E)-tert-butyl 2-(4-(methoxycarbonyl)styryl)pyrrolidin-1-carboxylate

To a solution of the product of Example 149A (as 4.02 g, 14,05 mmol) dissolved in THF (50 ml) and cooled to -78°C was added dropwise lithium bis(trimethylsilyl)amide of (1.0 M in THF, 12,05 ml, a 12.05 mmol) and the resulting solution was stirred at -78°C for another 1 hour. After this was added dropwise a solution of (S)-tert-butyl 2-formylpyridine-1-carboxylate (2.0 g, 10,04 mmol) in THF (20 ml), the cooling bath was then removed and, after the reaction mixture had reached room te is the temperature, it was maintained at this temperature for an additional 3 hours. To this mixture solution was added EtOAc and the mixture was extracted with water. The organic extract was then dried, filtered, concentrated and purified via chromatography (silica gel, 10-50% EtOAc in hexane) to give the 2,05 g (62%) specified in the connection header. MS (ESI) m/z 332 (M+H)+.

Example 149C

(S,E)-tert-butyl 2-(4-(hydroxymethyl)styryl)pyrrolidin-1-carboxylate

To a solution of the product of Example 149B (1.0 g, to 3.02 mmol) dissolved in dichloromethane (20 ml) and cooled to -78°C was added dropwise diisobutylaluminum of (1.0 M in dichloromethane, 10,56 ml, 10,56 mmol) and the resulting solution was stirred at -78°C for 10 minutes, the cooling bath was then removed, and after the reaction mixture had reached room temperature, it was maintained at this temperature for an additional 1 hour. To the solution was added acetone (1 ml), then thereto was added EtOAc and the mixture was extracted with aqueous solution of tartrate of potassium-sodium. The organic extract was then dried, filtered and concentrated to obtain 0.9 g (98%) specified in the connection header. MS (ESI) m/z 304 (M+H)+.

Example 149D

(S,E)-tert-butyl 2-(4-(methyl bromide)styryl)pyrrolidin-1-carboxylate

To a solution of the product of Example 149C (0.9 g, of 2.97 mmol) dissolved in THF (50 ml), was added linked resin Trife livostin (to 5.93 mmol) and tetrabromide carbon (1.48 g, of 4.45 mmol) and the resulting solution was stirred at room temperature for 2 hours. The resin was then filtered off, washed using THF and the combined filtrate was then dried, filtered and concentrated to obtain specified in the title compound, m/z 368 (M+H)+.

Example 149E

(S,E)-tert-butyl 2-(4-(((4-nitrobenzyl)(phenyl)amino)methyl)styryl)pyrrolidin-1-carboxylate

To a solution of the product of Example 149D (1,09 g of 2.97 mmol) and N-(4-nitrobenzyl)aniline (0,677 g of 2.97 mmol) dissolved in DMF (10 ml), was added potassium carbonate (1.23 g, 8.9 mmol) and the mixture was heated at 50°C for 1 hour. After cooling, the solution was added dichloromethane and the mixture was extracted with water. The organic extract was then dried, filtered, concentrated and purified via chromatography (silica gel, 0-2% methanol in dichloromethane) to give 0.85 grams (56%) specified in the connection header. MS (ESI) m/z 514 (M+H)+.

Example 149F

(S,E)-tert-butyl 2-(4-(((4-aminobenzyl)(phenyl)amino)methyl)styryl)pyrrolidin-1-carboxylate

A solution of the product of Example 149E (0.8 g, 1.56 mmol), dissolved in ethanol (20 ml), cooled in an ice bath to 0°C, then add the chloride of bismuth(III) (1.47 g, of 4.67 mmol) followed by the addition in portions sodium borohydride (943 mg, 24,92 mmol) and heating the solution to room t is mperature for 20 minutes. Was added methanol, and the solid was removed by filtration, the filtrate was concentrated to obtain oil, which was re-dissolved with dichloromethane and extracted with aqueous sodium bicarbonate solution. The organic solution was then dried, filtered and concentrated to obtain specified in the title compound, m/z 484 (M+H)+.

Example 149G

(S)-tert-butyl 2-(4-(((4-(((E)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)vinyl)benzyl)(phenyl)amino)methyl)phenylcarbamoyl)pyrrolidin-1-carboxylate

The product from Example 149F (700 mg, 1,45 mmol) and (S)-1-(tert-butoxycarbonyl)pyrrolidin-2-carboxylic acid (374 mg, of 1.74 mmol) were processed using the method described in Example 43, to obtain 240 mg (23%) specified in the connection header.1H NMR (500 MHz, DMSO-d6) δ M. D. 9,92 (s, 1H), 7,52 (d,J=8,4 Hz, 2H), 7,34 (l,J=7.9 Hz, 2H), 7,18 (m, 4H), 7,07 (m, 2H), only 6.64 (d,J=8,1 Hz, 2H), 6,55 (t,J=7.7 Hz, 1H), of 6.31 (d,J=15.6 Hz, 1H), 6,14 (DD,J=of 15.5 and 6.5 Hz, 1H), 4,63 (s, 2H), 4,60 (s, 2H), 4,22 (m, 1H), 4,17 (m, 1H), 3,38 (m, 2H), or 3.28 (m, 2H), of 1.85 (m, 8H), to 1.38 (s, 9H), of 1.30 (s, 9H).

Example 149H

(S)-N-(4-((phenyl(4-((E)-2-((S)-pyrrolidin-2-yl)vinyl)benzyl)amino)methyl)phenyl)pyrrolidin-2-carboxamide

To a solution of the product of Example 149G (50 mg, 0,073 mmol) dissolved in dichloromethane (0.3 ml), was added triperoxonane acid (2.7 ml) and the resulting solution was stirred PR the room temperature for 20 minutes. The solution is then concentrated under vacuum, the residue was dissolved in a mixture of chloroform/isopropanol and was extracted with aqueous sodium bicarbonate solution, the organic solution was then dried, filtered and concentrated to obtain specified in the title compound, m/z 481 (M+H)+.

Example 149I

N-(methoxycarbonyl)-3-methyl-L-poured-N-(4-{[{4-[((E)-2-{(2S)-1-[N-(methoxycarbonyl)-3-methyl-L-valil]pyrrolidin-2-yl}ethynyl]benzyl}(phenyl)amino]methyl}phenyl)-L-prolinamide

The product from Example 149H (35 mg, 0.73 mmol) and (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanol acid (33,1 mg, 0,175 mmol) were processed using the method described in Example 43, to obtain 33 mg (55%) specified in the connection header.1H NMR (500 MHz, DMSO-d6) δ M. D. 9,98 (s, 1H), 7,50 (d,J=8,4 Hz, 2H), 7,28 (l,J=8,3 Hz, 2H), 7,17 (m,4H), 7,06 (m, 3H), 6,63 (m, 2H), 6,55 (t,J=7,3 Hz, 1H), 6,37 (l,J=15.7 Hz, 1H), from 6.22 (m, 1H), 6,17 (DD, J=16,0, 6.3 Hz, 1H), 4,63 (m, 1H), br4.61 (s, 2H), 4,58 (s, 2H), 4,42 (m, 1H), 4,19 (m, 2H), of 3.77 (m, 1H), 3,70 (m, 1H), 3,63 (m, 2H), 3,52 (s, 6H), of 2.16 (m, 2H), a 1.96 (m, 2H), of 1.84 (m, 4H), of 0.95 (s, 9H), of 0.93 (s, 9H).

