Apoptosis inducing agents for treating cancer and immune and autoimmune diseases


FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula or its therapeutically acceptable salts, wherein A1 represents furyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, piperidinyl, morpholinyl, dihydro-1,3,4-thiadiazol-2-yl, benzothien-2-yl, banzothiazol-2-yl, tetrahydrothien-3-yl, [1,2,4]triazolo[1,5-a]pyrimidin-2-yl or imidazo[2,1-b][1,3]-thiazol-5-yl; wherein A1 is unsubstituted or substituted by one, or two, or three, or four, or five substitutes independently specified in R1, OR1, C(O)OR1, NHR1, N(R1)2, C(N)C(O)R1, C(O)NHR1, NHC(O)R1, NR1C(O)R1, (O), NO2, F, Cl, Br and CF3; R1 represents R2, R3, R4 or R5; R2 represents phenyl; R3 represents pyrazolyl or isoxazolyl; R4 represents piperidinyl; R5 represents C1-C10alkyl or C2-C10alkenyl each of which is not specified or specified by substitutes specified in R7, SR7, N(R7)2, NHC(O)R7, F and Cl; R7 represents R8, R9, R10 or R11; R8 represents phenyl; R9 represents oxadiazolyl; R10 represents morpholinyl, pyrrolidinyl or tetrahydropyranyl; R11 represents C1-C10alkyl; Z1 represents phenylene; Z2 represents piperidine unsubstituted or substituted by OCH3, or piperazine; both Z1A and Z2A are absent; L1 represents C1-C10alkyl or C2-C10alkenyl each of which is unsubstituted or substituted by R37B; R37B represents phenyl; Z3 represents R38 or R40; R38 represents phenyl; R40 represents cyclohexyl or cyclohexenyl; wherein phenylene presented by Z1 is unsubstituted or substituted by the group OR41; R41 represents R42 or R43; R42 represents phenyl, which is uncondensed or condensed with pyrrolyl, imidazolyl or pyrazole; R43 represents pyridinyl, which is uncondensed or condensed with pyrrolyl; wherein each cyclic fragment presented by R2, R3, R4, R8, R9, R10, R38, R40, R42 and R43 is independently unsubstituted or substituted by one or more substitutes independently specified in R57, OR57, C(O)OR57, F, Cl CF3 and Br; R57 represents R58 or R61; R58 represents phenyl; R61 represents C1-C10alkyl; and wherein phenyl presented by the group R58 is unsubstituted or substituted by one or more substitutes independently specified in F and Cl.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, and to a method of treating diseases involving the expression of anti-apoptotic Bcl-2 proteins.

7 cl, 2 tbl, 48 ex

 

In this application claims the priority of provisional patent application U.S. No. 61/145611, filed January 19, 2009, which in their entirety are included in this description by reference.

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to compounds that inhibit the activity of anti-apoptotic proteins Bcl-2, to compositions containing these compounds, and to methods of treating diseases during which is expressed anti-apoptotic proteins Bcl-2.

PREREQUISITES TO the CREATION of INVENTIONS

Antiapoptotic proteins Bcl-2 is associated with a number of diseases. Therefore, in the field of therapy there is a need for compounds that inhibit the activity of anti-apoptotic proteins Bcl-2.

Overexpression of proteins Bcl-2 correlates with resistance to chemotherapy, with clinical results, with the development of the disease, with an overall forecast of the further course of the disease or their combination with different types of cancer and diseases of the immune system.

The involvement of the protein Bcl-2 in the development of bladder cancer, brain cancer, breast cancer, cancer, bone marrow cancer, cervical region, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, leukemia, called T-lymphocytes or b-cle is kami, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, lung cancer or prostate cancer, small-cell lung cancer, cancer of the spleen, etc. described in the concurrently pending international application PCT US 2004/36770, published as WO 2005/049593, and international application PCT US 2004/37911, published as WO 2005/024636.

The involvement of the protein Bcl-2 in immune and autoimmune diseases are described in theCurrent Allergy and Asthma Reports2003, 3, 378-384;British Journal ofHaematology2000,110(3), 584-90;Blood2000, 95(4), 1283-92; andNew England Journal of Medicine2004, 351(14), 1409-1418. The involvement of the protein Bcl-2 in the development of arthritis are disclosed in pending provisional patent application U.S. No. 60/988479. The involvement of the protein Bcl-2 in the rejection of bone marrow transplant disclosed in pending application for U.S. patent No. 11/941196.

The INVENTION

Thus, one way of implementing the present invention relates to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs of such compounds that are useful as inhibitors of anti-apoptotic proteins Bcl-2, these compounds have the formula I

where

A1represents furyl, imidazolyl, isothiazolin, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 2-pyridinyl, 4-pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl, triazolyl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; each of which is not condensed or fused with benzene, heteroatom or A1A; A1Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

where A1not substituted or substituted by one, or two, or three, or four, or five independently selected substituents R1, OR1, SR1, S(O)R1, SO2R1C(O)R1C(O)OR1, OC(O)R1, Other1N(R1)2C(N)C(O)R1C(O)other1C(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, NHC(O)R1, NR1C(O)R1, NHC(O)OR1, NR1C(O)OR1, NR1C(O)other1, NR1C(O)N(R1)2, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2, SO2NH2, SO2Other1, SO2N(R1)2NHS(O)R1, NHSO2R1, NR1SO2R1, NHSO2Other1N(CH3)SO2N(CH3R1, (O), NH2, NO2N3, OH, F, Cl, Br, I, CN, CF3, OCF3, CF2CF3, OCF2CF3C(O)H, C(O)OH, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3C(O)NH2or C(O)OR1A;

R1the submitted is an R 2, R3, R4or R5;

R1Ais cycloalkyl, cycloalkenyl or cycloalkenyl;

R2represents phenyl, which is not condensed or fused with benzene, heteroatom or R2A; R2Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R3is heteroaryl that is not condensed or fused with benzene, heteroatom or R3A; R3Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R4is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R4A; R4Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R5represents alkyl, alkenyl or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R6, NC(R6A)(R6B), R7, OR7, SR7, S(O)R7, SO2R7, Other7N(R7)2C(O)R7C(O)NH2C(O)other7C(O)N(R7)2, NHC(O)R7, NR7C(O)R7, NHSO2R7, NHC(O)OR7, SO2NH2, SO2Other7, SO2N(R7)2, NHCO)NH 2, NHC(O)other7, NHC(O)CH(CH3)NHC(O)CH(CH3)NH2, NHC(O)CH(CH3)NHC(O)CH(CH3)Other1, OH, (O), C(O)OH, N3, CN, NH2, CF3, CF2CF3, F, Cl, Br or I;

R6represents a C2-C5-spiralcell, each of which is not substituted or substituted by substituents OH, (O), N3CN, CF3, CF2CF3, F, Cl, Br, I, NH2, NH(CH3) or N(CH3)2;

R6Aand R6Bindependently selected from alkyl or together with the N atom to which they are attached, form an R6C;

R6Cis aziridine-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidine-1-yl, each of which has one piece of CH2not replaced or replaced with O, C(O), CNOH, CNOCH3, S, S(O), SO2or NH;

R7is an R8, R9, R10or R11;

R8represents phenyl, which is not condensed or fused with benzene, heteroatom or R8A; R8Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R9is heteroaryl that is not condensed or fused with benzene, heteroatom or R9A; R9Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R10is cycloalkyl, cycloalkenyl, heteroseksualci or GE is eroticaolder, each of which is not condensed or fused with benzene, heteroatom or R10A; R10Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R11represents alkyl, alkenyl or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R12, OR12, SR12, S(O)R12, SO2R12C(O)R12C(O)OR12, OC(O)R12, OC(O)OR12, NH2, Other12N(R12)2, NHC(O)R12, NR12C(O)R12NHS(O)2R12, NR12S(O)2R12, NHC(O)OR12, NR12C(O)OR12, NHC(O)NH2, NHC(O)other12, NHC(O)N(R12)2, NR12C(O)other12, NR12C(O)N(R12)2C(O)NH2C(O)other12C(O)N(R12)2C(O)NHOH, C(O)NHOR12C(O)NHSO2R12C(O)NR12SO2R12, SO2NH2, SO2Other12, SO2N(R12)2C(O)H, C(O)OH, C(N)NH2C(N)other12C(N)N(R12)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R12is an R13, R14, R15or R16;

R13represents phenyl, which is not condensed or fused with benzene, heteroatom or R13A; R13Arepresents cyclea the Kang, cycloalken, geteroseksualen or geteroseksualen;

R14is heteroaryl that is not condensed or fused with benzene, heteroatom or R14A; R14Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R15is cycloalkane, cycloalkene, geteroseksualen or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R15A; R15Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R16represents alkyl, alkenyl or quinil;

Z1is an R26or R27;

Z2is an R28, R29or R30;

Z1Aand Z2Aboth are absent, or together form CH2CH2CH2or Z12A;

Z12Arepresents a C2-C6-alkene, in which one or two fragments of CH2replaced by NH, N(CH3), S, S(O) or SO2;

L1is an R37, OR37, SR37, S(O)R37, SO2R37C(O)R37C(O)OR37, OC(O)R37, OC(O)OR37, Other37C(O)NH, C(O)NR37C(O)NHOR37C(O)NHSO2R37, SO2NH, SO2Other37C(N)NH, C(N)other37;

R26represents phenylene which is not condensed is whether condensed with benzene, or heteroatom, or R26A; R26Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R27represents heteroaryl that is not condensed or fused with benzene, or heteroatom, or R27A; R27Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R28represents phenylene which is not condensed or fused with benzene, heteroatom or R28A; R28Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R29represents heteroaryl that is not condensed or fused with benzene, or heteroatom, or R29A; R29Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R30is cycloalkyl, cycloalkenyl, heterocyclochain or heterocyclization, each of which is not condensed or fused with benzene, heteroatom or R30A; R30Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R37represents a simple bond or R37A;

R37Ais alkylen, albaniles or akinyan, each of which is not substituted or is substituted by one, or two, or three Nezavisimoye substituents R 37B, OR37B, SR37B, S(O)R37BSO2R37BC(O)R37BC(O)OR37B, OC(O)R37B, OC(O)OR37B, NH2, Other37BN(R37B)2, NHC(O)R37B, NR37BC(O)R37BNHS(O)2R37B, NR37BS(O)2R37B, NHC(O)OR37B, NR37BC(O)OR37B, NHC(O)NH2, NHC(O)other37B, NHC(O)N(R37B)2, NR37BC(O)other37B, NR37BC(O)N(R37B)2C(O)NH2C(O)other37BC(O)N(R37B)2C(O)NHOH, C(O)NHOR37BC(O)NHSO2R37BC(O)NR37BSO2R37B, SO2NH2, SO2Other37B, SO2N(R37B)2C(O)H, C(O)OH, C(N)NH2C(N)other37BC(N)N(R37B)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R37Brepresents alkyl, alkenyl, quinil, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen;

Z3is an R38, R39or R40;

R38represents phenyl, which is not condensed or fused with benzene, heteroatom or R38A; R38Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R39is heteroaryl that is not condensed or fused with benzene, heteroatom or R39A; R39Athe stand is made by cycloalkane, cycloalken, geteroseksualen or geteroseksualen;

R40is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R40A; R40Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

where the fragments represented by the group R26and R27not substituted or substituted (i.e., if Z1Aand Z2Amissing) or not further substituted or further substituted (i.e., if Z1Aand Z2Athere are one or more substituents R41, OR41, SR41, S(O)R41, SO2R41C(O)R41C(O)OR41, OC(O)R41, OC(O)OR41, NH2, Other41N(R41)2, NHC(O)R41, NR41C(O)R41NHS(O)2R41, NR41S(O)2R41, NHC(O)OR41, NR41C(O)OR41, NHC(O)NH2, NHC(O)other41, NHC(O)N(R41)2, NR41C(O)other41, NR41C(O)N(R41)2C(O)NH2C(O)other41C(O)N(R41)2C(O)NHOH, C(O)NHOR41C(O)NHSO2R41C(O)NR41SO2R41, SO2NH2, SO2Other41, SO2N(R41)2C(O)H, C(O)OH, C(N)NH2C(N)other41C(N)N(R41)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2/sub> CF3, F, Cl, Br or I;

R41is an R42, R43, R44or R45;

R42represents phenyl, which is not condensed or fused with benzene, heteroatom or R42A; R42Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R43is heteroaryl that is not condensed or fused with benzene, heteroatom or R43A; R43Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R44is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R44A; R44Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R45represents alkyl, alkenyl or quinil, each of which is not substituted or substituted by one or two independently selected substituents R46, OR46, SR46, S(O)R46, SO2R46C(O)R46C(O)OR46, OC(O)R46, OC(O)OR46, NH2, Other46N(R46)2, NHC(O)R46, NR46C(O)R46NHS(O)2R46, NR46S(O)2R46, NHC(O)OR46, NR46C(O)OR46, NHC(O)NH2, NHC(O)other46, NHC(O)N(R46)2, NR46C(O)other 46, NR46C(O)N(R46)2C(O)NH2C(O)other46C(O)N(R46)2C(O)NHOH, C(O)NHOR46C(O)NHSO2R46C(O)NR46SO2R46, SO2NH2, SO2Other46, SO2N(R46)2C(O)H, C(O)OH, C(N)NH2C(N)other46C(N)N(R46)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R46represents alkyl, alkenyl or quinil, R47, R48or R49;

R47represents phenyl, which is not condensed or fused with benzene, heteroatom or R47A; R47Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R48is heteroaryl that is not condensed or fused with benzene, heteroatom or R48A; R48Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R49is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R49A; R49Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

where the fragments represented by the group R42, R43, R44, R47, R48and R49no not substituted or substituted by one or more independently selected substituents R 50, OR50, SR50, S(O)R50, SO2R50C(O)R50C(O)OR50, OC(O)R50, OC(O)OR50, NH2, Other50N(R50)2, NHC(O)R50, NR50C(O)R50NHS(O)2R50, NR50S(O)2R50, NHC(O)OR50, NR50C(O)OR50, NHC(O)NH2, NHC(O)other50, NHC(O)N(R50)2, NR50C(O)other50, NR50C(O)N(R50)2C(O)NH2C(O)other50C(O)N(R50)2C(O)NHOH, C(O)NHOR50C(O)NHSO2R50C(O)NR50SO2R50, SO2NH2, SO2Other50, SO2N(R50)2C(O)H, C(O)OH, C(N)NH2C(N)other50C(N)N(R50)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R50is an R51, R52, R53or R54;

R51represents phenyl, which is not condensed or fused with benzene, heteroatom or R51A; R51Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R52is heteroaryl that is not condensed or fused with benzene, heteroatom or R52A; R52Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R53is cycloalkyl, cycloalkenyl, heterocicluri geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R53A; R53Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R54represents alkyl, alkenyl or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R55, OR55, SR55, S(O)R55, SO2R55C(O)R55C(O)OR55, OC(O)R55, OC(O)OR55, NH2, Other55N(R55)2, NHC(O)R55, NR55C(O)R55NHS(O)2R55, NR55S(O)2R55, NHC(O)OR55, NR55C(O)OR55, NHC(O)NH2, NHC(O)other55, NHC(O)N(R55)2, NR55C(O)other55, NR55C(O)N(R55)2C(O)NH2C(O)other55C(O)N(R55)2C(O)NHOH, C(O)NHOR55C(O)NHSO2R55C(O)NR55SO2R55, SO2NH2, SO2Other55, SO2N(R55)2C(O)H, C(O)OH, C(N)NH2C(N)other55C(N)N(R55)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R55represents alkyl, alkenyl, quinil, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen;

where each of the above cyclic fragment independently is not a substituted, optionally n is substituted, substituted or optionally substituted by one or more independently selected substituents R57, OR57, SR57, S(O)R57, SO2R57C(O)R57C(O)OR57, OC(O)R57, OC(O)OR57, NH2, Other57N(R57)2, NHC(O)R57, NR57C(O)R57NHS(O)2R57, NR57S(O)2R57, NHC(O)OR57, NR57C(O)OR57, NHC(O)NH2, NHC(O)other57, NHC(O)N(R57)2, NR57C(O)other57, NR57C(O)N(R57)2C(O)NH2C(O)other57C(O)N(R57)2C(O)NHOH, C(O)NHOR57C(O)NHSO2R57C(O)NR57SO2R57, SO2NH2, SO2Other57, SO2N(R57)2C(O)H, C(O)OH, C(N)NH2C(N)other57C(N)N(R57)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R57is an R58, R59, R60or R61;

R58represents phenyl, which is not condensed or fused with benzene, heteroatom or R58A; R58Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R59is heteroaryl that is not condensed or fused with benzene, heteroatom or R59A; R59Ais cycloalkane, cycloalkene, geteroseksualen is whether geteroseksualen;

R60is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R60A; R60Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R61represents alkyl, alkenyl or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R62, OR62, SR62, S(O)R62, SO2R62C(O)R62C(O)OR62, OC(O)R62, OC(O)OR62, NH2, Other62N(R62)2, NHC(O)R62, NR62C(O)R62NHS(O)2R62, NR62S(O)2R62, NHC(O)OR62, NR62C(O)OR62, NHC(O)NH2, NHC(O)other62, NHC(O)N(R62)2, NR62C(O)other62, NR62C(O)N(R62)2C(O)NH2C(O)other62C(O)N(R62)2C(O)NHOH, C(O)NHOR62C(O)NHSO2R62C(O)NR62SO2R62, SO2NH2, SO2Other62, SO2N(R62)2C(O)H, C(O)OH, C(N)NH2C(N)other62C(N)N(R62)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R62is an R63, R64, R65or R66;

R63represents phenyl, which is not conden the new or fused with benzene, heteroatom or R63A; R63Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R64is heteroaryl that is not condensed or fused with benzene, heteroatom or R64A; R64Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R65is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R65A; R65Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R66represents alkyl, alkenyl or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R67, OR67, SR67, S(O)R67, SO2R67C(O)R67C(O)OR67, OC(O)R67, OC(O)OR67, NH2, Other67N(R67)2, NHC(O)R67, NR67C(O)R67NHS(O)2R67, NR67S(O)2R67, NHC(O)OR67, NR67C(O)OR67, NHC(O)NH2, NHC(O)other67, NHC(O)N(R67)2, NR67C(O)other67, NR67C(O)N(R67)2C(O)NH2C(O)other67C(O)N(R67)2C(O)NHOH, C(O)NHOR67C(O)NHSO2R67C(O)NR67SO2R67, SO2NH2, SOsub> 2Other67, SO2N(R67)2C(O)H, C(O)OH, C(N)NH2C(N)other67C(N)N(R67)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R67represents alkyl, alkenyl, quinil, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen;

where the fragments represented by the group R58, R59, R60, R63, R64, R65and R67not substituted or substituted by one or more independently selected substituents R68, OR68, SR68, S(O)R68, SO2R68C(O)R68C(O)OR68, OC(O)R68, OC(O)OR68, NH2, Other68N(R68)2, NHC(O)R68, NR68C(O)R68NHS(O)2R68, NR68S(O)2R68, NHC(O)OR68, NR68C(O)OR68, NHC(O)NH2, NHC(O)other68, NHC(O)N(R68)2, NR68C(O)other68, NR68C(O)N(R68)2C(O)NH2C(O)other68C(O)N(R68)2C(O)NHOH, C(O)NHOR68C(O)NHSO2R68C(O)NR68SO2R68, SO2NH2, SO2Other68, SO2N(R68)2C(O)H, C(O)OH, C(N)NH2C(N)other68C(N)N(R68)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R68is an R6 , R70, R71or R72;

R69represents phenyl, which is not condensed or fused with benzene, heteroatom or R69A; R69Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R70is heteroaryl that is not condensed or fused with benzene, heteroatom or R70A; R70Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R71is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R71A; R71Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R72represents alkyl, alkenyl or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R73, OR73, SR73, S(O)R73, SO2R73C(O)R73C(O)OR73, OC(O)R73, OC(O)OR73, NH2, Other73N(R73)2, NHC(O)R73, NR73C(O)R73NHS(O)2R73, NR73S(O)2R73, NHC(O)OR73, NR73C(O)OR73, NHC(O)NH2, NHC(O)other73, NHC(O)N(R73)2, NR73C(O)other73, NR73C(O)N(R73)2C(O)NH2 C(O)other73C(O)N(R73)2C(O)NHOH, C(O)NHOR73C(O)NHSO2R73C(O)NR73SO2R73, SO2NH2, SO2Other73, SO2N(R73)2C(O)H, C(O)OH, C(N)NH2C(N)other73C(N)N(R73)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R73represents alkyl, alkenyl, quinil, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; and

fragments represented by the group R69, R70and R71not substituted or substituted by one or more independently selected substituents NH2C(O)NH2C(O)NHOH, SO2NH2, CF3, CF2CF3C(O)H, C(O)OH, C(N)NH2, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I.

In another embodiment of formula (I)

A1represents furyl, imidazolyl, isothiazolin, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, heteroseksualci or geteroseksualen; each of which is not condensed or fused with benzene, heteroatom or A1A; A1Arepresents geteroseksualen;

where A1not substituted or substituted by one, or two, or three, or four, or five independently selected and substituents R 1, OR1C(O)OR1, Other1N(R1)2C(N)C(O)R1C(O)other1, NHC(O)R1, NR1C(O)R1, (O), NO2, F, Cl, Br, I, CF3;

R1is an R2, R3, R4or R5;

R2represents phenyl;

R3is heteroaryl;

R4is heteroseksualci;

R5represents an alkyl or alkenyl, each of which is not substituted or substituted by substituents R7, SR7N(R7)2, NHC(O)R7, F, Cl, Br or I;

R7is an R8, R9, R10or R11;

R8represents phenyl;

R9is heteroaryl;

R10is heteroseksualci;

R11represents alkyl;

Z1is an R26;

Z2is an R30;

L1is an R37;

R26represents a phenylene;

R30is heterocyclochain;

R37is an R37A;

R37Ais alkylene or albaniles, each of which is not substituted or is substituted by R37B;

R37Brepresents phenyl;

Z3is an R38or R40;

R38represents phenyl;

R40isone cycloalkyl or cycloalkenyl;

where the fragments represented by the group R26and R27not substituted or substituted by a group OR41;

R41is an R42or R43;

R42represents phenyl, which is not condensed or condensed with heteroatom;

R43is heteroaryl that is not condensed or condensed with heteroatom;

where each of the above cyclic fragment independently is not a substituted, is not further substituted, substituted or optionally substituted by one or more independently selected substituents R57, OR57C(O)OR57, F, Cl, Br or I;

R57is an R58or R61;

R58represents phenyl;

R61represents alkyl; and

where the fragments represented by the group R58not substituted or substituted by one or more independently selected substituents F, Cl, Br or I.

Another variant of implementation of the present invention relates to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs of such compounds that are useful as inhibitors of anti-apoptotic proteins Bcl-2, these compounds have the formula II

where

A1represents furyl, imidazolyl, isothiazolin, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 2-pyridinyl, 4-pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl, triazolyl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; each of which is not condensed or fused with benzene, heteroatom or A1A; A1Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

where A1not substituted or substituted by one, or two, or three, or four, or five independently selected substituents R1, OR1, SR1, S(O)R1, SO2R1C(O)R1C(O)OR1, OC(O)R1, Other1N(R1)2C(N)C(O)R1C(O)other1C(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, NHC(O)R1, NR1C(O)R1, NHC(O)OR1, NR1C(O)OR1, NR1C(O)other1, NR1C(O)N(R1)2, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2, SO2NH2, SO2Other1, SO2N(R1)2NHS(O)R1, NHSO2R1, NR1SO2R1, NHSO2Other1N(CH3)SO2N(CH3R1, (O), NH2, NO2N3, OH, F, Cl, Br, I, CN, CF3, OCF3, CF2CF3, OCF2CF3C(O)H, C(O)OH, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3C(O)NH2or C(O)OR1A;

R1is an R2, R3, R4or R5;

R1Ais cycloalkyl, cycloalkenyl or cycloalkenyl;

R2represents phenyl, which is not condensed or fused with benzene, heteroatom or R2A; R2Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R3is heteroaryl that is not condensed or fused with benzene, heteroatom or R3A; R3Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R4is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R4A; R4Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R5represents alkyl, alkenyl or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R6, NC(R6A)(R6B), R7, OR7, SR7, S(O)R7, SO2R7, Other7N(R7)2C(O)R7C(O)NH2C(O)other7C(O)N(R7)2, NHC(O)R7, NR7C(O)R7, NHSO2R7, NHC(O)OR7, SO2NH2, SO2Other , SO2N(R7)2, NHC(O)NH2, NHC(O)other7, NHC(O)CH(CH3)NHC(O)CH(CH3)NH2, NHC(O)CH(CH3)NHC(O)CH(CH3)Other1, OH, (O), C(O)OH, (O), N3, CN, NH2, CF3, CF2CF3, F, Cl, Br or I;

R6represents a C2-C5-spiralcell, each of which is not substituted or substituted by OH groups, (O), N3CN, CF3, CF2CF3, F, Cl, Br, I, NH2, NH(CH3) or N(CH3)2;

R6Aand R6Bindependently selected from alkyl or together with the N atom to which they are attached, form an R6C;

R6Cis aziridine-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidine-1-yl, each of which has one piece of CH2not replaced or replaced with O, C(O), CNOH, CNOCH3, S, S(O), SO2or NH;

R7is an R8, R9, R10or R11;

R8represents phenyl, which is not condensed or fused with benzene, heteroatom or R8A; R8Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R9is heteroaryl that is not condensed or fused with benzene, heteroatom or R9A; R9Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R10is cycloalkyl, the cycle is of alkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R10A; R10Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R11represents alkyl, alkenyl or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R12, OR12, SR12, S(O)R12, SO2R12C(O)R12C(O)OR12, OC(O)R12, OC(O)OR12, NH2, Other12N(R12)2, NHC(O)R12, NR12C(O)R12NHS(O)2R12, NR12S(O)2R12, NHC(O)OR12, NR12C(O)OR12, NHC(O)NH2, NHC(O)other12, NHC(O)N(R12)2, NR12C(O)other12, NR12C(O)N(R12)2C(O)NH2C(O)other12C(O)N(R12)2C(O)NHOH, C(O)NHOR12C(O)NHSO2R12C(O)NR12SO2R12, SO2NH2, SO2Other12, SO2N(R12)2C(O)H, C(O)OH, C(N)NH2C(N)other12C(N)N(R12)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R12is an R13, R14, R15or R16;

R13represents phenyl, which is not condensed or fused with benzene, heteroatom or R1A ; R13Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R14is heteroaryl that is not condensed or fused with benzene, heteroatom or R14A; R14Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R15is cycloalkane, cycloalkene, geteroseksualen or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R15A; R15Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R16represents alkyl, alkenyl or quinil;

where the fragment represented by the group R101represents the substituents H, R41, OR41, SR41, S(O)R41, SO2R41C(O)R41C(O)OR41, OC(O)R41, OC(O)OR41, NH2, Other41N(R41)2, NHC(O)R41, NR41C(O)R41NHS(O)2R41, NR41S(O)2R41, NHC(O)OR41, NR41C(O)OR41, NHC(O)NH2, NHC(O)other41, NHC(O)N(R41)2, NR41C(O)other41, NR41C(O)N(R41)2C(O)NH2C(O)other41C(O)N(R41)2C(O)NHOH, C(O)NHOR41C(O)NHSO2R41C(O)NR41SO2R41, SO2NH2, SO2Other41, SO2N(R41)2C(O)H, (O)OH, C(N)NH2C(N)other41C(N)N(R41)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R41is an R42, R43, R44or R45;

R42represents phenyl, which is not condensed or fused with benzene, heteroatom or R42A; R42Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R43is heteroaryl that is not condensed or fused with benzene, heteroatom or R43A; R43Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R44is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R44A; R44Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R45represents alkyl, alkenyl or quinil, each of which is not substituted or substituted by one or two independently selected substituents R46, OR46, SR46, S(O)R46, SO2R46C(O)R46C(O)OR46, OC(O)R46, OC(O)OR46, NH2, Other46N(R46)2, NHC(O)R46, NR46C(O)R46NHS(O)2 R46, NR46S(O)2R46, NHC(O)OR46, NR46C(O)OR46, NHC(O)NH2, NHC(O)other46, NHC(O)N(R46)2, NR46C(O)other46, NR46C(O)N(R46)2C(O)NH2C(O)other46C(O)N(R46)2C(O)NHOH, C(O)NHOR46C(O)NHSO2R46C(O)NR46SO2R46, SO2NH2, SO2Other46, SO2N(R46)2C(O)H, C(O)OH, C(N)NH2C(N)other46C(N)N(R46)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R46represents alkyl, alkenyl or quinil, R47, R48or R49;

R47represents phenyl, which is not condensed or fused with benzene, heteroatom or R47A; R47Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R48is heteroaryl that is not condensed or fused with benzene, heteroatom or R48A; R48Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R49is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R49A; R49Ais cycloalkane, cycloalkene, gets rotillon or geteroseksualen;

fragments represented by the group R42, R43, R44, R47, R48and R49regardless not substituted or substituted by one or more independently selected substituents R50, OR50, SR50, S(O)R50, SO2R50C(O)R50C(O)OR50, OC(O)R50, OC(O)OR50, NH2, Other50N(R50)2, NHC(O)R50, NR50C(O)R50NHS(O)2R50, NR50S(O)2R50, NHC(O)OR50, NR50C(O)OR50, NHC(O)NH2, NHC(O)other50, NHC(O)N(R50)2, NR50C(O)other50, NR50C(O)N(R50)2C(O)NH2C(O)other50C(O)N(R50)2C(O)NHOH, C(O)NHOR50C(O)NHSO2R50C(O)NR50SO2R50, SO2NH2, SO2Other50, SO2N(R50)2C(O)H, C(O)OH, C(N)NH2C(N)other50C(N)N(R50)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R50is an R51, R52, R53or R54;

R51represents phenyl, which is not condensed or fused with benzene, heteroatom or R51A; R51Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R52is heteroaryl that is not condensed or fused with benzene is m, heteroatom or R52A; R52Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R53is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R53A; R53Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R54represents alkyl, alkenyl or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R55, OR55, SR55, S(O)R55, SO2R55C(O)R55C(O)OR55, OC(O)R55, OC(O)OR55, NH2, Other55N(R55)2, NHC(O)R55, NR55C(O)R55NHS(O)2R55, NR55S(O)2R55, NHC(O)OR55, NR55C(O)OR55, NHC(O)NH2, NHC(O)other55, NHC(O)N(R55)2, NR55C(O)other55, NR55C(O)N(R55)2C(O)NH2C(O)other55C(O)N(R55)2C(O)NHOH, C(O)NHOR55C(O)NHSO2R55C(O)NR55SO2R55, SO2NH2, SO2Other55, SO2N(R55)2C(O)H, C(O)OH, C(N)NH2C(N)other55C(N)N(R55)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R55

where each of the above cyclic fragment independently is not a substituted, is not further substituted, substituted or optionally substituted by one or more independently selected substituents R57, OR57, SR57, S(O)R57, SO2R57C(O)R57C(O)OR57, OC(O)R57, OC(O)OR57, NH2, Other57N(R57)2, NHC(O)R57, NR57C(O)R57NHS(O)2R57, NR57S(O)2R57, NHC(O)OR57, NR57C(O)OR57, NHC(O)NH2, NHC(O)other57, NHC(O)N(R57)2, NR57C(O)other57, NR57C(O)N(R57)2C(O)NH2C(O)other57C(O)N(R57)2C(O)NHOH, C(O)NHOR57C(O)NHSO2R57C(O)NR57SO2R57, SO2NH2, SO2Other57, SO2N(R57)2C(O)H, C(O)OH, C(N)NH2C(N)other57C(N)N(R57)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R57is an R58, R59, R60or R61;

R58represents phenyl, which is not condensed or fused with benzene, heteroatom or R58A; R58Ais cycloalkane, cycloalkene, geteroseksualen or heterocycle is Ken;

R59is heteroaryl that is not condensed or fused with benzene, heteroatom or R59A; R59Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R60is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R60A; R60Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R61represents alkyl, alkenyl or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R62, OR62, SR62, S(O)R62, SO2R62C(O)R62C(O)OR62, OC(O)R62, OC(O)OR62, NH2, Other62N(R62)2, NHC(O)R62, NR62C(O)R62NHS(O)2R62, NR62S(O)2R62, NHC(O)OR62, NR62C(O)OR62, NHC(O)NH2, NHC(O)other62, NHC(O)N(R62)2, NR62C(O)other62, NR62C(O)N(R62)2C(O)NH2C(O)other62C(O)N(R62)2C(O)NHOH, C(O)NHOR62C(O)NHSO2R62C(O)NR62SO2R62, SO2NH2, SO2Other62, SO2N(R62)2C(O)H, C(O)OH, C(N)NH2C(N)other62C(N)N(R62)2, CNOH, CNOCH3, OH, (O), C, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R62is an R63, R64, R65or R66;

R63represents phenyl, which is not condensed or fused with benzene, heteroatom or R63A; R63Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R64is heteroaryl that is not condensed or fused with benzene, heteroatom or R64A; R64Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R65is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R65A; R65Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R66represents alkyl, alkenyl or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R67, OR67, SR67, S(O)R67, SO2R67C(O)R67C(O)OR67, OC(O)R67, OC(O)OR67, NH2, Other67N(R67)2, NHC(O)R67, NR67C(O)R67NHS(O)2R67, NR67S(O)2R67, NHC(O)OR67, NR 67C(O)OR67, NHC(O)NH2, NHC(O)other67, NHC(O)N(R67)2, NR67C(O)other67, NR67C(O)N(R67)2C(O)NH2C(O)other67C(O)N(R67)2C(O)NHOH, C(O)NHOR67C(O)NHSO2R67C(O)NR67SO2R67, SO2NH2, SO2Other67, SO2N(R67)2C(O)H, C(O)OH, C(N)NH2C(N)other67C(N)N(R67)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R67represents alkyl, alkenyl, quinil, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen;

where the fragments represented by the group R58, R59, R60, R63, R64, R65and R67not substituted or substituted by one or more independently selected substituents R68, OR68, SR68, S(O)R68, SO2R68C(O)R68C(O)OR68, OC(O)R68, OC(O)OR68, NH2, Other68N(R68)2, NHC(O)R68, NR68C(O)R68NHS(O)2R68, NR68S(O)2R68, NHC(O)OR68, NR68C(O)OR68, NHC(O)NH2, NHC(O)other68, NHC(O)N(R68)2, NR68C(O)other68, NR68C(O)N(R68)2C(O)NH2C(O)other68C(O)N(R68)2C(O)NHOH, C(O)NHOR68C(O)NHSO2R68C(O)NR68SO2R68, SO2 2, SO2Other68, SO2N(R68)2C(O)H, C(O)OH, C(N)NH2C(N)other68C(N)N(R68)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R68is an R69, R70, R71or R72;

R69represents phenyl, which is not condensed or fused with benzene, heteroatom or R69A; R69Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R70is heteroaryl that is not condensed or fused with benzene, heteroatom or R70A; R70Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R71is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R71A; R71Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R72represents alkyl, alkenyl or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R73, OR73, SR73, S(O)R73, SO2R73C(O)R73C(O)OR73, OC(O)R73, OC(O)OR73, NH2, NR 73N(R73)2, NHC(O)R73, NR73C(O)R73NHS(O)2R73, NR73S(O)2R73, NHC(O)OR73, NR73C(O)OR73, NHC(O)NH2, NHC(O)other73, NHC(O)N(R73)2, NR73C(O)other73, NR73C(O)N(R73)2C(O)NH2C(O)other73C(O)N(R73)2C(O)NHOH, C(O)NHOR73C(O)NHSO2R73C(O)NR73SO2R73, SO2NH2, SO2Other73, SO2N(R73)2C(O)H, C(O)OH, C(N)NH2C(N)other73C(N)N(R73)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R73represents alkyl, alkenyl, quinil, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; and

fragments represented by the group R69, R70and R71not substituted or substituted by one or more independently selected substituents NH2C(O)NH2C(O)NHOH, SO2NH2, CF3, CF2CF3C(O)H, C(O)OH, C(N)NH2, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I.