Example 150

di[(3S)-tetrahydrofuran-3-yl](2S,2'S)-2,2'-[(phenylimino)bis(metandienon-4,1-Vilcabamba)]dipyrrole-1-carboxylate

The product of Example 1D (25 mg, 0,050 mmol) and (S)-2,5-dioxopiperidin-1-yl tetrahydrofuran-3-ylcarbamate (to 25.3 mg, 0,111 mmol) was dissolved in dichloromethane (3 ml) was then added to the basis X is nig (0,026 ml, 0,151 mmol) and the mixture was stirred at room temperature for 18 hours. The solution contained added dichloromethane, and the mixture was extracted with water. The organic extract was then dried, filtered, concentrated and purified via chromatography (silica gel, 0-10% methanol in dichloromethane) to give 28 mg (77%) specified in the connection header.1H NMR (500 MHz, DMSO-d6) δ memorial plaques: 9,96 (s, 2H), of 7.48 (d, J=8,4 Hz, 4H), 7,17 (d, J=8.1 Hz, 4H), 7,06 (t, J=8.0 Hz, 2H), only 6.64 (d, J=8,4 Hz, 2H), 6,55 (t, J=7,3 Hz, 1H), of 5.05 (m, 2H), 4,59 (s, 4H), 4,24 (m, 2H), to 3.73 (m, 8H), 3,40 (m, 6H), of 2.15 (m, 4H), of 1.95 (m, 2H) and 1.83 (m, 4H).

These headlines Examples 1, 2, 3, 6, 7, 9, 10, 11, 12, 13, 14, 17, 18, 20, 21, 22, 23, 28, 31, 34, 35, 39, 42, 43, 50, 53, 54, 55, 56, 57, 58, 60, 64, 65, 66, 67, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 92, 95, 96, 98, 99, 101, 102, 103, 104, 105, 106, 110, 113, 114, 115, 116, 117, 119, 120, 121, 123, 124, 125, 127, 128, 131, 132, 133, 136, 137, 138, 142, 143 and 145 compounds showed EC50 values less than 1 nm in the analysis of the replication of hepatitis C virus (HCV) 1b-Con-1; specified in the headlines Examples 8, 15, 24, 25, 33, 36, 37, 38, 45, 46, 47, 48, 49, 51, 52, 61, 62, 91, 93, 94, 100, 108, 111, 112, 118, 129, 130, 134, 135, 139, 140 and 146 compounds showed EC50 values from 1 nm to 10 nm in the analysis of the replication of HCV 1b-Con-1; specified in the headlines Examples 4, 5, 16, 19, 26, 27, 40, 41, 44, 59, 63, 79, 80, 107, 109, 122, 126, 141, 149 and 150 compounds showed EC50 values ranging from 10 nm to 100 nm in the analysis of the replication of HCV 1b-Con-1; specified in the headlines Examples 29, 30, 32, 68, 97, 144, 147 and 148 compounds showed C is achene EC50 of 100 nm to 250 nm in the analysis of the replication of HCV 1b-Con-1. Each anti-HCV activity of the compounds was determined by measuring the activity of the reporter gene luciferase in the replicon in the presence of 5% FBS. The reporter gene luciferase was taken under translational control of the poliovirus IRES instead of the HCV IRES, and cells HuH-7 used to support replication of the replicon.

The following compounds were obtained in a similar manner, in accordance with the above-described Schemes and Examples:

In addition, the following compounds of formula I can be similar to arr is thus obtained in accordance with the present invention,

,

where a is selected from table Ia, B is selected from table Ib, D is selected from table 2, Y and Z, each independently, selected from table 3, and A, B, and D, each independently, optionally substituted by one or more substituents RAand where X, L1, L2, L3and RAhave the meanings given above. Preferably, X represents N, L1and L2each independently represents a C1-C6alkylene (for example, -(CH2)-), and L3that is the link, where L1and L2each independently optionally substituted by one or more substituents selected from halogen, RT, -O-Rs, -S-RS, -N(RSRS'), -OC(O)RS, -C(O)ORS, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano, and RT, RSand RS'have the meanings given above.

Inhibitory activity of compounds of the present invention can be assessed using various assays known in the prior art. For example, two stable containing subgenomic the replicon cell line can be used for har is cterization compounds in cell culture: one, originating from the genotype 1a H77, and the other derived from genotype 1b-Conl, obtained from University of Texas Medical Branch (Galveston, TX) and Apath, LLC (St. Louis, MO), respectively. Replicalouis design can be bicistronic subgenomic the replicons. Repnikova design of genotype 1a contains the NS3-NS5B coding region, originating from the H77 strain of HCV (1a-H77). The replicon also contains a reporter gene Firefly luciferase and breeding marker neomycin phosphotransferase (Neo). These two coding region separated FMDV 2a protease include first cistron bicistronic replicalouis design, with the second cistrana containing the NS3-NS5B coding region with the addition of adaptive mutations E1202G, K1691R, K2040R and S2204I. 1b-Conl Repnikova design is identical to 1a-the H77 replicon, except that the HCV 5' UTR, 3' UTR and NS3-NS5B coding region originate from the 1b-Con1 strain, and the adaptive mutations are K1609E, K1846T and Y3005C. In addition, the 1b-Con1 Repnikova design contains poliovirus IRES between the HCV IRES and gene luciferase. Containing the replicon cell lines can be maintained in the modified Dulbecco environment Needle (DMEM) containing 10% (V/V) fetal bovine serum (FBS), 100 Med./ml penicillin, 100 mg/ml streptomycin (Invitrogen) and 200 mg/ml G418 (Invitrogen).

The inhibitory effects of the compounds of the present invention in relation to the replication of HCV can define the ü by measuring the activity of the reporter gene luciferase. For example, the replicon-containing cells were seeded in 96-well tablets at a density of 5000 cells/well in 100 μl DMEM containing 5% FBS. The next day, compounds can be diluted in dimethyl sulfoxide (DMSO) to obtain 200x initial solution using eight serial half-log dilutions. Serial dilution can then be further diluted 100-fold in medium containing 5% FBS. Medium with inhibitor added to the tablets, which contain a cell culture during the night, already containing 100 μl of DMEM with 5% FBS. In assays measuring inhibitory activity in the presence of human plasma environment of tablets with cell culture contained in them during the night, could be replaced by DMEM containing 40% human plasma and 5% FBS. Cells can be incubated for three days in the incubator for tissue cultures, after which 30 μl of passive lisanova buffer (Promega) can be added to each well, and then tablets incubated for 15 minutes with swing for lysis of the cells. You can add the solution of luciferin (100 μl, Promega) to each well, and luciferase activity can be measured using a luminometer Victor II (Perkin-Elmer). The percentage inhibition of the replication of HCV RNA can be calculated for each concentration of the compound, and the value of EC50can be calculated using a nonlinear regression curve fitting to logistics the equation with 4 parameters and the program GraphPad Prism 4. When using the above-described assays or similar cellular replication analyses, representative compounds of the present invention showed significant inhibitory activity against HCV replication.

The present invention also includes pharmaceutical compositions containing the compounds of the present invention. The pharmaceutical composition of the present invention may contain one or more compounds of the present invention, each of which has the formula I (or IA, IBor Ic).

In addition, the present invention includes pharmaceutical compositions containing pharmaceutically acceptable salt, solvate or prodrug compounds of the present invention. Without limitation, pharmaceutically acceptable salts can be zwitterionic or derived from pharmaceutically acceptable inorganic or organic acids or bases. Preferably, pharmaceutically acceptable salt retains the biological effectiveness of the free acid or base compounds without excessive toxicity, irritation or allergic reactions, has a reasonable ratio of benefit/risk, is effective for its intended use and is not biologically or otherwise undesirable.