Another variant of implementation of the present invention relates to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs of these compounds, are suitable as Inga is itoro antiapoptotic proteins Bcl-2, these compounds have the formula III

where

A1represents furyl, imidazolyl, isothiazolin, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 2-pyridinyl, 4-pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl, triazolyl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; each of which is not condensed or fused with benzene, heteroatom or A1A; A1Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

where A1not substituted or substituted by one, or two, or three, or four, or five independently selected substituents R1, OR1, SR1, S(O)R1, SO2R1C(O)R1C(O)OR1, OC(O)R1, Other1N(R1)2C(N)C(O)R1C(O)other1C(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, NHC(O)R1, NR1C(O)R1, NHC(O)OR1, NR1C(O)OR1, NR1C(O)other1, NR1C(O)N(R1)2, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2, SO2NH2, SO2Other1, SO2N(R1)2NHS(O)R1, NHSO2R1, NR1SO2R1, NHSO2Other1N(CH3)SO2N(CH3R1, (O), NH2, NO2N3, OH F, Cl, Br, I, CN, CF3, OCF3, CF2CF3, OCF2CF3C(O)H, C(O)OH, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3C(O)NH2or C(O)OR1A;

R1is an R2, R3, R4or R5;

R1Ais cycloalkyl, cycloalkenyl or cycloalkenyl;

R2represents phenyl, which is not condensed or fused with benzene, heteroatom or R2A; R2Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R3is heteroaryl that is not condensed or fused with benzene, heteroatom or R3A; R3Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R4is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R4A; R4Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R5represents alkyl, alkenyl or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R6, NC(R6A)(R6B), R7, OR7, SR7, S(O)R7, SO2R7, Other7N(R7 2C(O)R7C(O)NH2C(O)other7C(O)N(R7)2, NHC(O)R7, NR7C(O)R7, NHSO2R7, NHC(O)OR7, SO2NH2, SO2Other7, SO2N(R7)2, NHC(O)NH2, NHC(O)other7, NHC(O)CH(CH3)NHC(O)CH(CH3)NH2, NHC(O)CH(CH3)NHC(O)CH(CH3)Other1, OH, (O), C(O)OH, N3, CN, NH2, CF3, CF2CF3, F, Cl, Br or I;

R6represents a C2-C5-spiralcell, each of which is not substituted or substituted by OH groups, (O), N3CN, CF3, CF2CF3, F, Cl, Br, I, NH2, NH(CH3) or N(CH3)2;

R6Aand R6Bindependently selected from alkyl or together with the N atom to which they are attached, form an R6C;

R6Cis aziridine-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidine-1-yl, each of which has one piece of CH2not replaced or replaced with O, C(O), CNOH, CNOCH3, S, S(O), SO2or NH;

R7is an R8, R9, R10or R11;

R8represents phenyl, which is not condensed or fused with benzene, heteroatom or R8A; R8Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R9is heteroaryl that is not condensed or condensed with benzene, heterodera the om or R 9A; R9Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R10is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R10A; R10Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R11represents alkyl, alkenyl or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R12, OR12, SR12, S(O)R12, SO2R12C(O)R12C(O)OR12, OC(O)R12, OC(O)OR12, NH2, Other12N(R12)2, NHC(O)R12, NR12C(O)R12NHS(O)2R12, NR12S(O)2R12, NHC(O)OR12, NR12C(O)OR12, NHC(O)NH2, NHC(O)other12, NHC(O)N(R12)2, NR12C(O)other12, NR12C(O)N(R12)2C(O)NH2C(O)other12C(O)N(R12)2C(O)NHOH, C(O)NHOR12C(O)NHSO2R12C(O)NR12SO2R12, SO2NH2, SO2Other12, SO2N(R12)2C(O)H, C(O)OH, C(N)NH2C(N)other12C(N)N(R12)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R12is a R 13, R14, R15or R16;

R13represents phenyl, which is not condensed or fused with benzene, heteroatom or R13A; R13Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R14is heteroaryl that is not condensed or fused with benzene, heteroatom or R14A; R14Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R15is cycloalkane, cycloalkene, geteroseksualen or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R15A; R15Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R16represents alkyl, alkenyl or quinil;

where the fragment represented by the group R101represents the substituents H, R41, OR41, SR41, S(O)R41, SO2R41C(O)R41C(O)OR41, OC(O)R41, OC(O)OR41, NH2, Other41N(R41)2, NHC(O)R41, NR41C(O)R41NHS(O)2R41, NR41S(O)2R41, NHC(O)OR41, NR41C(O)OR41, NHC(O)NH2, NHC(O)other41, NHC(O)N(R41)2, NR41C(O)other41, NR41C(O)N(R41)2C(O)NH2C(O)other41C()N(R 41)2C(O)NHOH, C(O)NHOR41C(O)NHSO2R41C(O)NR41SO2R41, SO2NH2, SO2Other41, SO2N(R41)2C(O)H, C(O)OH, C(N)NH2C(N)other41C(N)N(R41)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R41is an R42, R43, R44or R45;

R42represents phenyl, which is not condensed or fused with benzene, heteroatom or R42A; R42Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R43is heteroaryl that is not condensed or fused with benzene, heteroatom or R43A; R43Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R44is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R44A; R44Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R45represents alkyl, alkenyl or quinil, each of which is not substituted or substituted by one or two independently selected substituents R46, OR46, SR46, S(O)R 46, SO2R46C(O)R46C(O)OR46, OC(O)R46, OC(O)OR46, NH2, Other46N(R46)2, NHC(O)R46, NR46C(O)R46NHS(O)2R46, NR46S(O)2R46, NHC(O)OR46, NR46C(O)OR46, NHC(O)NH2, NHC(O)other46, NHC(O)N(R46)2, NR46C(O)other46, NR46C(O)N(R46)2C(O)NH2C(O)other46C(O)N(R46)2C(O)NHOH, C(O)NHOR46C(O)NHSO2R46C(O)NR46SO2R46, SO2NH2, SO2Other46, SO2N(R46)2C(O)H, C(O)OH, C(N)NH2C(N)other46C(N)N(R46)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R46represents alkyl, alkenyl or quinil, R47, R48or R49;

R47represents phenyl, which is not condensed or fused with benzene, heteroatom or R47A; R47Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R48is heteroaryl that is not condensed or fused with benzene, heteroatom or R48A; R48Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R49is cycloalkyl, cycloalkenyl, heteroseksualci or heterocycle is of alkenyl, each of which is not condensed or fused with benzene, heteroatom or R49A; R49Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

fragments represented by the group R42, R43, R44, R47, R48and R49regardless not substituted or substituted by one or more independently selected substituents R50, OR50, SR50, S(O)R50, SO2R50C(O)R50C(O)OR50, OC(O)R50, OC(O)OR50, NH2, Other50N(R50)2, NHC(O)R50, NR50C(O)R50NHS(O)2R50, NR50S(O)2R50, NHC(O)OR50, NR50C(O)OR50, NHC(O)NH2, NHC(O)other50, NHC(O)N(R50)2, NR50C(O)other50, NR50C(O)N(R50)2C(O)NH2C(O)other50C(O)N(R50)2C(O)NHOH, C(O)NHOR50C(O)NHSO2R50C(O)NR50SO2R50, SO2NH2, SO2Other50, SO2N(R50)2C(O)H, C(O)OH, C(N)NH2C(N)other50C(N)N(R50)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R50is an R51, R52, R53or R54;

R51represents phenyl, which is not condensed or fused with benzene, heteroatom or R51A; R51A/sup> is cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R52is heteroaryl that is not condensed or fused with benzene, heteroatom or R52A; R52Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R53is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R53A; R53Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R54represents alkyl, alkenyl or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R55, OR55, SR55, S(O)R55, SO2R55C(O)R55C(O)OR55, OC(O)R55, OC(O)OR55, NH2, Other55N(R55)2, NHC(O)R55, NR55C(O)R55NHS(O)2R55, NR55S(O)2R55, NHC(O)OR55, NR55C(O)OR55, NHC(O)NH2, NHC(O)other55, NHC(O)N(R55)2, NR55C(O)other55, NR55C(O)N(R55)2C(O)NH2C(O)other55C(O)N(R55)2C(O)NHOH, C(O)NHOR55C(O)NHSO2R55C(O)NR55SO2R55, SO2NH2, SO2Other55, SO2N(R55 2C(O)H, C(O)OH, C(N)NH2C(N)other55C(N)N(R55)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R55represents alkyl, alkenyl, quinil, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen;

where each of the above cyclic fragment independently is not a substituted, is not further substituted, substituted or optionally substituted by one or more independently selected substituents R57, OR57, SR57, S(O)R57, SO2R57C(O)R57C(O)OR57, OC(O)R57, OC(O)OR57, NH2, Other57N(R57)2, NHC(O)R57, NR57C(O)R57NHS(O)2R57, NR57S(O)2R57, NHC(O)OR57, NR57C(O)OR57, NHC(O)NH2, NHC(O)other57, NHC(O)N(R57)2, NR57C(O)other57, NR57C(O)N(R57)2C(O)NH2C(O)other57C(O)N(R57)2C(O)NHOH, C(O)NHOR57C(O)NHSO2R57C(O)NR57SO2R57, SO2NH2, SO2Other57, SO2N(R57)2C(O)H, C(O)OH, C(N)NH2C(N)other57C(N)N(R57)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R57is an R58, R59, R60or R61;

<> R58represents phenyl, which is not condensed or fused with benzene, heteroatom or R58A; R58Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R59is heteroaryl that is not condensed or fused with benzene, heteroatom or R59A; R59Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R60is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R60A; R60Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R61represents alkyl, alkenyl or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R62, OR62, SR62, S(O)R62, SO2R62C(O)R62C(O)OR62, OC(O)R62, OC(O)OR62, NH2, Other62N(R62)2, NHC(O)R62, NR62C(O)R62NHS(O)2R62, NR62S(O)2R62, NHC(O)OR62, NR62C(O)OR62, NHC(O)NH2, NHC(O)other62, NHC(O)N(R62)2, NR62C(O)other62, NR62C(O)N(R62)2C(O)NH2C(O)other62C(O)N(R62)2C(O)NHOH, C(O)NHOR62C(O)NHSO2R62C(O)NR62SO2R62, SO2NH2, SO2Other62, SO2N(R62)2C(O)H, C(O)OH, C(N)NH2C(N)other62C(N)N(R62)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R62is an R63, R64, R65or R66;

R63represents phenyl, which is not condensed or fused with benzene, heteroatom or R63A; R63Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R64is heteroaryl that is not condensed or fused with benzene, heteroatom or R64A; R64Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R65is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R65A; R65Ais cycloalkane, cycloalkene, geteroseksualen or heterocycle Walken;

R66represents alkyl, alkenyl or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R67, OR67, SR67, S(O)R67O 2R67C(O)R67C(O)OR67, OC(O)R67, OC(O)OR67, NH2, Other67N(R67)2, NHC(O)R67, NR67C(O)R67NHS(O)2R67, NR67S(O)2R67, NHC(O)OR67, NR67C(O)OR67, NHC(O)NH2, NHC(O)other67, NHC(O)N(R67)2, NR67C(O)other67, NR67C(O)N(R67)2C(O)NH2C(O)other67C(O)N(R67)2C(O)NHOH, C(O)NHOR67C(O)NHSO2R67C(O)NR67SO2R67, SO2NH2, SO2Other67, SO2N(R67)2C(O)H, C(O)OH, C(N)NH2C(N)other67C(N)N(R67)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R67represents alkyl, alkenyl, quinil, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen;

where the fragments represented by the group R58, R59, R60, R63, R64, R65and R67not substituted or substituted by one or more independently selected substituents R68, OR68, SR68, S(O)R68, SO2R68C(O)R68C(O)OR68, OC(O)R68, OC(O)OR68, NH2, Other68N(R68)2, NHC(O)R68, NR68C(O)R68NHS(O)2R68, NR68S(O)2R68, NHC(O)OR68, NR68C(O)OR68, NHC(O)NH2, NHC(O)other8 , NHC(O)N(R68)2, NR68C(O)other68, NR68C(O)N(R68)2C(O)NH2C(O)other68C(O)N(R68)2C(O)NHOH, C(O)NHOR68C(O)NHSO2R68C(O)NR68SO2R68, SO2NH2, SO2Other68, SO2N(R68)2C(O)H, C(O)OH, C(N)NH2C(N)other68C(N)N(R68)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R68is an R69, R70, R71or R72;

R69represents phenyl, which is not condensed or fused with benzene, heteroatom or R69A; R69Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R70is heteroaryl that is not condensed or fused with benzene, heteroatom or R70A; R70Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R71is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R71A; R71Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R72represents alkyl, alkenyl or quinil, each of which is unsubstituted or substituted one, or two, or three independently selected substituents R73, OR73, SR73, S(O)R73, SO2R73C(O)R73C(O)OR73, OC(O)R73, OC(O)OR73, NH2, Other73N(R73)2, NHC(O)R73, NR73C(O)R73NHS(O)2R73, NR73S(O)2R73, NHC(O)OR73, NR73C(O)OR73, NHC(O)NH2, NHC(O)other73, NHC(O)N(R73)2, NR73C(O)other73, NR73C(O)N(R73)2C(O)NH2C(O)other73C(O)N(R73)2C(O)NHOH, C(O)NHOR73C(O)NHSO2R73C(O)NR73SO2R73, SO2NH2, SO2Other73, SO2N(R73)2C(O)H, C(O)OH, C(N)NH2C(N)other73C(N)N(R73)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R73represents alkyl, alkenyl, quinil, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; and

fragments represented by the group R69, R70and R71not substituted or substituted by one or more independently selected substituents NH2C(O)NH2C(O)NHOH, SO2NH2, CF3, CF2CF3C(O)H, C(O)OH, C(N)NH2, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I.

Finally, another option is to implement the Oia, the present invention relates to compounds, having the formula I, which are

4-[4-(cyclohexylmethyl)-4-methoxypiperidine-1-yl]-N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}benzamide;

N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}-4-[4-methoxy-4-(3-methylbenzyl)piperidine-1-yl]benzamide;

N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}-4-[4-(3,3-diphenylprop-2-enyl)piperazine-1-yl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-{[2-(phenylthio)ethyl]amino}piperidine-1-yl)sulfonyl]benzamide;

N-[(4-{acetyl[2-(phenylthio)ethyl]amino}piperidine-1-yl)sulfonyl]-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-{methyl[2-(phenylthio)ethyl]amino}piperidine-1-yl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}benzamide;

4-(4-{[2-(4-chlorophenyl)cyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}benzamide;

4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}benzamide;

N-{[(5Z)-5-(acetylamino)-4-methyl-4,5-Digi the ro-1,3,4-thiadiazole-2-yl]sulfonyl}-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;

N-{[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]sulfonyl}-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;

N-({5-[(benzoylamine)methyl]Tien-2-yl}sulfonyl)-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-(morpholine-4-ylsulphonyl)benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[4-phenyl-5-(trifluoromethyl)Tien-3-yl]sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5-fluoro-3-methyl-1-benzothieno-2-yl)sulfonyl]benzamide;

N-(1,3-benzothiazol-2-ylsulphonyl)-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-(Tien-2-ylsulphonyl)benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]benzamide;

ethyl 4-{[(4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzoyl)amino]sulfonyl}-5-methyl-1,2-diphenyl-1H-pyrrole-3-carboxylate;

methyl 5-{[(4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzoyl)amino]sulfonyl}-1-methyl-1H-pyrrole-2-carboxylate;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[5-(1,3-dimethyl-1H-pyrazole-5-yl)isoxazol-4-and the]sulfonyl}benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-chloro-3-metalization-5-yl)sulfonyl]benzamide;

N-[(5-bromo-3-methyl-1-benzothieno-2-yl)sulfonyl]-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-({5-[(E)-2-(1,2,4-oxadiazol-3-yl)vinyl]Tien-2-yl}sulfonyl)benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[1-(2-chloroethyl)-3,5-dimethyl-1H-pyrazole-4-yl]sulfonyl}benzamide;

5-{[(4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzoyl)amino]sulfonyl}-N-(1-ethylpropyl)-1,3,4-thiadiazole-2-carboxamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5-chloro-1,3-dimethyl-1H-pyrazole-4-yl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-nitro-5-piperidine-1-Illian-2-yl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5-isoxazol-5-yl-2-furyl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3,5-dimethylisoxazol-4-yl)sulfonyl]benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-({4-nitro-5-[(3-pyrrolidin-1-ylpropyl)amino]Tien-2-yl}sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(5-{[3-(dimethylamino)propyl]amino}-4-nitration-2-yl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl} is piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({5-[(3-morpholine-4-ylpropyl)amino]-4-nitration-2-yl}sulfonyl)benzamide;

N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}-4-{4-[2-(trifluoromethyl)benzylidene]piperidine-1-yl}benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methylene]piperidine-1-yl}-N-[(1,1-dioxymethamphetamine-3-yl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methylene]piperidine-1-yl}-N-[(5-chloro-3-methyl-1-benzothieno-2-yl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5-chloro-3-methyl-1-benzothieno-2-yl)sulfonyl]-2-phenoxybenzamide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-Ν-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-[(6,7-debtor-1H-indol-5-yl)oxy]-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]benzamide;

tert-butyl (2S)-2-{[(5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;

tert-butyl (2S)-2-{[(5-{[2-(1H-benzimidazole-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-({2-[(4-Porterage-2H-Piran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)benzamide;

2-(1H-benzimidazole-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-({2-[(4-Porterage-2H-Piran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)benzamide;

tert-butyl (2S)-2-{[(5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indazol-4-yloxy)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-({2-[(4-Porterage-2H-Piran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;

and their therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites.

Another variant of implementation of the present invention relates to compositions for treating bladder cancer, brain cancer, breast cancer, cancer, bone marrow cancer, cervical region, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, leukemia, called T-lymphocytes or b-cells, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, lung cancer, prostate cancer, chalk is kletochnogo lung cancer or cancer of the spleen, while this composition includes an inert filler and a therapeutically effective amount of the compounds of formula (I).

Another variant of implementation of the present invention relates to a method of treating bladder cancer, brain cancer, breast cancer, cancer, bone marrow cancer, cervical region, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, leukemia, called T-lymphocytes or b-cells, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small-cell lung cancer or cancer of the spleen in a patient, includes introduction to the patient a therapeutically effective amount of the compounds of formula (I).

Another variant of implementation of the present invention relates to a method of treating bladder cancer, brain cancer, breast cancer, cancer, bone marrow cancer, cervical region, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, leukemia, called T-lymphocytes or b-cells, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, lung cancer, chronic Lee is polycose, myeloma, prostate cancer, small-cell lung cancer or cancer of the spleen in a patient, comprising the administration to a patient a therapeutically effective amount of the compounds of formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

DETAILED description of the INVENTION

In this description of variables fragments are represented by identifiers (in capital letters with numeric and/or alphabetic superscripts) and can be specifically defined.

It should be understood that suitable valency is designed for all fragments and their combinations, and that monovalent fragments containing more than one atom, pictured from left to right and joined their left ends, and divalent fragments also pictured from left to right.

It should also be understood that the specific variant variable fragment in this description may be the same or different as another specific variant variable fragment with the same identifier.

The term "alkenyl" in this specification means a straight or branched hydrocarbon chain containing from 2 to 10 carbon atoms that includes at least one double carbon-carbon bond. The term "Cx-Cyalkenyl" means the direct and the branched hydrocarbon chain, having at least one carbon-carbon double bond and containing from x to y carbon atoms. The term "C2-C4alkenyl" means alkenylphenol group containing 2-4 carbon atoms. Some examples of alkenyl include, but are not agrarias, buta-2,3-dienyl, ethynyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-Heptene and 3-decenyl.

The term "albaniles" means a divalent group derived from a hydrocarbon straight or branched chain, which includes from 2 to 4 carbon atoms and contains at least one double carbon-carbon bond. The term "Cx-Cyalbaniles" means a divalent group derived from a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond and containing from x to y carbon atoms. Some examples of Alcanena include, but are not agrarias, -CH=CH - and-CH2CH=CH-.

The term "alkyl" in this specification means a straight or branched chain saturated hydrocarbon containing from 1 to 10 carbon atoms. The term "Cx-Cyalkyl" means a straight or branched chain saturated hydrocarbon containing from x to y carbon atoms. For example, "C2-C10alkyl" means a straight or branched chain saturated hydrocarbon, sotiriadou is from 2 to 10 carbon atoms. Examples of alkyl include, but are not agrarias, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-etylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.

The term "alkylene" means a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 10 carbon atoms, for example, from 1 to 4 carbon atoms. The term "CxCyalkylene" means a divalent group derived from a straight or branched chain saturated hydrocarbon containing from x to y carbon atoms. For example, "C2-C6alkylene" means a straight or branched chain saturated hydrocarbon containing from 2 to 6 carbon atoms. Examples of alkylene include, but are not agrarias, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2- and-CH2CH(CH3)CH2-.

The term "quinil" in this description means a hydrocarbon group with a straight or branched chain, containing from 2 to 10 carbon atoms and containing at least one triple carbon-carbon bond. The term "Cx-Cyquinil" means a hydrocarbon group with a straight or branched chain, containing from x to y carbon atoms. Some examples of quinil in luchot, however, this is not agrarias, acetylenyl, 1-PROPYNYL, 2-PROPYNYL, 3-butynyl, 2-pentenyl and 1-butynyl.

The term "akinyan" in this description means a divalent radical derived from a hydrocarbon group with a straight or branched chain, containing from 2 to 10 carbon atoms and containing at least one triple carbon-carbon bond.

The term "aryl" herein means phenyl.

The term "cyclic fragment" in this description means benzene, phenyl, phenylene, cycloalkane, cycloalkyl, cycloalkyl, cycloalkene, cycloalkenyl, cycloalkenyl, cycloalkyl, cycloalkenyl, cycloalkenyl, heteroaryl, heteroaryl, geteroseksualen, heteroseksualci, geteroseksualen, geteroseksualen and spiralcell.

The term "cycloalkyl", or "cycloalkyl", or "cycloalkane" in this description means a monocyclic or bridged hydrocarbon ring system. Monocyclic cycloalkyl is a carbocyclic ring system containing three to eight carbon atoms, and zero heteroatoms and zero double bonds. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Monocyclic ring may contain one or two alkilinity bridge, each of which includes one, two or three carbon atoms and each the first of which connects two non-adjacent carbon atom of the ring system. Not limiting the present invention, examples of such bridge cycloalkyl ring systems include bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonan, bicyclo[3.3.1]nonan, bicyclo[4.2.1]nonan, tricyclo[3.3.1.03,7]nonan (octahydro-2,5-methanoindene or noradsanta) and tricyclo[3.3.1.13,7]decane (adamantane). Monocyclic and bridged cycloalkyl can be attached to a fragment of the parent molecule through any capable of substitution of an atom present in the cyclic system.

The term "cycloalkenyl", or "cycloalkenyl", or "cycloalkene" in this description means a ring system is monocyclic or bridged hydrocarbon. Monocyclic cycloalkenyl has four, five, six, seven, or eight carbon atoms and do not contain heteroatoms. Four-membered cyclic systems have one double bond, five - or six-membered cyclic system have one or two double bonds, and the seven - or eight-membered cyclic system have one, two or three double bonds. Some examples of monocyclic cycloalkenyl groups include, but are not agrarias, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctanol. Monocyclic cycloalkenyl ring may contain one or two alkilinity bridge, each of which including the AET one, two or three carbon atoms and each of which connects two non-adjacent carbon atom of the cyclic system. Some examples of bicyclic cycloalkenyl groups include, but are not agrarias, 4,5,6,7-tetrahydro-3aH-inden, octahydronaphthalene and 1,6-dihydroindole. Monocyclic and bicyclic cycloalkenyl can be attached to a fragment of the parent molecule through any capable of substitution of an atom present in cyclic systems.

The term "cycloalkyl", or "cycloalkenyl", or "cycloalkenyl" in this description means a ring system is monocyclic or bridged hydrocarbon. Monocyclic cycloalkenyl contains eight or more carbon atoms, contains no heteroatoms, and includes one or more triple bonds. Monocyclic cycloalkenyl ring may contain one or two alkilinity bridge, each of which includes one, two or three carbon atoms and each of which connects two non-adjacent carbon atom of the cyclic system. Monocyclic and bridged cycloalkenyl can be attached to a fragment of the parent molecule through any capable of substitution of an atom present in cyclic systems.

The term "heteroaryl", or "heteroaryl", or "heteroaryl" in this description means a five-membered or six-membered aromatic is the core, having at least one carbon atom and one or more than one independently selected atoms nitrogen, oxygen or sulfur. Heteroarenes of the present invention are connected through any adjacent atom in the ring, provided that the requirements of the valence. Some examples of heteroaryl include, but are not agrarias, furanyl (including, but not agrarias, furan-2-yl), imidazolyl (including, but not agrarias, 1H-imidazol-1-yl), isoxazolyl, isothiazolin, oxadiazolyl, oxazolyl, pyridinyl (e.g. pyridin-4-yl, pyridine-2-yl, pyridin-3-yl), pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl (including, but not agrarias, Tien-2-yl, Tien-3-yl), triazolyl and triazinyl.

The term "geteroseksualen", or "heteroseksualci", or "heterocyclochain" in this description means a monocyclic or bridged three-, four-, five-, six-, seven - or eight-membered cycle containing at least one heteroatom independently selected from the group comprising O, N and S, and containing no double bonds. Monocyclic and bridged geteroseksualen can be attached to a fragment of the parent molecule through any capable of substitution of the carbon atom or any capable of substitution of the nitrogen atom present in the cyclic si is theme. The heteroatoms nitrogen and sulfur heterocyclic nuclei may not necessarily be oxidized, and the nitrogen atoms may not necessarily be Quaternary. Some examples geterotsiklicheskikh groups include, but are not agrarias, morpholinyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, DIOXOLANYL, tetrahydrofuranyl, thiomorpholine, dioxane, tetrahydrothieno, tetrahydrothiopyran, oxetanyl, piperazinil, imidazolidinyl, azetidin, azepane, aziridinyl, diazepan, dithiolane, dithienyl, isoxazolidine, isothiazolinones, oxadiazolidine, oxazolidinyl, pyrazolidine, tetrahydrothieno, thiadiazolidine, diazolidinyl, thiomorpholine and tritional.

The term "geteroseksualen", or "geteroseksualen", or "heterocyclization" in this description means a monocyclic or bridged three-, four-, five-, six-, seven - or eight-membered cycle containing at least one heteroatom independently selected from the group comprising O, N and S, and containing one or more double bonds. Monocyclic and bridged geteroseksualen can be attached to a fragment of the parent molecule through any capable of substitution of the carbon atom or any capable of substitution of the nitrogen atom present in the cyclic system. The heteroatoms nitrogen and sulfur heterocyclic nuclei may not necessarily is to be oxidized, and the nitrogen atoms may not necessarily be Quaternary. Some examples geterotsiklicheskikh groups include, but are not agrarias, tetrahydrocortisol, 1,4,5,6-tetrahydropyridines, 1,2,3,6-tetrahydropyridine, dihydropyran, imidazolines, isothiazolines, oxadiazolyl, isoxazolyl, oxazolyl, pyranyl, pyrazolyl, pyrrolyl, thiadiazolyl, thiazolyl, dihydro-1,3,4-thiadiazole-2-yl and tiopronin.

The term "phenylene" in this description means a divalent radical formed by removal of a hydrogen atom of the phenyl.

The term "spirooli" in this description means alkylen, both ends of which are attached to the same carbon atom, examples of which are2-spiralcell,3-spiralcell,4-spiralcell,5-spiralcell,6-spiralcell,7-spiralcell,8-spiralcell,9-spiralcell etc.

The term "spirolaterals" in this description means spiralcell, in which one or two fragments of CH2replaced with independently selected O, C(O), CNOH, CNOCH3, S, S(O), SO2or NH and one or two fragments of CH is not substituted or substituted n

The term "spiroheterocyclic" in this description means serialkeys, has one or two fragments of CH2replaced with independently selected O, C(O), CNOH, CNOCH3, S, S(O), SO2or NH and one or two fragm the NTA CH is not replaced or replaced with N, and means serialkeys, has one or two fragments of CH2not replaced or replaced with independently selected O, C(O), CNOH, CNOCH3, S, S(O), SO2or NH and one or two fragments CH replaced by N.

The term "Spirito" in this description means two Deputy at one and the same carbon atom, taken together with the carbon atom to which they are attached, form cycloalkane, geteroseksualnoe, cycloalkene or geterotsyklicescoe the kernel.

The term "C2-C5spiralcell" in this description means C2-spiralcell, C3-spiralcell, C4-spiralcell and C5-spiralcell.

The term "C2-spiralcell" in this description means et-1,2-ilen, both ends of which replace hydrogen atoms of the same fragment of CH2.

The term "C3-spiralcell" in this description means the prop-1,3-ilen, both ends of which replace hydrogen atoms of the same fragment of CH2.

The term "C4-spiralcell" in this description means a buta-1,4-ilen, both ends of which replace hydrogen atoms of the same fragment of CH2.

The term "C5-spiralcell" in this description means the Penta-1,5-ilen, both ends of which replace hydrogen atoms of the same fragment of CH2.

The term "C6-spiralcell" in this description means Gex-1,6-ilen, both late to the showing replaces the hydrogen atoms of the same fragment of CH 2.

The term "NH protective group" in this description means trichlorocyanuric, tribromoethanol, benzyloxycarbonyl, para-nitrobenzylamine, ortho-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, TRIFLUOROACETYL, phenylacetyl, formyl, acetyl, benzoyl, tert-aryloxyalkyl, tert-butoxycarbonyl, para-methoxybenzeneboronic, 3,4-dimethoxyphenylacetone, 4-(phenylazo)benzyloxycarbonyl, 2-furfurylalcohol, diphenylcarbinol, 1,1-dimethylpropanolamine, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantanecarbonyl, 8-hinolincarbonova, benzyl, diphenylmethyl, triphenylmethyl, 2 nitrophenylthio, methanesulfonyl, para-toluensulfonyl, N,N-dimethylaminomethylene, benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethyl, 3-hydroxy-4-pyridylmethylene, cyclohexylidene, 2-ethoxycarbonylphenyl, 2-ethoxycarbonylphenyl, 2-acetylcyclohexanone, 3,3-dimethyl-5-oxocyclohexyl, diphenylphosphoryl, dibenzoyltartaric, 5-methyl-2-oxo-2H-1,3-dioxol-4-ylmethyl, trimethylsilyl, triethylsilyl and triphenylsilane.

The term "C(O)HE protective group" in this description means methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl, naphthyl, benzyl, diphenylmethyl, triphenylmethyl, para-nitrobenzyl, a pair of methods is dibenzyl, bis(para-methoxyphenyl)methyl, acetylethyl, benzoylmethyl, para-nitrobenzoyl, para-bromobenzoyl, para-methanesulfonylaminoethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, acetoxymethyl, propionylacetate, pivaloyloxymethyl, phthalimidomethyl, Succinimidyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzoyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylenediamine, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilane and tert-butylperoxyisopropyl.

The term "HE or SH protective group" in this description means benzyloxycarbonyl, 4-nitrobenzenesulfonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzenesulfonyl, 3,4-dimethoxyphenylacetone, methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropanolamine, isopropoxycarbonyl, isobutoxide, diphenylcarbinol, 2,2,2-trichlorocyanuric, 2,2,2-tribromoethyl, 2-(trimethylsilyl)etoxycarbonyl, 2-(phenylsulfonyl)etoxycarbonyl, 2-(triphenylphosphonio)etoxycarbonyl, 2-furfurylalcohol, 1-adamantanecarbonyl, vinyloxycarbonyl, allyloxycarbonyl, S-gasoline thiocarbonyl, 4 ethoxy-1-naphthaleneboronic, 8-hinolincarbonova, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, TRIFLUOROACETYL, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylmethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), para-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydropyranyl, methoxymethyl, methylthiomethyl, benzoyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloromethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methanesulfonyl, para-toluensulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylenediamine, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilane and tert-butylperoxyisopropyl.