The present invention also includes pharmaceutical is septicemia composition, containing the compound of the present invention or its salt, MES or prodrug) and another therapeutic agent. To illustrate and not to limit, the other therapeutic agent can be selected from antiviral agents (e.g., anti-HIV funds, anti-HBV funds or other anti-HCV tools, such as inhibitors of HCV protease, inhibitors of HCV polymerase, inhibitors of HCV helicase, IRES inhibitors, or inhibitors NS5A), antibacterial agents, antifungal agents, immunomodulators, anti-cancer or chemotherapeutic agents, antiinflammatory agents, antisense RNA, siRNA, antibodies or remedies for the treatment of cirrhosis or liver inflammation. Specific examples of such other therapeutic agents include, but are not limited to, ribavirin, α-interferon, β-interferon, targeted interferon-α, targeted interferon-lambda, ribavirin, viramidine, R-5158, nitazoxanide, amantadine, Debio-025, NIM-811, R7128, R1626, R4048, T-1106, PSI-7851, PF-00868554, ANA-598, IDX184, IDX102, IDX375, GS-9190, VCH-759, VCH-916, MK-3281, BCX-4678, MK-3281, VBY708, ANA598, GL59728, GL60667, BMS-790052, BMS-791325, BMS-650032, GS-9132, ACH-1095, AP-H005, A-831, and A-689, AZD2836, telaprevir, boceprevir, ITMN-191, BI-201335, VBY-376, VX-500 (Vertex), PHX-B, ACH-1625, IDX136, IDX316, VX-813 (Vertex), SCH 900518 (Schering-Plough), TMC-435 (Tibotec), ITMN-191 (Intermune, Roche), MK-7009 (Merck), IDX-PI (Novartis), BI-201335 (Boehringer Ingelheim), R7128 (Roche), PSI-7851 (Pharmasset), MK-3281 (Merck), PF-868554 (Pfizer), IDX-184 (Novartis), IDX-375 (Pharmasset), BILB-1941(Boehringer Ingelheim), GS-9190 (Gilead), BMS-790052 (BMS), Albuferon (Novartis), ritonavir, another inhibitor of mono-oxidase cytochrome P450 or any combination of such means.

In one variant embodiment of the pharmaceutical composition of the present invention contains one or more compounds of the present invention (or salts, solvate, or prodrugs) and one or more other antiviral agents.

In another variant embodiment of the pharmaceutical composition of the present invention contains one or more compounds of the present invention (or salts, solvate, or prodrugs) and one or more other anti-HCV funds. For example, the pharmaceutical composition of the present invention may contain the compound (compounds) of the present invention having the formula I, IA, IBor Ic(or its salt, MES or prodrug) and a means selected from inhibitors of HCV polymerase (including polymerase inhibitors nucleoside or non-nucleoside-type inhibitors), inhibitors of HCV protease, inhibitors of HCV helicase, CD81 inhibitors, inhibitors of cyclophilin, IRES inhibitors, or inhibitors of NS5A.

In another variant embodiment of the pharmaceutical composition of the present invention contains one or more compounds of the present invention (or salts, solvate, or prodrugs) and one sludge is several other antiviral agents, such as anti-HBV, anti-HIV funds or funds against hepatitis A, hepatitis D, hepatitis E, or against hepatitis G. non-limiting examples of anti-HBV funds include adenovir, lamivudine and tenofovir. Non-limiting examples of anti-HIV medicines include ritonavir, lopinavir, indinavir, nelfinavir, saquinavir, APV, atazanavir, tipranavir, TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide, T-1249, or other inhibitors of HIV protease, reverse transcriptase, integrase, or merge. Any other desirable antiviral agents may also be included in the pharmaceutical composition of the present invention, as should be clear to the experts and this area.

The pharmaceutical composition of the present invention typically includes a pharmaceutically acceptable carrier or excipient. Non-limiting examples of suitable pharmaceutically acceptable carriers/excipients include sugars (e.g. lactose, glucose or sucrose, starches (e.g. corn starch or potato starch), cellulose or its derivatives (for example, sodium carboxymethyl cellulose, ethylcellulose or cellulose acetate), oils (e.g. peanut oil, cotton seeds, afforable oil, sesame oil, olive oil, corn oil or soybean oil), glycols (e.g. propylene glycol), buffering agents (such as magnesium hydroxide or aluminum hydroxide), agar, alginic acid, powdered tragakant, malt, gelatin, talc, cocoa butter, pyrogen-free water, isotonic saline, ringer's solution, ethanol or phosphate buffer solutions. Lubricants, colorants, release agents, substances, coatings, sweeteners, fragrances or flavors, preservatives or antioxidants may also be included in the pharmaceutical composition of the present invention.

The pharmaceutical compositions of the present invention can be formulated according to the ways of their introduction, using methods well known in the prior art. For example, a sterile preparation for injection can be obtained in the form of a sterile aqueous or oily suspension for injection using suitable dispersing or wetting agents and suspension agents. Suppositories for rectal injection can be obtained by mixing the drug with a suitable non-irritating by excipients, such as cocoa butter or polyethylene glycols, which are solid at ordinary temperatures but liquid at rectal temperature and therefore melt in the rectum and h is wait for a remedy. Solid dosage forms for oral administration can consist of capsules, tablets, pills, powders or granules. In such solid dosage forms the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Solid dosage forms can also include other substances in addition to the inert diluents, such as lubricants. In the case of capsules, tablets and pills, the dosage form can also include buffering agents. Tablets and pills can also be obtained with intersolubility coatings. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs containing inert diluents conventionally used in this field. Liquid dosage forms can also include wetting, emulsifying, suspendresume agents, sweeteners, fragrances or flavors. The pharmaceutical compositions of the present invention can also be entered in the form of liposomes, as described in U.S. patent No. 6703403. The formulation of drugs that are applicable to the present invention, in General, is discussed, for example, Hoover, John E., REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Publishing Co., Easton, PA: 1975) and Lachman, L., eds., PHARMACEUTICAL DOSAGE FORMS (Marcel Decker, New York, N. Y, 1980).

Any connection that is described in this application, or its pharmaceutically acceptable salt can be used to obtain pharmaceutical compositions of the present invention.

The present invention also includes methods of using compounds of the present invention (or salts, solvate, or prodrugs) to inhibit the replication of HCV. The methods include contacting cells infected with the HCV virus with an effective amount of the compounds of the present invention (or salts, MES or prodrugs), inhibiting thus, the replication of the HCV virus in the cells. As used in this application, "inhibition" means a significant reduction or elimination of the activity, subject to inhibition (for example, replication of the virus). In many cases, representative compounds of the present invention can reduce the replication of the HCV virus (e.g., HCV analysis of replication as described above) at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more.

Compounds of the present invention can inhibit one or more subtypes of HCV. Examples of subtypes of HCV, which can be inhibited in accordance with the present invention include, but are not limited to, HCV genotypes 1, 2, 3, 4, 5 and 6, including HCV genotypes 1a, 1b, 2a, 2b, 2c or 3a. In one variant embodiment of the connection Il the compounds of the present invention (or their salts, the solvate or prodrug) is used for inhibiting replication of HCV genotype 1a. In another variant embodiment, the compound or compounds of the present invention (or a salt, solvate or prodrug) is used for inhibiting replication of HCV genotype 1b. In another variant embodiment, the compound or compounds of the present invention (or a salt, solvate or prodrug) is used for inhibiting replication of HCV in both genotypes 1a and 1b.

The present invention also includes methods of using compounds of the present invention (or salts, solvate, or prodrugs) to treat HCV infection. The methods typically include the introduction of a therapeutically effective amount of the compounds of the present invention (or salts, MES or prodrugs) or pharmaceutical compositions containing them, HCV patient, thus reducing the level of HCV virus in the blood or liver of the patient. As used in this application, the term "treatment" refers to the reverse development, the alleviation, inhibition of progression, or prevention of a disorder or condition or one or more symptoms of such disorder or condition is applied to this term. The term "treatment" refers to the act of treatment. In one variant embodiment, the methods include the introduction of therapeutically effectiveagainst two or more compounds of the present invention (or salts, the solvate, or prodrugs) or pharmaceutical compositions containing such compounds, HCV patient, thus reducing the level of HCV virus in the blood or liver of the patient.