Connection

The compounds of the present invention can be geometric isomers. Compounds of the present invention may contain double carbon-carbon links or a double carbon-nitrogen relationships in E - or Z-configuration, where the term "E" represents substituents of a higher order with opposite sides of the double carbon-carbon or carbon-nitrogen relationships, and the term "Z" represents substituents of higher order on the same side relative to the double carbon-carbon or carbon-AZ is based communications, as determined in accordance with the rules of priority Cana-Ingold-Prelog. Compounds of the present invention may also exist as a mixture of E and Z isomers. The substituents in cycloalkyl or heteroseksualci defined as having CIS - or TRANS-configuration. In addition, the present invention addresses the various isomers and mixtures thereof resulting from the disposal of substituents in the cyclic system adamantane. Two Deputy in one cycle adamantanol kernel is defined as having a relative configuration Z or E. Examples, see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le Noble,J. Org. Chem.1998, 63, 2758-2760 and E. L. Eliel and S. H. Wilen. (1994)Stereochemistry of Organic Compounds. New York, NY: John Wiley & Sons, Inc.

Compounds of the present invention may contain asymmetrically substituted carbon atoms in the R - or S-configuration, where the terms "R" and "S" is defined in accordance with the recommendations of the IUPAC 1974 in section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10. Compounds having an equal number of asymmetrically substituted carbon atoms with R - and S-configurations are racemic indicated carbon atoms. Atoms with an excess of one configuration versus another define the configuration that is present in the sick amount, preferably in excess of about 85-90%, more preferably in excess comp is engaged in approximately 95-99%, and even more preferably in excess, amounting to more than about 99%. Thus, the present invention includes racemic mixtures, relative and absolute stereoisomers and a mixture of relative and absolute stereoisomers.

In the compounds of the present invention, containing fragments NH, C(O)HE HE or SH, to these fragments can be attached fragments forming a prodrug. Forming a prodrug fragments are removed in the process of metabolic processes in vivo release of compounds containing the liberated hydroxyl, amino or carboxylic acid. Prodrugs suitable for regulation of such pharmacokinetic properties of compounds, such as solubility and/or hydrophobicity, absorption in the gastrointestinal tract, bioavailability, ability to penetrate into the tissue and the rate of excretion from the body.

Isotopically enriched compounds or compounds containing the tag

Compounds of the present invention may contain isotopic labels or may exist in isotopically enriched form, containing one or more atoms, the atomic mass or mass number different from the atomic mass or mass number most common in nature. Isotopes can be radioactive or non-radioactive isotopes. The isotopes at the MOU such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not agrarias,2H,3H,13C,14C,15N18Oh,32P,35S18F,36Cl125I. Compounds that contain other isotopes of these and/or other atoms are included in the scope of the present invention.

In another embodiment, the present invention isotope-labeled compounds contain isotopes deuterium (2H), tritium (3H) or14C. isotope-Labeled compounds of the present invention can be obtained by common methods known to experts from the field of technology. Such isotope-labeled compounds conveniently be obtained by the method described in the above, in the present description, the examples and schemes, replacing not containing the label of the reagent is readily available isotope-labeled reagent. In some cases, the compounds can be treated containing the isotope label reagents in order to exchange the atom on its isotope, for example, a hydrogen atom by deuterium can be exchanged by the action of deuterated acids, such as D2SO4/D2O. In addition to the above, appropriate methodologies and intermediate compounds disclosed, for example, Lizondo, J. et al.,Drugs Fut., 21(11), 1116 (1996); Brickner, S. J. et al.,J. Med. Chem., 39(3), 673 (1996); Mallesham, B. et al.,Org. Lett.,5(7), 963 (2003); PCT is publikatsiah WO 1997/010223, WO 2005/099353, WO 1995/007271, WO 2006/008754; U.S. patent№ 7538189; 7534814; 7531685; 7528131; 7521421; 7514068; 7511013; and published patent applications U.S.№ 2009/0137457; 2009/0131485; 2009/0131363; 2009/0118238; 2009/0111840; 2009/0105338; 2009/0105307; 2009/0105147; 2009/0093422; 2009/0088416 and 20090082471, and these methods are included in this description by reference.

Labeled isotope compounds of the present invention can be used as standards to determine the effectiveness of inhibitors of Bcl-2 in the analysis of binding. Containing the isotope compounds used in conducting pharmaceutical research for in vivo studies of the fate of compounds in the metabolism process in order to evaluate the mechanism of action and metabolic path not containing the label of the parent compounds (Blake et al.J. Pharm. Sci.64, 3, 367-391 (1975)). Such studies metabolism important for the design of safe, effective therapeutic drugs, asin vivoas an active compound, administered to the patient, and the metabolites formed from the parent compounds, are toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985; Kato et al.,J. Labelled Comp. Radiopharmaceut.,36(10):927-932 (1995); Kushner et al.,Can. J. Physiol. Pharmacol.,77, 79-88 [in Russian] (1999).

In addition, drugs containing radioactive isotope, such as datareaders medicines to the which is called "hard drugs", can be used for treating diseases and conditions associated with the activity of Bcl-2. The increase in the number present in the connection of the isotope in excess of its natural distribution in nature is called enrichment. Examples of the magnitude of enrichment include from about 0,5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96 to about 100 mol%. Replacement of up to approximately 15% of conventional heavy atom isotope in mammals, including rodents and dogs, and is supported for a period of from several days to several weeks, causing the lowest observed adverse effects (Czajka D. M. and A. J. Finkel, Ann. N. Y. Acad. Sci. 1960 84: 770; Thomson J. F., Ann. New York Acad. Sci., 1960 84: 736; Czakja D. M. et al., Am. J. Physiol. 1961 201: 357). It was shown that a single substitution in humans up to 15-23% on a liquid deuterium does not cause toxicity (Blagojevic N. et al. "Dosimetry &Treatment Planning for Neutron Capture Therapy", Zamenhof R, Solares, G. and O. Harling Eds. 1994. Advanced Medical Publishing, Madison Wis. pp.125-134; Diabetes Metab. 23: 251 (1997)).

The introduction of labels of stable isotopes in medicine may alter its physico-chemical properties, such as the value of pKa and solubility in lipids. These effects and changes can cause pharmacodynamic response of the molecule drugs, if the isotopic substitution affects the region involved in the interaction of the ligand to the receptor. Despite the fact that some of the physical properties of the labeled stable isotope molecules differ from those not containing the label molecules, their chemical and biological properties are the same, with one important exception: due to the increased mass of the heavy isotope, any link involving heavy isotope with another atom will be stronger than the same relationship between a light isotope and the specified atom. Thus, the incorporation of the isotope into a place that is associated with metabolism or enzymatic transformation, slows similar reactions and potentially alter the pharmacokinetic profile or efficacy of the compounds in comparison with not containing the isotope connection.

Amides, esters and prodrugs

Prodrugs are derivatives of the compounds active drugs that are developed to improve some of the identified undesirable physical or biological properties. Physical properties typically are solubility (too much or insufficient solubility in lipids or water) or the corresponding stability, while problematic biological properties include too quick metabolism or low bioavailability, which, in turn, may be related to the physico-chemical properties.

is alacarta usually get a) the formation of esters, partial esters, esters of carbonic acid, nitrofuran, amides, derivatives of hydroxamic acids, carbamates, Iminov, bases, manniche, phosphates, phosphate esters and enamino active drugs, b) functionalization of drugs with the use of azo, glycosidic, peptide functional groups and functional groups of ester, c) through the use of aminolink, hemiaminals, polymer, salt, complex, phosphoramide, acetylenic, polyacetylene and katalinich forms of medicines. Examples can be found in the document andrejus on Korolkovas's, "Essentials of Medicinal Chemistry", John Wiley-Interscience Publications, John Wiley and Sons, New York (1988), pp. 97-118, which is entirely included in the present description by reference.

Esters can be obtained from the parent compounds of formula (I) containing or hydroxyl group, or carboxyl group, using General methods known in the art. Typical reactions of these compounds represent a substitution reaction with the replacement of one of the heteroatoms to another atom, for example:

Scheme 1

Amides can be obtained similarly from the source compounds of the formula (I) containing either the amino group or carboxyl group. Esters can also interact with amines or ammonia with the formation of the amides:

Scheme 2

Another way of obtaining the amides of the compounds of formula (I) is the joint heated carboxylic acids and amines.

Scheme 3

In the above schemes 2 and 3, R and R' independently denote a substrate of the formula (I), the alkyl or a hydrogen atom.

Suitable groups for A1L1, Z1A, Z2A, Z1, Z2and Z3in the compounds of formula (I) selected independently. The above embodiments of the present invention can be combined. This combination provided and included in the scope of the present invention. For example, it is assumed that the options for any of the A1L1, Z1A, Z2A, Z1, Z2and Z3can be combined with the options defined for any other of the A1L1, Z1A, Z2A, Z1, Z2and Z3.

One way of implementing the present invention relates to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs, which are suitable as inhibitors of anti-apoptotic proteins Bcl-2, and the compounds have the formula (I):

where

A1represents furyl, imidazolyl, isothiazolin, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, p is Rasool, pyridazinyl, 2-pyridinyl, 4-pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl, triazolyl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; each of which is not condensed or fused with benzene, heteroatom or A1A; A1Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

where A1not substituted or substituted by one, or two, or three, or four, or five independently selected substituents R1, OR1, SR1, S(O)R1, SO2R1C(O)R1C(O)OR1, OC(O)R1, Other1N(R1)2C(N)C(O)R1C(O)other1C(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, NHC(O)R1, NR1C(O)R1, NHC(O)OR1, NR1C(O)OR1, NR1C(O)other1, NR1C(O)N(R1)2, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2, SO2NH2, SO2Other1, SO2N(R1)2NHS(O)R1, NHSO2R1, NR1SO2R1, NHSO2Other1N(CH3)SO2N(CH3R1, (O), NH2, NO2N3, OH, F, Cl, Br, I, CN, CF3, OCF3, CF2CF3, OCF2CF3C(O)H, C(O)OH, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3C(O)NH2or C(O)OR1A;

R1is an R2, R3 , R4or R5;

R1Ais cycloalkyl, cycloalkenyl or cycloalkenyl;

R2represents phenyl, which is not condensed or fused with benzene, heteroatom or R2A; R2Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R3is heteroaryl that is not condensed or fused with benzene, heteroatom or R3A; R3Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R4is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R4A; R4Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R5represents alkyl, alkenyl, or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R6, NC(R6A)(R6B), R7, OR7, SR7, S(O)R7, SO2R7, Other7N(R7)2C(O)R7C(O)NH2C(O)other7C(O)N(R7)2, NHC(O)R7, NR7C(O)R7, NHSO2R7, NHC(O)OR7, SO2NH2, SO2Other7, SO2N(R7)2, NHC(O)NH2, NHCO)other 7, NHC(O)CH(CH3)NHC(O)CH(CH3)NH2, NHC(O)CH(CH3)NHC(O)CH(CH3)Other1, OH, (O), C(O)OH, N3, CN, NH2, CF3, CF2CF3, F, Cl, Br or I;

R6represents a C2-C5-spiralcell, each of which is not substituted or substituted by substituents OH, (O), N3CN, CF3, CF2CF3, F, Cl, Br, I, NH2, NH(CH3) or N(CH3)2;

R6Aand R6Bindependently selected from alkyl or together with the N atom to which they are attached, form an R6C;

R6Cis aziridine-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidine-1-yl, each of which has one piece of CH2not replaced or replaced with O, C(O), CNOH, CNOCH3, S, S(O), SO2or NH;

R7is an R8, R9, R10or R11;

R8represents phenyl, which is not condensed or fused with benzene, heteroatom or R8A; R8Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R9is heteroaryl that is not condensed or fused with benzene, heteroatom or R9A; R9Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R10is cycloalkyl, cycloalkenyl, heteroseksualci or heterocyclic the Nile, each of which is not condensed or fused with benzene, heteroatom or R10A; R10Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R11represents alkyl, alkenyl or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R12, OR12, SR12, S(O)R12, SO2R12C(O)R12C(O)OR12, OC(O)R12, OC(O)OR12, NH2, Other12N(R12)2, NHC(O)R12, NR12C(O)R12NHS(O)2R12, NR12S(O)2R12, NHC(O)OR12, NR12C(O)OR12, NHC(O)NH2, NHC(O)other12, NHC(O)N(R12)2, NR12C(O)other12, NR12C(O)N(R12)2C(O)NH2C(O)other12C(O)N(R12)2C(O)NHOH, C(O)NHOR12C(O)NHSO2R12C(O)NR12SO2R12, SO2NH2, SO2Other12, SO2N(R12)2C(O)H, C(O)OH, C(N)NH2C(N)other12C(N)N(R12)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R12is an R13, R14, R15or R16;

R13represents phenyl, which is not condensed or fused with benzene, heteroatom or R13A; R13Arepresents cyclea the Kang, cycloalken, geteroseksualen or geteroseksualen;

R14is heteroaryl that is not condensed or fused with benzene, heteroatom or R14A; R14Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R15is cycloalkane, cycloalkene, geteroseksualen or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R15A; R15Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R16represents alkyl, alkenyl or quinil;

Z1is an R26or R27;

Z2is an R28, R29or R30;

Z1Aand Z2Aboth are absent, or together form CH2CH2CH2or Z12A;

Z12Arepresents a C2-C6-alkene, in which one or two fragments of CH2replaced by NH, N(CH3), S, S(O) or SO2;

L1is an R37, OR37, SR37, S(O)R37, SO2R37C(O)R37C(O)OR37, OC(O)R37, OC(O)OR37, Other37C(O)NH, C(O)NR37C(O)NHOR37C(O)NHSO2R37, SO2NH, SO2Other37C(N)NH, C(N)other37;

R26represents phenylene which is not condensed is whether condensed with benzene, or heteroatom, or R26A; R26Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R27represents heteroaryl that is not condensed or fused with benzene, or heteroatom, or R27A; R27Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R28represents phenylene which is not condensed or fused with benzene, heteroatom or R28A; R28Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R29represents heteroaryl that is not condensed or fused with benzene, or heteroatom, or R29A; R29Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R30is cycloalkyl, cycloalkenyl, heterocyclochain or heterocyclization, each of which is not condensed or fused with benzene, heteroatom or R30A; R30Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R37represents a simple bond or R37A;

R37Ais alkylen, albaniles or akinyan, each of which is not substituted or is substituted by one, or two, or three Nezavisimoye substituents R 37B, OR37B, SR37B, S(O)R37BSO2R37BC(O)R37BC(O)OR37B, OC(O)R37B, OC(O)OR37B, NH2, Other37BN(R37B)2, NHC(O)R37B, NR37BC(O)R37BNHS(O)2R37B, NR37BS(O)2R37B, NHC(O)OR37B, NR37BC(O)OR37B, NHC(O)NH2, NHC(O)other37B, NHC(O)N(R37B)2, NR37BC(O)other37B, NR37BC(O)N(R37B)2C(O)NH2C(O)other37BC(O)N(R37B)2C(O)NHOH, C(O)NHOR37BC(O)NHSO2R37BC(O)NR37BSO2R37B, SO2NH2, SO2Other37B, SO2N(R37B)2C(O)H, C(O)OH, C(N)NH2C(N)other37BC(N)N(R37B)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R37Brepresents alkyl, alkenyl, quinil, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen;

Z3is an R38, R39or R40;

R38represents phenyl, which is not condensed or fused with benzene, heteroatom or R38A; R38Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R39is heteroaryl that is not condensed or fused with benzene, heteroatom or R39A; R39Athe stand is made by cycloalkane, cycloalken, geteroseksualen or geteroseksualen;

R40is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R40A; R40Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

where the fragments represented by the group R26and R27not substituted or substituted (i.e., if Z1Aand Z2Amissing) or not further substituted or further substituted (i.e., if Z1Aand Z2Athere are one or more substituents R41, OR41, SR41, S(O)R41, SO2R41C(O)R41C(O)OR41, OC(O)R41, OC(O)OR41, NH2, Other41N(R41)2, NHC(O)R41, NR41C(O)R41NHS(O)2R41, NR41S(O)2R41, NHC(O)OR41, NR41C(O)OR41, NHC(O)NH2, NHC(O)other41, NHC(O)N(R41)2, NR41C(O)other41, NR41C(O)N(R41)2C(O)NH2C(O)other41C(O)N(R41)2C(O)NHOH, C(O)NHOR41C(O)NHSO2R41C(O)NR41SO2R41, SO2NH2, SO2Other41, SO2N(R41)2C(O)H, C(O)OH, C(N)NH2C(N)other41C(N)N(R41)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2/sub> CF3, F, Cl, Br or I;

R41is an R42, R43, R44or R45;

R42represents phenyl, which is not condensed or fused with benzene, heteroatom or R42A; R42Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R43is heteroaryl that is not condensed or fused with benzene, heteroatom or R43A; R43Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R44is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R44A; R44Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R45represents alkyl, alkenyl or quinil, each of which is not substituted or substituted by one or two independently selected substituents R46, OR46, SR46, S(O)R46, SO2R46C(O)R46C(O)OR46, OC(O)R46, OC(O)OR46, NH2, Other46N(R46)2, NHC(O)R46, NR46C(O)R46NHS(O)2R46, NR46S(O)2R46, NHC(O)OR46, NR46C(O)OR46, NHC(O)NH2, NHC(O)other46, NHC(O)N(R46)2, NR46C(O)other 46, NR46C(O)N(R46)2C(O)NH2C(O)other46C(O)N(R46)2C(O)NHOH, C(O)NHOR46C(O)NHSO2R46C(O)NR46SO2R46, SO2NH2, SO2Other46, SO2N(R46)2C(O)H, C(O)OH, C(N)NH2C(N)other46C(N)N(R46)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R46represents alkyl, alkenyl or quinil, R47, R48or R49;