The compound of the present invention or its salt, MES or prodrug) can be entered as the only active pharmaceutical agents or in combination with other desirable drug, such as other anti-HCV tools, anti-HIV funds, anti-HBV funds funds against hepatitis A, anti-hepatitis D, anti-hepatitis E, anti-hepatitis G or other antiviral drugs. Any connection that is described in this application, or its pharmaceutically acceptable salt can be used in the methods of the present invention.

The compound of the present invention or its salt, MES or prodrug), you can enter the patient in a single dose or divided doses. A typical daily dose is within, without limitation, from 0.1 to 200 mg/kg body weight, for example, from 0.25 to 100 mg/kg of body weight. Compositions for one dose can contain such number or fraction of units that make up the daily dose. Preferably, each dose contains sufficient amounts of the compounds of the present invention, which is effective to reduce HCV viral on the power in the blood or liver of the patient. The amount of the active ingredient or active ingredients, which are combined to obtain the standard unit dosage form may vary depending on the host, which is treated and the particular route of administration. It should be clear that a particular level of dosage for any particular patient depends upon a variety of factors including the activity of the specific compound, the age, body weight, General health, sex, diet, time of administration, route of administration, rate of excretion, combination of drugs and the severity of the particular disease being treated.

The present invention also includes methods of using pharmaceutical compositions of the present invention for treatment of HCV infection. The methods typically include the introduction of a pharmaceutical composition of the present invention HCV patient, thus reducing the level of HCV virus in the blood or liver of the patient. Any pharmaceutical composition described in this application can be used in the methods of the present invention.

In addition, the present invention includes the use of compounds or salts of the present invention to obtain drugs for treatment of HCV infection. Any connection that is described in this application, or its pharmaceutically acceptable salt mo is to obtain drugs of the present invention.

Compounds of the present invention can also be isotopically substituted. The preferred isotope substitution include substitution stable or non-radioactive isotopes, such as deuterium,13C,15N or18O. Incorporation of a heavy atom, for example, substitution of hydrogen by deuterium, can lead to isotope effects, which may alter the pharmacokinetics of drugs. In one example, at least 10 mol.% hydrogen in the compound of the present invention substituted by deuterium. In another example, at least 25 mol.% hydrogen in the compound of the present invention substituted by deuterium. In the following example, at least 50, 60,70, 80, or 90 mol.% hydrogen in the compound of the present invention substituted by deuterium. The natural abundance of deuterium is about 0.015 percent. Substitution or enrichment of deuterium can be obtained, without limitation, either by exchange of protons for deuterium, or by synthesis of molecules with enriched or replaced the original substances. Other methods known from the prior art, can also be used to isotopic substitution.

The above description of the present invention provides illustration and description, but is not intended as exhaustive or limiting the present invention specifically those described. Modifications the AI and changes are possible in light of the above guidance, or may be required to practice the present invention. Thus, it is noted that the scope of the present invention defined by the claims and its equivalents.

1. The compound of formula I or its pharmaceutically acceptable salt,
,
where:
A regardless of B means phenyl,
orand
B regardless of A means phenyl,
or,
and A and B are each independently optionally substituted by one or more substituents RA; and Z1independently in each instance selected from O or NH; and Z2means N;
D represents phenyl, cyclopentyl, 3-10-membered saturated, partially unsaturated or fully unsaturated heterocycle, containing one or two heteroatoms independently selected from O, N and S, and optionally substituted by one or more substituents RA;
or D represents a C1-C6alkyl, optionally substituted-O-Rsor oxo;
X represents N;
L1and L2each independently mean C1-C6alkylen;
L3that is the link;
Y is selected from-T'-C(R1R2)N(R5)-T-RDor-LK-T-RD;
R1and R2each independently represent Rcand R5is an RB; or R1presented yet a R cand R2and R5taken together with the atoms to which they are attached, form a 3-8-membered heterocyclic ring containing one or two heteroatoms, independently selected from N and S, which is optionally substituted by one or more substituents RA;
Z is selected from-T'-C(R8R9)N(R12)-T-RDor-LK-T-RD;
R8and R9each independently represent Rcand R12is an RB; or R8is an Rcand R9and R12taken together with the atoms to which they are attached, form a 3-8-membered heterocyclic ring containing one or two heteroatoms, independently selected from N and S, which is optionally substituted by one or more substituents RA;
LKeach independently in each instance selected from, link to, or-N(RB) C(O)-Ls;
T and T' each independently in each instance selected from-Ls-, -Ls-M-Ls', -Ls-M-Ls'-M'-Ls"-, where M and M' each independently in each instance selected from-O-, -N(RB)-; -C(O)-, -C(O)O-, -OC(O)- N(RB)C(O) -, or 3-10-membered heterocycle containing one or two heteroatoms, independently selected from N and O, and where specified 3-10-membered heterocycle, each independently, optionally substituted in each case one or more to cover the firs R A;
RAindependently selected in each case from halogen, hydroxy, amino, oxo, -LAor-Ls-RE;
RBindependently in each instance selected from hydrogen or RF;
Rcindependently selected in each instance from hydrogen or RF;
RDeach independently selected in each instance from hydrogen or RA;
REindependently selected in each case from-O-Rs, -C(O)Rs, -C(O)ORs, -N(RsRs'), -N(RS)C(O)ORS', phenyl or 3-10-membered heterocyclyl containing one or two heteroatoms, independently selected from N and O, where specified phenyl and 3-10-membered heterocyclyl, each independently, optionally substituted in each case by one or more substituents selected from halogen, -O-RB, oxo;
RFindependently selected in each case from C1-C6the alkyl or C3-C6carbocycle;
LAindependently selected in each case from C1-C6the alkyl or C2-C6alkenyl, each of which, independently, optionally substituted in each case by one or more substituents selected from-O-RS;
-LS, -LS'and-LS"each independently, in each case selected from the communication; or (C1-C6alkylene or C2-C6Alcanena, each of which, independently, optionally substituted in to the each case by one or more substituents, selected from halogen, RT, -O-RSor oxo;
RSand RS'each independently in each instance selected from hydrogen or RT;
RTindependently selected in each case from C1-C6of alkyl, C2-C6alkenyl, C3-C6carbocyclic or a 3-6-membered heterocyclyl containing one or two heteroatoms, independently selected from N and O, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, RF, -O-RBor oxo.

2. The compound of formula I or its pharmaceutically acceptable salt,
,
where:
A and B each independently denote phenyl, and are each independently optionally substituted by one or more substituents RA;
D represents phenyl, cyclopentyl, 3-10-membered saturated, partially unsaturated or fully unsaturated heterocycle, containing one or two heteroatoms independently selected from O, N and S, and optionally substituted by one or more substituents RA;
or D represents a C1-C6alkyl, optionally substituted-O-RSor oxo;
X represents N;
L1and L2each independently represent -(CH2)-;
L3that is the link;
Y is selected from-N(RB)C(O)C(R1R2)NR 5)-T-RD;
R1is an Rc; and R2and R5taken together with the atoms to which they are attached, form a 3-8-membered heterocyclic ring containing one or two heteroatoms, independently selected from N and S, which is optionally substituted by one or more substituents RA;
Z is selected from-N(R)C(O)-C(R8R9)N(R12)-T-RD;
R8is an Rcand R9and R12taken together with the atoms to which they are attached, form a 3-8-membered heterocyclic ring containing one or two heteroatoms, independently selected from N and S, which is optionally substituted by one or more substituents RA;
T is independently in each instance selected from-Ls-, -Ls-M-Ls'-, -Ls-M-Ls'-M'-Ls"-, where M and M' each independently in each instance selected from-O-, -N(RB)-, -C(O)-, -C(O)O-, -OC(O)-; -N(RB)C(O)-; -N (RB)C(O)O -, or 3-10-membered saturated heterocycle containing one nitrogen atom, and where specified 3-10-membered heterocycle, each independently, optionally substituted in each case by one or more substituents RA;
RAindependently selected in each case from halogen, hydroxy, amino, oxo, or-LA;
RBand RB'is independently in each instance selected from hydrogen or RF;
R cindependently selected in each instance from hydrogen or RF;
RDeach independently selected in each instance from hydrogen or RA;
REindependently selected in each case from-O-Rs, -C(O)Rs, -C(O)ORs, -N(RsRs'), -N(RS)C(O)ORS', phenyl or 3-10-membered heterocyclyl containing one or two heteroatoms, independently selected from N and O, where specified 3-10-membered heterocyclyl, each independently, optionally substituted in each case by one or more substituents selected from halogen, -O-RB, oxo;
RFindependently selected in each case from C1-C6the alkyl or C3-C6carbocycle;
LAindependently selected in each case from C1-C6the alkyl or C2-C6alkenyl, each of which, independently, optionally substituted in each case by one or more substituents selected from-O-RS;
-LS, -LS'and-LS"each independently, in each case selected from the communication; or (C1-C6alkylene or C2-C6Alcanena, each of which, independently, optionally substituted in each case by one or more substituents selected from RT, -O-RSor oxo;
RSand RS'each independently, in each case denote hydrogen;
RTindependently selected ka the case of C 1-C6of alkyl, C2-C6alkenyl, C3-C6carbocycle, (phenyl) C1-C6the alkyl or a 3-6-membered heterocyclyl containing one or two heteroatoms, independently selected from N and O, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, -O-RBor oxo.

3. The compound or salt according to p. 2 where:
T is independently selected in each case from-C(O)-LS'-M'-LS"- or-N(RB)C(O)-LS'-M'-LS"-; and
LS'independently represents a C1-C6alkylen and, independently, optionally replaced, in each case, by one or more substituents selected from RT, -O-RSor oxo.

4. The compound or salt according to p. 2 where:
T is independently selected in each case from-C(O)-LS'-M'-LS"-; and
D represents phenyl, cyclopentyl, 5-6-membered heterocycle, or 6-10-membered Bicycle and substituted by one or more substituents RMwhere RMrepresents a halogen or oxo.

5. The compound or salt according to p. 4, where T is independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"- or-C(O)-LS'-N(RB)C(O)O-LS"-.

6. The compound or salt according to p. 4, where RArepresents halogen, hydroxy, amino, or oxo; or C1-C6alkyl, C2-C6 alkenyl, each of which, independently, optionally substituted in each case by one or more substituents selected from hydroxy.

7. The compound of formula I or its pharmaceutically acceptable salt,
,
where:
A represents:B represents, Z1independently selected in each case from O or NH, Z2independently selected in each case from N;
D represents phenyl and optionally substituted by one or more substituents RA;
X represents N;
L1and L2represent -(CH2)-;
L3that is the link;
Y is selected from-C(R1R2)N(R5)-T-RD,
R1is an Rcand R2and R5taken together with the atoms to which they are attached, form a 3-8-membered heterocyclic ring containing one nitrogen atom;
Z is selected from-C(R8R9)N(R12)-T-RD;
R8is an Rcand R9and R12taken together with the atoms to which they are attached, form a 3-8-membered heterocyclic ring containing one nitrogen atom;
T is independently selected in each case of Ls-M-LS'or LS-M-LS'-M'-LS"-, where M and M' each independently in each instance selected from-C(O)-,-N(R B)C(O)-, -N(RB)C(O)O-;
RAindependently selected in each case from halogen, amino, -LAor-LS-RE;
RBindependently in each instance selected from hydrogen or RF;
RCmeans hydrogen;
RDindependently selected in each instance from hydrogen or RA;
REindependently selected in each case from-O-RS, -C(O)ORS, -N(RSRS'), 5-membered heterocyclyl containing one heteroatom N or 6-membered heterocyclyl containing two heteroatoms, independently selected from N and O;
RFindependently selected in each case from C1-C6of alkyl;
LAindependently selected in each case from C1-C6of alkyl;
-LS, -LS'and-LS"each independently, in each case selected from the communication; or (C1-C6alkylene, which is independently optionally substituted in each case by one or more substituents selected from RT, -O-RS;
RSor RS'each independently in each instance selected from hydrogen or RT;
RTindependently selected in each case from C1-C6of alkyl, phenyl, or a 4-6-membered heterocyclyl containing one atom of nitrogen or oxygen, or 6-membered heterocycle containing 2 heteroatoms, of which one is nitrogen and the other is oxygen.

8. The connection is whether salt p. 7, where:
Z1represents NH;
T is independently selected in each case from-C(O)-LS'-M'-LS"- or-N(RB)C(O)-LS'-M'-LS"-; and
LS'independently represents a C1-C6alkylen and, independently, optionally replaced, in each case, by one or more substituents selected from RTor-O-RS.

9. The compound or salt according to p. 7, where:
Z1represents NH, and
T is independently selected in each case from-C(O)-LS'-M'-LS.

10. The compound or salt according to p. 9, where T is independently selected in each case from-C(O)-LS'-N(RB)C(O)-Ls"- or-C(O)-LS'-N(RB)C(O)O-LS"-.

11. The compound of formula I or its pharmaceutically acceptable salt,
,
where:
A representsZ1selected from NH2, Z2selected from N;
B represents phenyl;
D represents phenyl and optionally substituted by one or more substituents RA;
X represents N;
L1and L2represent -(CH2)-;
L3that is the link;
Y is selected from-C(R1R2)N(R5)-T-RD,
R1is an Rcand R2and R5taken together with the atoms to which they are attached, form a 3-8-membered heterocyclic number of the TSO, containing one nitrogen atom;
Z is selected from-N(RB)C(O)C(R8R9)N(R12)-T-RD;
R8is an RCand R9and R12taken together with the atoms to which they are attached, form a 3-8-membered heterocyclic ring containing one nitrogen atom;
T is independently selected in each case of LS-M-LS'-, -LS-M-LS'-M'-LS"-, where M and M' each independently in each instance selected from-C(O)-, -N(RB)C(O) -, or-N(RB)C(O)O;
RAindependently selected in each case from halogen or-Ls-RE;
RBselected from hydrogen;
Rcmeans hydrogen;
RDindependently selected in each instance from hydrogen or RA;
REindependently selected in each case from-O-RS;
RFindependently selected in each case from C1-C6of alkyl, C2-C6alkenyl,2-C6the quinil,3-C6carbocycle, C3-C6carbocyclic1-C6of alkyl, 3-6-membered heterocyclyl or (3 - or 6-membered heterocyclyl) C1-C6of alkyl, each of which, independently, optionally substituted in each case by one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonooxy, phosphono, thioxo, formyl or cyano;
-LS, -LS'and-LS"what gdy independently in each case selected from the communication; or (C1-C6alkylene, each of which, independently, optionally substituted in each case by one or more substituents selected from RTor-O-RS;
RSindependently in each instance selected from hydrogen or RT;
RTindependently selected in each case from C1-C6of alkyl, which is, independently, optionally substituted in each case by one or more substituents selected from-O-RB.

12. The compound or salt according to p. 11 where:
T is independently selected in each case from-C(O)-LS'-M'-Ls"- or-N(RB)C(O)-LS'-M'-LS"-; and
LS'independently represents a C1-C6alkylen and, independently, optionally replaced, in each case, by one or more substituents selected from RTor-O-Rs.

13. The compound or salt according to p. 11 where:
T is independently selected in each case from-C(O)-LS'-M'-LS"-.

14. The compound or salt according to p. 13, where T is independently selected in each case from-C(O)-LS'-N(RB)C(O)-LS"- or-C(O)-LS'-N(RB)C(O)O-LS"-.

15. The pharmaceutical composition inhibitory activity against HCV replication, containing the compound or salt under item 1.