R47represents phenyl, which is not condensed or fused with benzene, heteroatom or R47A; R47Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R48is heteroaryl that is not condensed or fused with benzene, heteroatom or R48A; R48Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R49is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R49A; R49Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

where the fragments represented by the group R42, R43, R44, R47, R48and R49no not substituted or substituted by one or more independently selected substituents R 50, OR50, SR50, S(O)R50, SO2R50C(O)R50C(O)OR50, OC(O)R50, OC(O)OR50, NH2, Other50N(R50)2, NHC(O)R50, NR50C(O)R50NHS(O)2R50, NR50S(O)2R50, NHC(O)OR50, NR50C(O)OR50, NHC(O)NH2, NHC(O)other50, NHC(O)N(R50)2, NR50C(O)other50, NR50C(O)N(R50)2C(O)NH2C(O)other50C(O)N(R50)2C(O)NHOH, C(O)NHOR50C(O)NHSO2R50C(O)NR50SO2R50, SO2NH2, SO2Other50, SO2N(R50)2C(O)H, C(O)OH, C(N)NH2C(N)other50C(N)N(R50)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R50is an R51, R52, R53or R54;

R51represents phenyl, which is not condensed or fused with benzene, heteroatom or R51A; R51Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R52is heteroaryl that is not condensed or fused with benzene, heteroatom or R52A; R52Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R53is cycloalkyl, cycloalkenyl, heterocicluri geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R53A; R53Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R54represents alkyl, alkenyl or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R55, OR55, SR55, S(O)R55, SO2R55C(O)R55C(O)OR55, OC(O)R55, OC(O)OR55, NH2, Other55N(R55)2, NHC(O)R55, NR55C(O)R55NHS(O)2R55, NR55S(O)2R55, NHC(O)OR55, NR55C(O)OR55, NHC(O)NH2, NHC(O)other55, NHC(O)N(R55)2, NR55C(O)other55, NR55C(O)N(R55)2C(O)NH2C(O)other55C(O)N(R55)2C(O)NHOH, C(O)NHOR55C(O)NHSO2R55C(O)NR55SO2R55, SO2NH2, SO2Other55, SO2N(R55)2C(O)H, C(O)OH, C(N)NH2C(N)other55C(N)N(R55)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R55represents alkyl, alkenyl, quinil, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen;

where each of the above cyclic fragment independently is not a substituted, optionally n is substituted, substituted or optionally substituted by one or more independently selected substituents R57, OR57, SR57, S(O)R57, SO2R57C(O)R57C(O)OR57, OC(O)R57, OC(O)OR57, NH2, Other57N(R57)2, NHC(O)R57, NR57C(O)R57NHS(O)2R57, NR57S(O)2R57, NHC(O)OR57, NR57C(O)OR57, NHC(O)NH2, NHC(O)other57, NHC(O)N(R57)2, NR57C(O)other57, NR57C(O)N(R57)2C(O)NH2C(O)other57C(O)N(R57)2C(O)NHOH, C(O)NHOR57C(O)NHSO2R57C(O)NR57SO2R57, SO2NH2, SO2Other57, SO2N(R57)2C(O)H, C(O)OH, C(N)NH2C(N)other57C(N)N(R57)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R57is an R58, R59, R60or R61;

R58represents phenyl, which is not condensed or fused with benzene, heteroatom or R58A; R58Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R59is heteroaryl that is not condensed or fused with benzene, heteroatom or R59A; R59Ais cycloalkane, cycloalkene, geteroseksualen is whether geteroseksualen;

R60is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R60A; R60Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R61represents alkyl, alkenyl or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R62, OR62, SR62, S(O)R62, SO2R62C(O)R62C(O)OR62, OC(O)R62, OC(O)OR62, NH2, Other62N(R62)2, NHC(O)R62, NR62C(O)R62NHS(O)2R62, NR62S(O)2R62, NHC(O)OR62, NR62C(O)OR62, NHC(O)NH2, NHC(O)other62, NHC(O)N(R62)2, NR62C(O)other62, NR62C(O)N(R62)2C(O)NH2C(O)other62C(O)N(R62)2C(O)NHOH, C(O)NHOR62C(O)NHSO2R62C(O)NR62SO2R62, SO2NH2, SO2Other62, SO2N(R62)2C(O)H, C(O)OH, C(N)NH2C(N)other62C(N)N(R62)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R62is an R63, R64, R65or R66;

R63represents phenyl, which is not conden the new or fused with benzene, heteroatom or R63A; R63Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R64is heteroaryl that is not condensed or fused with benzene, heteroatom or R64A; R64Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R65is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R65A; R65Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R66represents alkyl, alkenyl or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R67, OR67, SR67, S(O)R67, SO2R67C(O)R67C(O)OR67, OC(O)R67, OC(O)OR67, NH2, Other67N(R67)2, NHC(O)R67, NR67C(O)R67NHS(O)2R67, NR67S(O)2R67, NHC(O)OR67, NR67C(O)OR67, NHC(O)NH2, NHC(O)other67, NHC(O)N(R67)2, NR67C(O)other67, NR67C(O)N(R67)2C(O)NH2C(O)other67C(O)N(R67)2C(O)NHOH, C(O)NHOR67C(O)NHSO2R67C(O)NR67SO2R67, SO2NH2, SOsub> 2Other67, SO2N(R67)2C(O)H, C(O)OH, C(N)NH2C(N)other67C(N)N(R67)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R67represents alkyl, alkenyl, quinil, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen;

where the fragments represented by the group R58, R59, R60, R63, R64, R65and R67not substituted or substituted by one or more independently selected substituents R68, OR68, SR68, S(O)R68, SO2R68C(O)R68C(O)OR68, OC(O)R68, OC(O)OR68, NH2, Other68N(R68)2, NHC(O)R68, NR68C(O)R68NHS(O)2R68, NR68S(O)2R68, NHC(O)OR68, NR68C(O)OR68, NHC(O)NH2, NHC(O)other68, NHC(O)N(R68)2, NR68C(O)other68, NR68C(O)N(R68)2C(O)NH2C(O)other68C(O)N(R68)2C(O)NHOH, C(O)NHOR68C(O)NHSO2R68C(O)NR68SO2R68, SO2NH2, SO2Other68, SO2N(R68)2C(O)H, C(O)OH, C(N)NH2C(N)other68C(N)N(R68)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R68is an R6 , R70, R71or R72;

R69represents phenyl, which is not condensed or fused with benzene, heteroatom or R69A; R69Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R70is heteroaryl that is not condensed or fused with benzene, heteroatom or R70A; R70Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R71is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R71A; R71Ais cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R72represents alkyl, alkenyl or quinil, each of which is not substituted or is substituted by one, or two, or three independently selected substituents R73, OR73, SR73, S(O)R73, SO2R73C(O)R73C(O)OR73, OC(O)R73, OC(O)OR73, NH2, Other73N(R73)2, NHC(O)R73, NR73C(O)R73NHS(O)2R73, NR73S(O)2R73, NHC(O)OR73, NR73C(O)OR73, NHC(O)NH2, NHC(O)other73, NHC(O)N(R73)2, NR73C(O)other73, NR73C(O)N(R73)2C(O)NH2 C(O)other73C(O)N(R73)2C(O)NHOH, C(O)NHOR73C(O)NHSO2R73C(O)NR73SO2R73, SO2NH2, SO2Other73, SO2N(R73)2C(O)H, C(O)OH, C(N)NH2C(N)other73C(N)N(R73)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

R73represents alkyl, alkenyl, quinil, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; and

fragments represented by the group R69, R70and R71not substituted or substituted by one or more independently selected substituents NH2C(O)NH2C(O)NHOH, SO2NH2, CF3, CF2CF3C(O)H, C(O)OH, C(N)NH2, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I.

In another embodiment of formula (I)

A1represents furyl, imidazolyl, isothiazolin, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, heteroseksualci or geteroseksualen; each of which is not condensed or fused with benzene, heteroatom or A1A; A1Arepresents geteroseksualen;

where A1not substituted or substituted by one, or two, or three, or four, or five independently selected and substituents R 1, OR1C(O)OR1, Other1N(R1)2C(N)C(O)R1C(O)other1, NHC(O)R1, NR1C(O)R1, (O), NO2, F, Cl, Br, I, CF3;

R1is an R2, R3, R4or R5;

R2represents phenyl;

R3is heteroaryl;

R4is heteroseksualci;

R5represents an alkyl or alkenyl, each of which is not substituted or substituted by substituents R7, SR7N(R7)2, NHC(O)R7, F, Cl, Br or I;

R7is an R8, R9, R10or R11;

R8represents phenyl;

R9is heteroaryl;

R10is heteroseksualci;

R11represents alkyl;

Z1is an R26;

Z2is an R30;

L1is an R37;

R26represents a phenylene;

R30is heterocyclochain;

R37is an R37A;

R37Ais alkylene or albaniles, each of which is not substituted or is substituted by R37B;

R37Brepresents phenyl;

Z3is an R38or R40;

R38represents phenyl;

R40isone cycloalkyl or cycloalkenyl;

where the fragments represented by the group R26and R27not substituted or substituted by a group OR41;

R41is an R42or R43;

R42represents phenyl, which is not condensed or condensed with heteroatom;

R43is heteroaryl that is not condensed or condensed with heteroatom;

where each of the above cyclic fragment independently is not a substituted, is not further substituted, substituted or optionally substituted by one or more independently selected substituents R57, OR57C(O)OR57, F, Cl, Br or I;

R57is an R58or R61;

R58represents phenyl;

R61represents alkyl; and

where the fragments represented by the group R58not substituted or substituted by one or more independently selected substituents F, Cl, Br or I.

In one variant embodiment of formula (I) A1represents furyl, imidazolyl, isothiazolin, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, heteroseksualci or geteroseksualen; each of which is not condensed or fused with benzene, heteroatom or A1A; A1Arepresents geteroseksualen. In another variant embodiment of formula (I) A1pre whom represents a furyl. In another variant embodiment of formula (I) A1is imidazolyl. In another variant embodiment of formula (I) A1represents isothiazolin. In another variant embodiment of formula (I) A1represents isoxazolyl. In another variant embodiment of formula (I) A1represents pyrazolyl. In another variant embodiment of formula (I) A1represents pyrrolyl. In another variant embodiment of formula (I) A1represents thiazolyl. In another variant embodiment of formula (I) A1represents thiadiazolyl. In another variant embodiment of formula (I) A1is thienyl. In another variant embodiment of formula (I) A1represents triazolyl. In another variant embodiment of formula (I) A1is heteroseksualci. In another variant embodiment of formula (I) A1represents geteroseksualen. In another variant embodiment of formula (I) A1is piperidinyl. In another variant embodiment of formula (I) A1is morpholinyl. In another variant embodiment of formula (I) A1represents a dihydro-1,3,4-thiadiazole-2-yl. In another variant embodiment of formula (I) A1is bestien-2-yl. In another variant embodiment of formula (I) A1represents benzothiazol--Il. In another variant embodiment of formula (I) A1represents [1,2,4]triazolo[1,5-a]pyrimidine-2-yl. In another variant embodiment of formula (I) A1is tetrahydrothieno-3-yl. In another variant embodiment of formula (I) A1represents [1,2,4]triazolo[1,5-a]pyrimidine-2-yl. In another variant embodiment of formula (I) A1represents imidazo[2,1-b][1,3]thiazol-5-yl.

In one variant embodiment of formula (I) A1not substituted. In another variant embodiment of formula (I) A1substituted with one, or two, or three, or four, or five independently selected substituents R1, OR1C(O)OR1, Other1N(R1)2C(N)C(O)R1C(O)other1, NHC(O)R1, NR1C(O)R1, (O), NO2, F, Cl, Br, I or CF3. In one variant embodiment of formula (I) A1not substituted. In another variant embodiment of formula (I) A1substituted with other1. In another variant embodiment of formula (I) A1substituted with other1and NO2. In another variant embodiment of formula (I) A1substituted with other1. In another variant embodiment of formula (I) A1replaced NR1C(O)R1. In another variant embodiment of formula (I) A1substituted N(R1)2. In another variant embodiment of formula (I) A1replaced by C(N)C(O)R1and R1. In another variant embodiment of formula (I) A1substituted NHC(O)R1 and R1. In another variant embodiment of formula (I) A1substituted R1. In another variant embodiment of formula (I) A1substituted with two independently selected R1. In another variant embodiment of formula (I) A1substituted Cl. In another variant embodiment of formula (I) A1substituted CF3. In another variant embodiment of formula (I) A1substituted F. In another variant embodiment of formula (I) A1substituted with three independently selected R1and C(O)OR1. In another variant embodiment of formula (I) A1represents a substituted R1and C(O)OR1. In another variant embodiment of formula (I) A1substituted R1and Cl. In another variant embodiment of formula (I) A1substituted R1and Br. In another variant embodiment of formula (I) A1substituted with three independently selected R1. In another variant embodiment of formula (I) A1substituted C(O)other1. In another variant embodiment of formula (I) A1substituted with two independently selected R1and Cl. In another variant embodiment of formula (I) A1substituted R1and NO2. In another variant embodiment of formula (I) A1substituted with other1and NO2. In another variant embodiment of formula (I) A1replaced by (O). In another variant embodiment of formula (I) A1substituted OR1.

In one variant embodiment of formula (I) R1presented yet a phenyl. In another variant embodiment of formula (I) R1represents pyrazolyl. In another variant embodiment of formula (I) R1is morpholinyl. In another variant embodiment of formula (I) R1represents isoxazolyl. In another variant embodiment of formula (I) R1is piperidinyl. In another variant embodiment of formula (I) R1represents alkyl, which is not substituted. In another variant embodiment of formula (I) R1represents alkyl, which is substituted by one or more R7, SR7N(R7)2, NHC(O)R7or Cl.

In one variant embodiment of formula (I) R7represents phenyl. In one variant embodiment of formula (I) R7represents methyl. In one variant embodiment of formula (I) R7represents isopropyl. In one variant embodiment of formula (I) R7is pyrrolidyl. In one variant embodiment of formula (I) R7is morpholinyl. In one variant embodiment of formula (I) R7is tetrahydropyranyl.

Another variant implementation of the present invention relates to compounds having formula I, which are

4-[4-(cyclohexylmethyl)-4-methoxypiperidine-1-yl]-N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]Sul who were radioactive}benzamide;

N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}-4-[4-methoxy-4-(3-methylbenzyl)piperidine-1-yl]benzamide;

N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}-4-[4-(3,3-diphenylprop-2-enyl)piperazine-1-yl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-{[2-(phenylthio)ethyl]amino}piperidine-1-yl)sulfonyl]benzamide;

N-[(4-{acetyl[2-(phenylthio)ethyl]amino}piperidine-1-yl)sulfonyl]-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-{methyl[2-(phenylthio)ethyl]amino}piperidine-1-yl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}benzamide;

4-(4-{[2-(4-chlorophenyl)cyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}benzamide;

4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}benzamide;

N-{[(5Z)-5-(acetylamino)-4-methyl-4,5-dihydro-1,3,4-thiadiazole-2-yl]sulfonyl}-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;

N-{[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]sulfonyl}-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-ylbenzene;

N-({5-[(benzoylamine)methyl]Tien-2-yl}sulfonyl)-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-(morpholine-4-ylsulphonyl)benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[4-phenyl-5-(trifluoromethyl)Tien-3-yl]sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5-fluoro-3-methyl-1-benzothieno-2-yl)sulfonyl]benzamide;

N-(1,3-benzothiazol-2-ylsulphonyl)-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-(Tien-2-ylsulphonyl)benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]benzamide;

ethyl 4-{[(4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzoyl)amino]sulfonyl}-5-methyl-1,2-diphenyl-1H-pyrrole-3-carboxylate;

methyl 5-{[(4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzoyl)amino]sulfonyl}-1-methyl-1H-pyrrole-2-carboxylate;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[5-(1,3-dimethyl-1H-pyrazole-5-yl)isoxazol-4-yl]sulfonyl}benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-chloro-3-metalization-5-yl)sulfo the Il]benzamide;

N-[(5-bromo-3-methyl-1-benzothieno-2-yl)sulfonyl]-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-({5-[(E)-2-(1,2,4-oxadiazol-3-yl)vinyl]Tien-2-yl}sulfonyl)benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[1-(2-chloroethyl)-3,5-dimethyl-1H-pyrazole-4-yl]sulfonyl}benzamide;

5-{[(4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzoyl)amino]sulfonyl}-N-(1-ethylpropyl)-1,3,4-thiadiazole-2-carboxamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5-chloro-1,3-dimethyl-1H-pyrazole-4-yl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-nitro-5-piperidine-1-Illian-2-yl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5-isoxazol-5-yl-2-furyl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3,5-dimethylisoxazol-4-yl)sulfonyl]benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-({4-nitro-5-[(3-pyrrolidin-1-ylpropyl)amino]Tien-2-yl}sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(5-{[3-(dimethylamino)propyl]amino}-4-nitration-2-yl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-({5-[(3-morpholine-4-ylpropyl)amino]-4-nitration-2-yl}sulfonyl)benzamide;

N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}-4-{4-[2-(trifluoromethyl)benzylidene]piperidine-1-yl}benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methylene]piperidine-1-yl}-N-[(1,1-dioxymethamphetamine-3-yl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methylene]piperidine-1-yl}-N-[(5-chloro-3-methyl-1-benzothieno-2-yl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5-chloro-3-methyl-1-benzothieno-2-yl)sulfonyl]-2-phenoxybenzamide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-Ν-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-[(6,7-debtor-1H-indol-5-yl)oxy]-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]benzamide;

tert-butyl (2S)-2-{[(5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;

tert-butyl (2S)-2-{[(5-{[2-(1H-benzimidazole-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-({2-[(4-Porterage-2H-Piran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)benzamide;

2-(1H-benzimidazole-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-({2-[(4-Porterage-2H-Piran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)benzamide;

tert-butyl (2S)-2-{[(5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indazol-4-yloxy)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-({2-[(4-Porterage-2H-Piran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;

and their therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites.

Another variant of implementation of the present invention relates to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs of such compounds that are useful as inhibitors of anti-apoptotic proteins Bcl-2, these compounds have the formula (II)

where R101represents H or has the meanings given for substituents at R26and the value of A1shown in the formula (I).

In one embodiment, in which proxenia formula (II) A 1represents furyl, imidazolyl, isothiazolin, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, heteroseksualci or geteroseksualen; each of which is not condensed or fused with benzene, heteroatom or A1A; and A1Arepresents geteroseksualen. In another variant embodiment of formula (II) A1represents a furyl. In another variant embodiment of formula (II) A1is imidazolyl. In another variant embodiment of formula (II) A1represents isothiazolin. In another variant embodiment of formula (II) A1represents isoxazolyl. In another variant embodiment of formula (II) A1represents pyrazolyl. In another variant embodiment of formula (II) A1represents pyrrolyl. In another variant embodiment of formula (II) A1represents thiazolyl. In another variant embodiment of formula (II) A1represents thiadiazolyl. In another variant embodiment of formula (II) A1is thienyl. In another variant embodiment of formula (II) A1represents triazolyl. In another variant embodiment of formula (II) A1is heteroseksualci. In another variant embodiment of formula (II) A1represents geteroseksualen. In another embodiment, vopl is of formula (II) A 1is piperidinyl. In another variant embodiment of formula (II) A1is morpholinyl. In another variant embodiment of formula (II) A1represents a dihydro-1,3,4-thiadiazole-2-yl. In another variant embodiment of formula (II) A1is bestien-2-yl. In another variant embodiment of formula (II) A1represents benzothiazol-2-yl. In another variant embodiment of formula (II) A1represents benzothiazol-2-yl. In another variant embodiment of formula (II) A1represents [1,2,4]triazolo[1,5-a]pyrimidine-2-yl. In another variant embodiment of formula (II) A1is tetrahydrothieno-3-yl. In another variant embodiment of formula (II) A1represents [1,2,4]triazolo[1,5-a]pyrimidine-2-yl. In another variant embodiment of formula (II) A1represents imidazo[2,1-b][1,3]thiazol-5-yl.

In one variant embodiment of formula (II) A1not substituted. In another variant embodiment of formula (II) A1substituted with one, or two, or three, or four, or five independently selected substituents R1, OR1C(O)OR1, Other1N(R1)2C(N)C(O)R1C(O)other1, NHC(O)R1, NR1C(O)R1, (O), NO2, F, Cl, Br, I or CF3. In one variant embodiment of formula (II) A1not substituted. In other variant embodiments of formulas is (II) A 1substituted with other1. In another variant embodiment of formula (II) A1substituted with other1and NO2. In another variant embodiment of formula (II) A1substituted with other1. In another variant embodiment of formula (II) A1replaced NR1C(O)R1. In another variant embodiment of formula (II) A1substituted N(R1)2. In another variant embodiment of formula (II) A1replaced by C(N)C(O)R1and R1. In another variant embodiment of formula (II) A1substituted NHC(O)R1and R1. In another variant embodiment of formula (II) A1substituted R1. In another variant embodiment of formula (II) A1substituted with two independently selected R1. In another variant embodiment of formula (II) A1substituted Cl. In another variant embodiment of formula (II) A1substituted CF3. In another variant embodiment of formula (II) A1substituted F. In another variant embodiment of formula (II) A1substituted with three independently selected R1and C(O)OR1. In another variant embodiment of formula (II) A1represents a substituted R1and C(O)OR1. In another variant embodiment of formula (II) A1substituted R1and Cl. In another variant embodiment of formula (II) A1substituted R1and Br. In another variant embodiment of formula (II) A1substituted with three independently selected R1. In another embodiment of embodiment f is rmula (II) A 1substituted C(O)other1. In another variant embodiment of formula (II) A1substituted with two independently selected R1and Cl. In another variant embodiment of formula (II) A1substituted R1and NO2. In another variant embodiment of formula (II) A1substituted with other1and NO2. In another variant embodiment of formula (II) A1replaced by (O). In another variant embodiment of formula (II) A1substituted OR1.

In one variant embodiment of formula (II) R1represents phenyl. In another variant embodiment of formula (II) R1represents pyrazolyl. In another variant embodiment of formula (II) R1is morpholinyl. In another variant embodiment of formula (II) R1represents isoxazolyl. In another variant embodiment of formula (II) R1is piperidinyl. In another variant embodiment of formula (II) R1represents alkyl, which is not substituted. In another variant embodiment of formula (II) R1represents alkyl, which is substituted by one or more R7, SR7N(R7)2, NHC(O)R7or Cl.

In one variant embodiment of formula (II) R7represents phenyl. In one variant embodiment of formula (II) R7represents methyl. In one variant embodiment of formula (II) R7represents isopropyl. In about the nom variant embodiment of formula (II) R 7is pyrrolidyl. In one variant embodiment of formula (II) R7is morpholinyl. In one variant embodiment of formula (II) R7is tetrahydropyranyl.

Another variant implementation of the present invention relates to compounds having the formula II, which are

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-{[2-(phenylthio)ethyl]amino}piperidine-1-yl)sulfonyl]benzamide;

N-[(4-{acetyl[2-(phenylthio)ethyl]amino}piperidine-1-yl)sulfonyl]-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-{methyl[2-(phenylthio)ethyl]amino}piperidine-1-yl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}benzamide;

N-{[(5Z)-5-(acetylamino)-4-methyl-4,5-dihydro-1,3,4-thiadiazole-2-yl]sulfonyl}-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;

N-{[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]sulfonyl}-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;

N-({5-[(benzoylamine)methyl]Tien-2-yl}sulfonyl)-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-the l}-N-(morpholine-4-ylsulphonyl)benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[4-phenyl-5-(trifluoromethyl)Tien-3-yl]sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5-fluoro-3-methyl-1-benzothieno-2-yl)sulfonyl]benzamide;

N-(1,3-benzothiazol-2-ylsulphonyl)-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-(Tien-2-ylsulphonyl)benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]benzamide;

ethyl 4-{[(4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzoyl)amino]sulfonyl}-5-methyl-1,2-diphenyl-1H-pyrrole-3-carboxylate;

methyl 5-{[(4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzoyl)amino]sulfonyl}-1-methyl-1H-pyrrole-2-carboxylate;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[5-(1,3-dimethyl-1H-pyrazole-5-yl)isoxazol-4-yl]sulfonyl}benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-chloro-3-metalization-5-yl)sulfonyl]benzamide;

N-[(5-bromo-3-methyl-1-benzothieno-2-yl)sulfonyl]-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-({5-[(E)-2-(1,2,4-oxadiazol-3-yl)vinyl]Tien-2-yl}sulfonyl)benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[1-(2-chloroethyl)-,5-dimethyl-1H-pyrazole-4-yl]sulfonyl}benzamide;

5-{[(4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzoyl)amino]sulfonyl}-N-(1-ethylpropyl)-1,3,4-thiadiazole-2-carboxamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5-chloro-1,3-dimethyl-1H-pyrazole-4-yl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-nitro-5-piperidine-1-Illian-2-yl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5-isoxazol-5-yl-2-furyl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3,5-dimethylisoxazol-4-yl)sulfonyl]benzamide;

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5-chloro-3-methyl-1-benzothieno-2-yl)sulfonyl]-2-phenoxybenzamide;

and their therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites.

Another variant of implementation of the present invention relates to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs of such compounds that are useful as inhibitors of anti-apoptotic proteins Bcl-2, these compounds have the formula (III)

where R101represents H or has the meanings given for substituents at R26and the value of A1shown in the formula (I).

In one variant embodiment of formula (III) (A1represents furyl, imidazolyl, isothiazolin, from suzail, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, heteroseksualci or geteroseksualen; each of which is not condensed or fused with benzene, heteroatom or A1A; A1Arepresents geteroseksualen. In another variant embodiment of formula (III) (A1represents a furyl. In another variant embodiment of formula (III) (A1is imidazolyl. In another variant embodiment of formula (III) (A1represents isothiazolin. In another variant embodiment of formula (III) (A1represents isoxazolyl. In another variant embodiment of formula (III) (A1represents pyrazolyl. In another variant embodiment of formula (III) (A1represents pyrrolyl. In another variant embodiment of formula (III) (A1represents thiazolyl. In another variant embodiment of formula (III) (A1represents thiadiazolyl. In another variant embodiment of formula (III) (A1is thienyl. In another variant embodiment of formula (II) A1represents triazolyl. In another variant embodiment of formula (III) (A1is heteroseksualci. In another variant embodiment of formula (III) (A1represents geteroseksualen. In another variant embodiment of formula (III) (A1is piperidinyl. In other the Ohm variant embodiment of formula (III) (A 1is morpholinyl. In another variant embodiment of formula (III) (A1represents a dihydro-1,3,4-thiadiazole-2-yl. In another variant embodiment of formula (III) (A1is bestien-2-yl. In another variant embodiment of formula (III) (A1represents benzothiazol-2-yl. In another variant embodiment of formula (III) (A1represents benzothiazol-2-yl. In another variant embodiment of formula (III) (A1represents [1,2,4]triazolo[1,5-a]pyrimidine-2-yl. In another variant embodiment of formula (III) (A1is tetrahydrothieno-3-yl. In another variant embodiment of formula (III) (A1represents [1,2,4]triazolo[1,5-a]pyrimidine-2-yl. In another variant embodiment of formula (III) (A1represents imidazo[2,1-b][1,3]thiazol-5-yl.

In one variant embodiment of formula (III) (A1not substituted. In another variant embodiment of formula (III) (A1substituted with one, or two, or three, or four, or five independently selected substituents R1, OR1C(O)OR1, Other1N(R1)2C(N)C(O)R1C(O)other1, NHC(O)R1, NR1C(O)R1, (O), NO2, F, Cl, Br, I or CF3. In one variant embodiment of formula (III) (A1not substituted. In another variant embodiment of formula (III) (A1substituted with other1. In another variant embodiment of formula (III) (A1 substituted with other1and NO2. In another variant embodiment of formula (III) (A1substituted with other1. In another variant embodiment of formula (III) (A1replaced NR1C(O)R1. In another variant embodiment of formula (III) (A1substituted N(R1)2. In another variant embodiment of formula (III) (A1replaced by C(N)C(O)R1and R1. In another variant embodiment of formula (III) (A1substituted NHC(O)R1and R1. In another variant embodiment of formula (III) (A1substituted R1. In another variant embodiment of formula (III) (A1substituted with two independently selected R1. In another variant embodiment of formula (III) (A1substituted Cl. In another variant embodiment of formula (III) (A1substituted CF3. In another variant embodiment of formula (III) (A1substituted F. In another variant embodiment of formula (III) (A1substituted with three independently selected R1and C(O)OR1. In another variant embodiment of formula (III) (A1represents a substituted R1and C(O)OR1. In another variant embodiment of formula (III) (A1substituted R1and Cl. In another variant embodiment of formula (III) (A1substituted R1and Br. In another variant embodiment of formula (III) (A1substituted with three independently selected R1. In another variant embodiment of formula (III) (A1substituted C(O)other1. In another embodiment, waples is of formula (III) (A 1substituted with two independently selected R1and Cl. In another variant embodiment of formula (III) (A1substituted R1and NO2. In another variant embodiment of formula (III) (A1substituted with other1and NO2. In another variant embodiment of formula (III) (A1replaced by (O). In another variant embodiment of formula (III) (A1substituted OR1.

In one variant embodiment of formula (III), R1represents phenyl. In another variant embodiment of formula (III), R1represents pyrazolyl. In another variant embodiment of formula (III), R1is morpholinyl. In another variant embodiment of formula (III), R1represents isoxazolyl. In another variant embodiment of formula (III), R1is piperidinyl. In another variant embodiment of formula (III), R1represents alkyl, which is not substituted. In another variant embodiment of formula (III), R1represents alkyl, which is substituted by one or more R7, SR7N(R7)2, NHC(O)R7or Cl.

In one variant embodiment of formula (III), R7represents phenyl. In one variant embodiment of formula (III), R7represents methyl. In one variant embodiment of formula (III), R7represents isopropyl. In one variant embodiment of formula (III), R7is the nd pyrrolidyl. In one variant embodiment of formula (III), R7is morpholinyl. In one variant embodiment of formula (III), R7is tetrahydropyranyl.

Another variant implementation of the present invention relates to compounds having the formula III, which are

4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-({4-nitro-5-[(3-pyrrolidin-1-ylpropyl)amino]Tien-2-yl}sulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(5-{[3-(dimethylamino)propyl]amino}-4-nitration-2-yl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-({5-[(3-morpholine-4-ylpropyl)amino]-4-nitration-2-yl}sulfonyl)benzamide;

2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-Ν-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-yl)-2-[(6,7-debtor-1H-indol-5-yl)oxy]-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]benzamide;

tert-butyl (2S)-2-{[(5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;

tert-butyl (2S)-2-{[(5-{[2-(1H-benzimidazole-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-({2-[(4-Porterage-2H-Piran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)benzamide;

2-(1H-benzimidazole-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-({2-[(4-Porterage-2H-Piran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)benzamide;

tert-butyl (2S)-2-{[(5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indazol-4-yloxy)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-({2-[(4-Porterage-2H-Piran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;

and their therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites.

Another variant of implementation of the present invention relates to compounds or therapeutically acceptable salts, n is lekarstv, metabolites, or salts of prodrugs of such compounds that are useful as inhibitors of anti-apoptotic proteins Bcl-2, these compounds have the formula (IV)

where R102represents the attachment point to the indole, and the others denote H or have the meanings given to substituents at R42and the value of A1and Z3shown in the formula (I).

In one variant embodiment of formula (IV), A1represents furyl, imidazolyl, isothiazolin, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, heteroseksualci or geteroseksualen; each of which is not condensed or fused with benzene, heteroatom or A1A; A1Arepresents geteroseksualen. In another variant embodiment of formula (IV), A1represents a furyl. In another variant embodiment of formula (IV), A1is imidazolyl. In another variant embodiment of formula (IV), A1represents isothiazolin. In another variant embodiment of formula (IV), A1represents isoxazolyl. In another variant embodiment of formula (IV), A1represents pyrazolyl. In another variant embodiment of formula (IV), A1represents pyrrolyl. In another variant embodiment of formula (IV), A1PR is dstanley thiazolyl. In another variant embodiment of formula (IV), A1represents thiadiazolyl. In another variant embodiment of formula (IV), A1is thienyl. In another variant embodiment of formula (IV), A1represents triazolyl. In another variant embodiment of formula (IV), A1is heteroseksualci. In another variant embodiment of formula (IV), A1represents geteroseksualen. In another variant embodiment of formula (IV), A1is piperidinyl. In another variant embodiment of formula (IV), A1is morpholinyl. In another variant embodiment of formula (IV), A1represents a dihydro-1,3,4-thiadiazole-2-yl. In another variant embodiment of formula (IV), A1is bestien-2-yl. In another variant embodiment of formula (IV), A1represents benzothiazol-2-yl. In another variant embodiment of formula (IV), A1represents [1,2,4]triazolo[1,5-a]pyrimidine-2-yl. In another variant embodiment of formula (IV), A1is tetrahydrothieno-3-yl. In another variant embodiment of formula (IV), A1represents [1,2,4]triazolo[1,5-a]pyrimidine-2-yl. In another variant embodiment of formula (IV), A1represents imidazo[2,1-b][1,3]thiazol-5-yl.