16. The pharmaceutical composition according to p. 15, optionally containing another anti-HCV agent, is such an approach as an inhibitor of HCV protease, or an inhibitor of HCV polymerase.

17. A method of obtaining a connection on p. 1, including the state combinations of the compounds of formula II

with the compound of the formula III

and with the compound of the formula VI

where Q denotes halogen and a, b, D, L1, L2, L3X, Y and Z defined in paragraph 1.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel heterocyclic compound, representing cyclo-bis[(1Z)-1-imino -2-methyl-1H-inden-3-yl-1,2,4-thiadiazole-3,5-diamine]

EFFECT: compound as acid dye for silk, wool and polyamide 6.

3 dwg, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compounds of formula I

and to their pharmaceutically acceptable salts, where A is selected from CH or N; R1 is selected from the group, consisting of C3-6-cycloalkyl, C3-6-cycloalkyl-C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl, halogen-C1-7-alkyl; R2 and R6 independently on each other represent hydrogen of halogen; R3 and R5 independently on each other are selected from the group, consisting of hydrogen, C1-7-alkyl and halogen; R4 is selected from the group, consisting of hydrogen, C1-7-alkyl, halogen and amino; R7 is selected from the group, consisting of C1-7-alkyl, C1-7alkoxy-C1-7-alkyl, C1-7-alkoxyimino-C1-7-alkyl, 4-6-membered heterocyclyl, containing one heteroatom O, phenyl, with said phenyl being non-substituted or substituted with one hydroxy group, and 5-10-membered heteroaryl, containing 1-3 heteroatoms, selected from N, S and O, said heteroaryl is not substituted or is substituted with one or two groups, selected from the group, consisting of C1-7-alkyl, hydroxy, C1-7-alkoxy, cyano, C1-7-alkylaminocarbonyl and halogen. Invention also relates to pharmaceutical composition based on formula I compound and to method of obtaining formula I compound.

EFFECT: obtained are novel heterocyclic compounds, which are agents, increasing level of LDLP.

17 cl, 2 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: described are novel heteroaryl-N-aryl-carbamates of general formula , where: Ar1 is phenyl, probably substituted with C1-C6halogenalkyl or C1-C6halogenalkoxy; Het is triazolyl; Ar2 is phenyl; X1 represents O or S; X2 - O; R4 - H or C1-C6alkyl; n=0, 1 or 2; and R1, R2 and R3 are independently selected from H, CN, C1-C6alkyl, C1-C6halogenalkyl, C3-C6cycloalkyl, C2-C6alkenyl, C2-C6alkinyl, C(=O)O(C1-C6alkyl), phenyl and Het-1, where Het-1 is a 5-membered unsaturated heterocyclic ring, containing one heteroatom, selected from sulphur or hydrogen, or a 6-membered unsaturated heterocyclic ring, containing one nitrogen atom as a heteroatom, and Het-1 can be substituted with F, Cl, C1-C6alkyl, C1-C6halogenalkyl or C1-C6alkoxy, and a method of fighting pest insects Lepidoptera or Homoptera with the application of the said compounds as insecticides and acaricides.

EFFECT: increased efficiency.

5 cl, 2 tbl, 80 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), possessing an activity with respect to cytokines, versions of based on them pharmaceutical compositions and their application. Formula (I) compounds can be applied for treatment or prevention asthma, COPD, ARDS, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis or gouty arthritis. In general formula (I) L is selected from the group, consisting of -C(O)-, -CH2-, Ar1 represents a mono-, di- or trisubstituted phenyl ring, where substituents are independently selected from the group, consisting of a halogen and -C1-4alkyl; Ar2 represents an optionally substituted thiadiazolyl ring, where the substituent represents -C1-4alkyl, -C3-5cycloalkyl, -methylcyclopropyl, phenyl or a 5- or 6-membered monocyclic heteroaromatic ring or a bicyclic heteroaromatic ring with 9 or 10 atoms, with the said heteroaromatic ring containing 1, 2 or 3 heteroatoms, selected from the group, consisting of S, O and N, where the said phenyl or heteroaromatic ring is optionally mono- or disubstituted with substituents, independently selected from the group, consisting of a halogen, -C1-6alkyl, optionally substituted with 1-4 fluorine atoms, -O-C1-6alkyl, -CF3 and oxo.

EFFECT: increased efficiency of the application of the compounds.

16 cl, 1 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and a method of producing 3,3'-[bis-(1,4-phenylene)]bis-1,3,5-dithiazinanes of formula (1): wherein diphenylenediamine (diaminodiphenylmethane, diaminodiphenyl oxide) reacts with N-tert-butyl-1,3,5-dithiazinane in the presence of a Sm(NO3)3·6H2O catalyst in an argon atmosphere in molar ratio diphenylenediamine: N-tert-butyl-1,3,5-dithiazinane:Sm(NO3)3·6H2O=1:2:(0.03-0.07) at about 20°C in an ethanol-chloroform solvent system (1:1, by volume) for 2.5-3.5 hours.

EFFECT: method of obtaining novel compounds which can be used as antimicrobial and antifungual agents, selective sorbents and extractants of precious metals, special reagents for inhibiting bacterial activity in different process media.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to a method for selective production of 3,3'-[bis-(1,4-phenylene)]bis-1,5,3-dithiazepinanes of formula (1) where R = 4-C6H4-CH2-C6H4-4', 4-C6H4-O-C6H4-4', 4-H3COC6H3-C6H3OCH3-4', where diphenylenediamines (diaminodiphenylmethane, diaminodiphenyl oxide, dimethoxybenzidine) react with 1-oxa-3,6-dithiacycloheptane in the presence of a Sm(NO3)3·6H2O catalyst in an argon atmosphere in molar ratio diphenylenediamine:1-oxa-3,6-dithiacycloheptane:Sm(NO3)3·6H2O=1:2:(0.03-0.07) at about 20°C in an ethanol-chloroform solvent system for 2.5-3.5 hours.

EFFECT: novel method of producing 3,3'-[bis-(1,4-phenylene)]bis-1,5,3-dithiazepinanes, which can be used as antimicrobial, antifungal and anti-inflammatory agents, sorbents and extractants of precious metals and selective complexing agents.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 6-substituted isoquinoline and isoquinolinone derivatives of formula or to its stereoisomer and/or tautomer forms and/or a pharmaceutically acceptable salt, wherein R1 represents H, OH or NH2; R3 represents H; R4 represents H, a halogen atom, CN or (C1-C6)alkylene-(C6-C10)aryl; R5 represents H, a halogen atom, (C1-C6)alkyl; R7 represents H, a halogen atom, (C1-C6)alkyl, O-(C1-C6)alkyl; R8 represents H; R9 and R6 are absent; R10 represents (C1-C6)alkyl, (C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (C6)hetrocycloalkyl, (C1-C6)alkylene-(C3-C8)cycloalkyl, (C1-C6)alkylene-(C6-C10)aryl, (C1-C6)alkylene-(C6)heterocycloalkyl; R11 represents H; R12 represents (C1-C6)alkyl, (C3-C8)cycloalkyl, (C5)heteroaryl or (C6-C10)aryl; R13 and R14 independently represent H, (C1-C6)alkyl, (C1-C6)alkylene-R'; n is equal to 0; m is equal to 2 or 3; s is equal to 1 or 2; r is equal to 1; L represents O or NH; R' represents (C3-C8)cycloalkyl, (C6-C10)aryl; wherein in the rests, R10, R12-R14 alkyl or alkylene are unsubstituted or optionally substituted by one or more OCH3; wherein in the rests, R10, R12-R14 alkyl or alkylene are unsubstituted or optionally substituted by one or more halogen atoms; wherein (C1-C8)heteroaryl group means (C1-C8)alkyl groups, wherein at least one carbon atom is substituted by O;. (C6)heterocycloalkyl group means a monocyclic carbon ring system containing 6 ring atoms wherein one carbon atom can be substituted by 1 oxygen atom or 1 sulphur atom which can be optionally oxidated; (C5)heteroaryl means a monoring system wherein one or more carbon atoms can be substituted by 1 nitrogen atom or 1 sulphur atom or a combination of various heteroatoms. Also, the invention refers to using the compound of formula (I) and to a therapeutic agent based on the compound of formula (I).

EFFECT: there are prepared new compounds effective for treating and/or preventing diseases associated with Rho-kinase and/or mediated by Rho-kinase by phosphorylation of myosin light chain phosphatase, and the compositions containing these compounds.

32 cl, 111 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel chromenone derivatives of formula II or its pharmaceutically acceptable salts, where each R20 is hydrogen; R11 is selected from phenyl and 5-6 member saturated or aromatic heterocycle, including one or two heteroatoms, selected from N, O or S, where R11 is optionally substituted with one-two substituents, independently selected from C1-C4alkyl, =O, -O-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from hydrogen and -C1-C4alkyl; or two R13 together with nitrogen atom, to which they are bound, form 5-6-member saturated heterocycle, optionally including one additional O, where, when R13 is alkyl, alkyl is optionally substituted with one or more substituents, selected from -OH, fluorine, and, when two R13 together with nitrogen atom, to which they are bound, form 6-member saturated heterocycle, saturated heterocycle is optionally substituted on each carbon atom with -C1-C4alkyl; R12 is selected from phenyl and pyridyl, where R12 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen; and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, - -S(=O)2-NH-†, where † stands for place, where X1 is bound with R11; and, when R14 is H; R12is phenyl; and X1 is - C(=O)-NH-†, then R11 is not 1H-pyrazol-3-yl, possessing stimulating activity.

EFFECT: invention relates to pharmaceutical composition based on said compounds, method of treating subject, suffering from or having resistance to insulin, metabolic syndrome or diabetes, as well as to method of increasing sensitivity to insulin.

16 cl, 1 tbl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compounds can find application for preventing or treating cancer, lung cancer, non-small cells lung cancer, small-cell lung cancer, EML4-ALK hybrid polynucleotide-positive cancer, EML4-ALK hybrid polynucleotide-positive lung cancer or EML4-ALK hybrid polynucleotide-positive non-small cells lung cancer. In formula (I) -X-: group of formula , A represents chlorine, ethyl or isopropyl; R1 represents phenyl wherein carbon in the 4th position is substituted by the group -W-Y-Z, and carbon in the 3rd position can be substituted by a group specified in a group consisting of halogen, R00 and -O-R00; R00: lower alkyl which can be substituted by one or more halogen atoms; -W-: a bond, piperidine-1,4-diyl or piperazine-1,4-diyl; -Y- represents a bond; Z represents a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more substitutes R00; R2 represents (i) an optionally bridged saturated C3-10cycloalkyl which can be substituted by one or more groups specified in -N(lower alkyl)2, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZB and morpholinyl, or (ii) a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more groups specified in a group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZB and benzene; and RZB: phenyl which can be substituted by a group consisting of halogen and -O-lower alkyl; R3 represents -H.

EFFECT: invention refers to new compounds of formula or their pharmaceutically acceptable salts possessing the properties of a selective inhibitor of EML4-ALK hybrid protein kinase activity.

16 cl, 201 tbl, 582 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to methods of treating or relieving severity of disease in patient, where disease is selected from mucoviscidosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), "dry eye" disease. Methods include introduction of effective amount of N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide or pharmaceutical composition, containing said compound, to patient.

EFFECT: treatment of relief of disease severity in patient, where disease is selected from mucoviscidosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), "dry eye" disease.

16 cl, 15 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining di-{ 4-[(tetrahydro -4H-1,4-oxazin-4-yl)-methylsulphanyl]-phenyl} ether oxalate of formula

as water-soluble substance with fungicidal activity. Essence of method consists in interaction of di-{ 4-[(tetrahydro -4H-1,4-oxazin-4-yl)-methylsulphanyl]-phenyl} ether with equimolar quantity of oxalic acid (COOH)2 at room (~20°C) temperature for 15 min.

EFFECT: output constitutes 99%.

2 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compounds of formula I

and to their pharmaceutically acceptable salts, where A is selected from CH or N; R1 is selected from the group, consisting of C3-6-cycloalkyl, C3-6-cycloalkyl-C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl, halogen-C1-7-alkyl; R2 and R6 independently on each other represent hydrogen of halogen; R3 and R5 independently on each other are selected from the group, consisting of hydrogen, C1-7-alkyl and halogen; R4 is selected from the group, consisting of hydrogen, C1-7-alkyl, halogen and amino; R7 is selected from the group, consisting of C1-7-alkyl, C1-7alkoxy-C1-7-alkyl, C1-7-alkoxyimino-C1-7-alkyl, 4-6-membered heterocyclyl, containing one heteroatom O, phenyl, with said phenyl being non-substituted or substituted with one hydroxy group, and 5-10-membered heteroaryl, containing 1-3 heteroatoms, selected from N, S and O, said heteroaryl is not substituted or is substituted with one or two groups, selected from the group, consisting of C1-7-alkyl, hydroxy, C1-7-alkoxy, cyano, C1-7-alkylaminocarbonyl and halogen. Invention also relates to pharmaceutical composition based on formula I compound and to method of obtaining formula I compound.

EFFECT: obtained are novel heterocyclic compounds, which are agents, increasing level of LDLP.

17 cl, 2 tbl, 89 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to isoxazoline FAAH inhibitors of formula (I) or their pharmaceutically acceptable forms, wherein each of G, Ra, Rb, Rc and Rd has a value described in the present application, to pharmaceutical compositions, and methods of treating a FAAH-mediated condition.

EFFECT: developing the method of treating the FAAH-mediated condition.

32 cl, 22 tbl, 351 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

Amide derivative // 2536409

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where R1 is a hydrogen atom or a C1-C6-alkyl group, substituted with one or two substitutes selected from C1-C6-alkoxy group, hydroxyl group, which can be substituted with a C1-C6-alkylcarbonyl group (substituted with one or two substitutes γ), and a 4-6-member saturated monocyclic heterocyclic carbonyl group containing a N atom; γ is a hydroxyl group, amino group, di(C1-C6-alkyl)amino group and carbamoyl group; R2 is a H atom or a C1-C6alkyl group, which can be substituted with a hydroxyl group; or R1 and R2, together with the nitrogen atom with which they are bonded, can be combined to form an azetidine group, a pyrrolidine group or morpholine group, which can be substituted with one hydroxyl group or a hydroxy-C1-C6-alkyl group; R3 and R4 is a C1-C6-alkyl group; R5 is a halogen atom or a C1-C6-alkyl group; R6 is a halogen atom; m and n denote an integer from 0 to 1; V and W are CH; X, Y and Z each independently can be CH or N. The invention also relates to a pharmaceutical composition containing a compound of formula (I), use of the compound of formula (I) and a method of treating sugar diabetes a disease associated with diabetes.

EFFECT: compounds of formula (I), having hypoglycemic activity.

21 cl, 6 tbl, 72 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and (II), which possess the blocking activity on voltage-sensitive sodium channels, such as TTX-S channels, and their pharmaceutically salts. In general formula (I) and (II), R1 represents -CF3, -CHF2, -OCF3, -OCHF2, -OCH2CHF2/ -OCH2CF3, -OCF2CHF2; -OCF2CF3, -OCH2CH2CF3, -OCH(CH3)CF3, -OCH2C(CH3)F2, -OCH2CF2CHF2, -OCH2CF2CF3, OCH2CH2OCH2CF3, -NHCH2CF3, -SCF3, -SCH2CF3, -CH2CF3 -CH2CH2CF3, -CH2OCH2CF3 and -OCH2CH2OCF3; R2 is specified in (1) hydrogen, (2) halogen (3) -On-C1-6 alkyl, (4) -On-C3-6 cycloalkyl, (5) -On-phenyl, (6) -On-heterocyclic group, (7) -NR7 (C=O)R8; wherein n is equal to 0 or 1, p is equal to 1, 2; R3 and R4 represents hydrogen or C1-6 alkyl, X represents carbon atom; Y represents hydrogen or C1-6 alkyl; Ar represents 4-pyridyl, 4-pyrimidyl or 6-pyrimidyl, which is substituted in the 2nd position by a substitute, which is independently specified in (1) -(C=O)-NR7R8, (2) -NR7(C=O)R8; R9 is specified in: (1) hydrogen, (2) halogen, (3) -On-C1-6 alkyl, wherein alkyl is unsubstituted or substituted by hydroxyl; q is equal to 1, 2 or 3; R10 independently represents hydrogen, C1-6 alkyl, C2-6alkenyl, C3-7 cycloalkyl or phenyl, which is unsubstituted or substituted by one or substitutes independently specified in hydroxyl, -On-C1-6 alkyl and -C3-7 cycloalkyl.

EFFECT: preparing the compounds possessing the blocking activity on voltage-sensitive sodium channels.

7 cl, 2 tbl, 1281 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula

,

where values A, R1-R6 are given in i.1 of the invention formula. Methods of obtaining the formula (I) compound are described.

EFFECT: compounds demonstrate an inhibiting activity of the cathepsin enzyme, which makes it possible to use them for the preparation of a pharmaceutical composition and for the preparation of a medication.

38 cl, 12 dwg, 495 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinoxaline derivatives of general formula

,

a based pharmaceutical composition, using them as therapeutic agents, as well as to a based therapeutic agent for treating tumour diseases. In general formula I X represents: oxygen or sulphur; R1 represents hydrogen, R2/R3 represents hydrogen, R4 represents: (i) C1-C12-alkyl, (ii) saturated C3-C8-cycloalkyl, optionally substituted by C6-aryl, (iii) unsaturated C3-C8-cycloalkyl, (iv) heterocyclyl substituted by C(O)CF3, (v) C1-C6-alkyl substituted by C6-aryl, the above C6-aryl can be substituted by F, Cl, Br, I, -O-C1-C6-alkyl, C1-C6-alkyl, C6-aryl or hydroxy, (vi) C1-C6-alkyl substituted by C5-heteroaryl, (vii) C1-C8-alkylene, (viii) 1-adamantyl, (ix) C1-C6-alkyl substituted by C6-heterocyclyl containing a nitrogen atom and an oxygen atom, (x) C1-C6-alkyl substituted by C3-C6-cycloalkyl, or (xi) C1-C6-alkyl substituted by C6-heteroaryl; R5 represents hydrogen, R6 represents (i) aryl optionally substituted by C1-C6-alkyl, -O-C1-C6-alkyl, hydroxy, F, Cl, Br, I or amino, or (ii) C5-heteroaryl containing 2 nitrogen atoms optionally substituted by C1-C6-alkyl, R7 and R8 represent hydrogen.

EFFECT: producing the therapeutic agent for treating the tumour diseases.

7 cl, 3 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: described are novel heteroaryl-N-aryl-carbamates of general formula , where: Ar1 is phenyl, probably substituted with C1-C6halogenalkyl or C1-C6halogenalkoxy; Het is triazolyl; Ar2 is phenyl; X1 represents O or S; X2 - O; R4 - H or C1-C6alkyl; n=0, 1 or 2; and R1, R2 and R3 are independently selected from H, CN, C1-C6alkyl, C1-C6halogenalkyl, C3-C6cycloalkyl, C2-C6alkenyl, C2-C6alkinyl, C(=O)O(C1-C6alkyl), phenyl and Het-1, where Het-1 is a 5-membered unsaturated heterocyclic ring, containing one heteroatom, selected from sulphur or hydrogen, or a 6-membered unsaturated heterocyclic ring, containing one nitrogen atom as a heteroatom, and Het-1 can be substituted with F, Cl, C1-C6alkyl, C1-C6halogenalkyl or C1-C6alkoxy, and a method of fighting pest insects Lepidoptera or Homoptera with the application of the said compounds as insecticides and acaricides.

EFFECT: increased efficiency.

5 cl, 2 tbl, 80 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in general formula A1 stands for CR10R11 or S; A2 stands for CR12R13, C(=O), O, S or S(=O)2; R1 stands for C1-10-alkyl, saturated or unsaturated, branched or non-branched, non-substituted, or monosubstituted, or polysubstituted; C3-10-cycloalkyl or 5- or 6-membered heterocyclyl with the O-atom, each time saturated or unsaturated, non-substituted, or monosubstituted, or polysubstituted; C6-10-aryl or C5-10-heteroaryl with 1-3 heteroatoms, selected from N, O or S, each time non-substituted, or monosubstituted, or polysubstituted; through C1-8-alkyl or C2-8-heteroalkyl bound by the bridge bond C3-10-cycloalkyl, each time saturated, non-substituted, and the alkyl or heteroalkyl chain each time can be branched or non-branched, saturated, non-substituted; or through C1-8-alkyl, bound by the bridge bond aryl or heteroaryl, each time non-substituted, or monosubstituted, or polysubstituted, and the alkyl chain each time can be branched or non-branched, saturated or unsaturated, non-substituted, or monosubstituted, or polysubstituted; R2, R3 and R4 each time independently on each other stand for H; F; Cl; Br; I; methyl; O-C1-6-alkyl or NRaRb, and Ra and Rb together with the nitrogen atom that binds them form heterocyclyl, saturated, non-branched, non-substituted; R5, R6, R7, R8, R10, R11, R12 and R13each time independently on each other stand for H; F; Cl; Br; I; OH or C1-10-alkul; or R5 and R6 or R7 and R11 together with carbon atom(s), that bind(s) them form C3-8-cycloalkyl, each time saturated or non-saturated, non-substituted, or monosubstituted, or polysubstituted; with respective remaining substituents R5, R6, R7, R8, R10, R11, R12 and R13 having the value given above; R9 stands for C3-10-cycloalkyl, saturated, non-substituted; C6-10-aryl or 5- or 6-membered heteroaryl with heteroatom, selected from N and S, each time non-substituted or monosubstituted.

EFFECT: invention relates to substituted nicotinamides of general formula (1), to a medication based on them and their application for treating KCNQ2/3-mediated diseases.

13 cl, 3 tbl, 224 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compounds of formula I

and to their pharmaceutically acceptable salts, where A is selected from CH or N; R1 is selected from the group, consisting of C3-6-cycloalkyl, C3-6-cycloalkyl-C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl, halogen-C1-7-alkyl; R2 and R6 independently on each other represent hydrogen of halogen; R3 and R5 independently on each other are selected from the group, consisting of hydrogen, C1-7-alkyl and halogen; R4 is selected from the group, consisting of hydrogen, C1-7-alkyl, halogen and amino; R7 is selected from the group, consisting of C1-7-alkyl, C1-7alkoxy-C1-7-alkyl, C1-7-alkoxyimino-C1-7-alkyl, 4-6-membered heterocyclyl, containing one heteroatom O, phenyl, with said phenyl being non-substituted or substituted with one hydroxy group, and 5-10-membered heteroaryl, containing 1-3 heteroatoms, selected from N, S and O, said heteroaryl is not substituted or is substituted with one or two groups, selected from the group, consisting of C1-7-alkyl, hydroxy, C1-7-alkoxy, cyano, C1-7-alkylaminocarbonyl and halogen. Invention also relates to pharmaceutical composition based on formula I compound and to method of obtaining formula I compound.

EFFECT: obtained are novel heterocyclic compounds, which are agents, increasing level of LDLP.

17 cl, 2 tbl, 89 ex

Up!