In one variant embodiment of formula (IV), A1not substituted. In another embodiment, the GP is osenia formula (IV), A 1substituted with one, or two, or three, or four, or five independently selected substituents R1, OR1C(O)OR1, Other1N(R1)2C(N)C(O)R1C(O)other1, NHC(O)R1, NR1C(O)R1, (O), NO2, F, Cl, Br, I or CF3. In one variant embodiment of formula (IV), A1not substituted. In another variant embodiment of formula (IV), A1substituted with other1. In another variant embodiment of formula (IV), A1substituted with other1and NO2. In another variant embodiment of formula (IV), A1substituted with other1. In another variant embodiment of formula (IV), A1replaced NR1C(O)R1. In another variant embodiment of formula (IV), A1substituted N(R1)2. In another variant embodiment of formula (IV), A1replaced by C(N)C(O)R1and R1. In another variant embodiment of formula (IV), A1substituted NHC(O)R1and R1. In another variant embodiment of formula (IV), A1substituted R1. In another variant embodiment of formula (IV), A1substituted with two independently selected R1. In another variant embodiment of formula (IV), A1substituted Cl. In another variant embodiment of formula (IV), A1substituted CF3. In another variant embodiment of formula (IV), A1substituted F. In another variant embodiment of formula (IV), A1substituted with three independently selected R1and C(O)OR1. In another VA who ianthe embodiment of formula (IV), A 1represents a substituted R1and C(O)OR1. In another variant embodiment of formula (IV), A1substituted R1and Cl. In another variant embodiment of formula (IV), A1substituted R1and Br. In another variant embodiment of formula (IV), A1substituted with three independently selected R1. In another variant embodiment of formula (IV), A1substituted C(O)other1. In another variant embodiment of formula (IV), A1substituted with two independently selected R1and Cl. In another variant embodiment of formula (IV), A1substituted R1and NO2. In another variant embodiment of formula (IV), A1substituted with other1and NO2. In another variant embodiment of formula (IV), A1replaced by (O). In another variant embodiment of formula (IV), A1substituted OR1.

In one variant embodiment of formula (IV) R1represents phenyl. In another variant embodiment of formula (IV) R1represents pyrazolyl. In another variant embodiment of formula (IV) R1is morpholinyl. In another variant embodiment of formula (IV) R1represents isoxazolyl. In another variant embodiment of formula (IV) R1is piperidinyl. In another variant embodiment of formula (IV) R1represents alkyl, which is not substituted. In another variant embodiment of formula (IV) R1is own the th alkyl, which is substituted by one or more R7, SR7N(R7)2, NHC(O)R7or Cl.

In one variant embodiment of formula (IV) R7represents phenyl. In one variant embodiment of formula (IV) R7represents methyl. In one variant embodiment of formula (IV) R7represents isopropyl. In one variant embodiment of formula (IV) R7is pyrrolidyl. In one variant embodiment of formula (IV) R7is morpholinyl. In one variant embodiment of formula (IV) R7is tetrahydropyranyl.

Another variant of implementation of the present invention relates to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs of such compounds that are useful as inhibitors of anti-apoptotic proteins Bcl-2, these compounds have the formula (V)

where R102represents the attachment point to indazole, and the others denote H or have the meanings given to substituents at R42and the value of A1and Z3shown in the formula (I).

In one variant embodiment of formula (V) A1represents furyl, imidazolyl, isothiazolin, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, hetero is cloacal or geteroseksualen; each of which is not condensed or fused with benzene, heteroatom or A1A; and A1Arepresents geteroseksualen. In another variant embodiment of formula (V) A1represents a furyl. In another variant embodiment of formula (V) A1is imidazolyl. In another variant embodiment of formula (V) A1represents isothiazolin. In another variant embodiment of formula (V) A1represents isoxazolyl. In another variant embodiment of formula (V) A1represents pyrazolyl. In another variant embodiment of formula (V) A1represents pyrrolyl. In another variant embodiment of formula (V) A1represents thiazolyl. In another variant embodiment of formula (V) A1represents thiadiazolyl. In another variant embodiment of formula (V) A1is thienyl. In another variant embodiment of formula (V) A1represents triazolyl. In another variant embodiment of formula (V) A1is heteroseksualci. In another variant embodiment of formula (V) A1represents geteroseksualen. In another variant embodiment of formula (V) A1is piperidinyl. In another variant embodiment of formula (V) A1is morpholinyl. In another variant embodiment of formula (V) A 1represents a dihydro-1,3,4-thiadiazole-2-yl. In another variant embodiment of formula (V) A1is bestien-2-yl. In another variant embodiment of formula (V) A1represents benzothiazol-2-yl. In another variant embodiment of formula (V) A1represents [1,2,4]triazolo[1,5-a]pyrimidine-2-yl. In another variant embodiment of formula (V) A1is tetrahydrothieno-3-yl. In another variant embodiment of formula (V) A1represents [1,2,4]triazolo[1,5-a]pyrimidine-2-yl. In another variant embodiment of formula (V) A1represents imidazo[2,1-b][1,3]thiazol-5-yl.

In one variant embodiment of formula (V) A1not substituted. In another variant embodiment of formula (V) A1substituted with one, or two, or three, or four, or five independently selected substituents R1, OR1C(O)OR1, Other1N(R1)2C(N)C(O)R1C(O)other1, NHC(O)R1, NR1C(O)R1, (O), NO2, F, Cl, Br, I or CF3. In one variant embodiment of formula (V) A1not substituted. In another variant embodiment of formula (V) A1substituted with other1. In another variant embodiment of formula (V) A1substituted with other1and NO2. In another variant embodiment of formula (V) A1substituted with other1. In another variant embodiment of formula (V) A1replaced NR1C(O)R1. the other variant embodiments of formula (V) A 1substituted N(R1)2. In another variant embodiment of formula (V) A1replaced by C(N)C(O)R1and R1. In another variant embodiment of formula (V) A1substituted NHC(O)R1and R1. In another variant embodiment of formula (V) A1substituted R1. In another variant embodiment of formula (V) A1substituted with two independently selected R1. In another variant embodiment of formula (V) A1substituted Cl. In another variant embodiment of formula (V) A1substituted CF3. In another variant embodiment of formula (V) A1substituted F. In another variant embodiment of formula (V) A1substituted with three independently selected R1and C(O)OR1. In another variant embodiment of formula (V) A1represents a substituted R1and C(O)OR1. In another variant embodiment of formula (V) A1substituted R1and Cl. In another variant embodiment of formula (V) A1substituted R1and Br. In another variant embodiment of formula (V) A1substituted with three independently selected R1. In another variant embodiment of formula (V) A1substituted C(O)other1. In another variant embodiment of formula (V) A1substituted with two independently selected R1and Cl. In another variant embodiment of formula (V) A1substituted R1and NO2. In another variant embodiment of formula (V) A1substituted with other1and NO2. In each the m variant embodiment of formula (V) A 1replaced by (O). In another variant embodiment of formula (V) A1substituted OR1.

In one variant embodiment of formula (V) R1represents phenyl. In another variant embodiment of formula (V) R1represents pyrazolyl. In another variant embodiment of formula (V) R1is morpholinyl. In another variant embodiment of formula (V) R1represents isoxazolyl. In another variant embodiment of formula (V) R1is piperidinyl. In another variant embodiment of formula (V) R1represents alkyl, which is not substituted. In another variant embodiment of formula (V) R1represents alkyl, which is substituted by one or more R7, SR7N(R7)2, NHC(O)R7or Cl.

In one variant embodiment of formula (V) R7represents phenyl. In one variant embodiment of formula (V) R7represents methyl. In one variant embodiment of formula (V) R7represents isopropyl. In one variant embodiment of formula (V) R7is pyrrolidyl. In one variant embodiment of formula (V) R7is morpholinyl. In one variant embodiment of formula (V) R7is tetrahydropyranyl.

Another variant implementation of the present invention relates to compounds of the region have the formula V, which are

tert-butyl (2S)-2-{[(5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indazol-4-yloxy)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-({2-[(4-Porterage-2H-Piran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;

and their therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites.

Another variant of implementation of the present invention relates to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs of such compounds that are useful as inhibitors of anti-apoptotic proteins Bcl-2, these compounds have the formula (VI)

where R102represents the attachment point to Benincasa, and the others denote H or have the meanings given to substituents at R42and the value of A1and Z3shown in the formula (I).

In one variant embodiment of formula (VI), A1represents furyl, imidazolyl, isothiazolin, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, heteroseksualci or geteroseksualen; each of which is not condensed, or condensed with benzo is scrap, heteroatom or A1A; A1Arepresents geteroseksualen. In another variant embodiment of formula (VI), A1represents a furyl. In another variant embodiment of formula (VI), A1is imidazolyl. In another variant embodiment of formula (VI), A1represents isothiazolin. In another variant embodiment of formula (VI), A1represents isoxazolyl. In another variant embodiment of formula (VI), A1represents pyrazolyl. In another variant embodiment of formula (VI), A1represents pyrrolyl. In another variant embodiment of formula (VI), A1represents thiazolyl. In another variant embodiment of formula (VI), A1represents thiadiazolyl. In another variant embodiment of formula (VI), A1is thienyl. In another variant embodiment of formula (VI), A1represents triazolyl. In another variant embodiment of formula (VI), A1is heteroseksualci. In another variant embodiment of formula (VI), A1represents geteroseksualen. In another variant embodiment of formula (VI), A1is piperidinyl. In another variant embodiment of formula (VI), A1is morpholinyl. In another variant embodiment of formula (VI), A1represents a dihydro-1,3,4-thiadiazole-2-yl. In each the m variant embodiment of formula (VI), A 1is bestien-2-yl. In another variant embodiment of formula (VI), A1represents benzothiazol-2-yl. In another variant embodiment of formula (VI), A1represents [1,2,4]triazolo[1,5-a]pyrimidine-2-yl. In another variant embodiment of formula (VI), A1is tetrahydrothieno-3-yl. In another variant embodiment of formula (VI), A1represents [1,2,4]triazolo[1,5-a]pyrimidine-2-yl. In another variant embodiment of formula (VI), A1represents imidazo[2,1-b][1,3]thiazol-5-yl.

In one variant embodiment of formula (VI), A1not substituted. In another variant embodiment of formula (VI), A1substituted with one, or two, or three, or four, or five independently selected substituents R1, OR1C(O)OR1, Other1N(R1)2C(N)C(O)R1C(O)other1, NHC(O)R1, NR1C(O)R1, (O), NO2, F, Cl, Br, I or CF3. In one variant embodiment of formula (VI), A1not substituted. In another variant embodiment of formula (VI), A1substituted with other1. In another variant embodiment of formula (VI), A1substituted with other1and NO2. In another variant embodiment of formula (VI), A1substituted with other1. In another variant embodiment of formula (VI), A1replaced NR1C(O)R1. In another variant embodiment of formula (VI), A1substituted N(R1)2. In other options, the ante embodiment of formula (VI), A 1replaced by C(N)C(O)R1and R1. In another variant embodiment of formula (VI), A1substituted NHC(O)R1and R1. In another variant embodiment of formula (VI), A1substituted R1. In another variant embodiment of formula (VI), A1substituted with two independently selected R1. In another variant embodiment of formula (VI), A1substituted Cl. In another variant embodiment of formula (VI), A1substituted CF3. In another variant embodiment of formula (VI), A1substituted F. In another variant embodiment of formula (VI), A1substituted with three independently selected R1and C(O)OR1. In another variant embodiment of formula (VI), A1represents a substituted R1and C(O)OR1. In another variant embodiment of formula (VI), A1substituted R1and Cl. In another variant embodiment of formula (VI), A1substituted R1and Br. In another variant embodiment of formula (VI), A1substituted with three independently selected R1. In another variant embodiment of formula (VI), A1substituted C(O)other1. In another variant embodiment of formula (VI), A1substituted with two independently selected R1and Cl. In another variant embodiment of formula (VI), A1substituted R1and NO2. In another variant embodiment of formula (VI), A1substituted with other1and NO2. In another variant embodiment of formula (VI), A1replaced by (O). In another variant is NTE embodiment of formula (VI), A 1substituted OR1.

In one variant embodiment of formula (VI), R1represents phenyl. In another variant embodiment of formula (VI), R1represents pyrazolyl. In another variant embodiment of formula (VI), R1is morpholinyl. In another variant embodiment of formula (VI), R1represents isoxazolyl. In another variant embodiment of formula (VI), R1is piperidinyl. In another variant embodiment of formula (VI), R1represents alkyl, which is not substituted. In another variant embodiment of formula (VI), R1represents alkyl, which is substituted by one or more R7, SR7N(R7)2, NHC(O)R7or Cl.

In one variant embodiment of formula (VI), R7represents phenyl. In one variant embodiment of formula (VI), R7represents methyl. In one variant embodiment of formula (VI), R7represents isopropyl. In one variant embodiment of formula (VI), R7is pyrrolidyl. In one variant embodiment of formula (VI), R7is morpholinyl. In one variant embodiment of formula (VI), R7is tetrahydropyranyl.

Another variant implementation of the present invention relates to compounds having the formula VI, which are

tert-Buti is (2S)-2-{[(5-{[2-(1H-benzimidazole-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;

2-(1H-benzimidazole-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-({2-[(4-Porterage-2H-Piran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)benzamide;

and their therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites.

Another variant of implementation of the present invention relates to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs of such compounds that are useful as inhibitors of anti-apoptotic proteins Bcl-2, these compounds have the formula (VII)

where R102represents the attachment point to the pyridine, and the others denote H or have the meanings given to substituents at R42and the value of A1and Z3shown in the formula (I).

In one variant embodiment of formula (VII) A1represents furyl, imidazolyl, isothiazolin, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, heteroseksualci or geteroseksualen; each of which is not condensed or fused with benzene, heteroatom or A1A; A1Arepresents geteroseksualen. In another variant embodiment of formula (VII) A1represents a furyl. In another variant embodiment of formula (VII) A1pre who is imidazolyl. In another variant embodiment of formula (VII) A1represents isothiazolin. In another variant embodiment of formula (VII) A1represents isoxazolyl. In another variant embodiment of formula (VII) A1represents pyrazolyl. In another variant embodiment of formula (VII) A1represents pyrrolyl. In another variant embodiment of formula (VII) A1represents thiazolyl. In another variant embodiment of formula (VII) A1represents thiadiazolyl. In another variant embodiment of formula (VII) A1is thienyl. In another variant embodiment of formula (VII) A1represents triazolyl. In another variant embodiment of formula (VII) A1is heteroseksualci. In another variant embodiment of formula (VII) A1represents geteroseksualen. In another variant embodiment of formula (VII) A1is piperidinyl. In another variant embodiment of formula (VII) A1is morpholinyl. In another variant embodiment of formula (VII) A1represents a dihydro-1,3,4-thiadiazole-2-yl. In another variant embodiment of formula (VII) A1is bestien-2-yl. In another variant embodiment of formula (VII) A1represents benzothiazol-2-yl. In another variant embodiment of formula (VII) A1not only is et a [1,2,4]triazolo[1,5-a]pyrimidine-2-yl. In another variant embodiment of formula (VII) A1is tetrahydrothieno-3-yl. In another variant embodiment of formula (VII) A1represents [1,2,4]triazolo[1,5-a]pyrimidine-2-yl. In another variant embodiment of formula (VII) A1represents imidazo[2,1-b][1,3]thiazol-5-yl.

In one variant embodiment of formula (VII) A1not substituted. In another variant embodiment of formula (VII) A1substituted with one, or two, or three, or four, or five independently selected substituents R1, OR1C(O)OR1, Other1N(R1)2C(N)C(O)R1C(O)other1, NHC(O)R1, NR1C(O)R1, (O), NO2, F, Cl, Br, I or CF3. In one variant embodiment of formula (VII) A1not substituted. In another variant embodiment of formula (VII) A1substituted with other1. In another variant embodiment of formula (VII) A1substituted with other1and NO2. In another variant embodiment of formula (VII) A1substituted with other1. In another variant embodiment of formula (VII) A1replaced NR1C(O)R1. In another variant embodiment of formula (VII) A1substituted N(R1)2. In another variant embodiment of formula (VII) A1replaced by C(N)C(O)R1and R1. In another variant embodiment of formula (VII) A1substituted NHC(O)R1and R1. In another variant embodiment of formula (VII) A1substituted R1. In the other variant embodiments of formula (VII) A 1substituted with two independently selected R1. In another variant embodiment of formula (VII) A1substituted Cl. In another variant embodiment of formula (VII) A1substituted CF3. In another variant embodiment of formula (VII) A1substituted F. In another variant embodiment of formula (VII) A1substituted with three independently selected R1and C(O)OR1. In another variant embodiment of formula (VII) A1represents a substituted R1and C(O)OR1. In another variant embodiment of formula (VII) A1substituted R1and Cl. In another variant embodiment of formula (VII) A1substituted R1and Br. In another variant embodiment of formula (VII) A1substituted with three independently selected R1. In another variant embodiment of formula (VII) A1substituted C(O)other1. In another variant embodiment of formula (VII) A1substituted with two independently selected R1and Cl. In another variant embodiment of formula (VII) A1substituted R1and NO2. In another variant embodiment of formula (VII) A1substituted with other1and NO2. In another variant embodiment of formula (VII) A1replaced by (O). In another variant embodiment of formula (VII) A1substituted OR1.

In one variant embodiment of formula (VII) R1represents phenyl. In another variant embodiment of formula (VII) R1represents pyrazolyl. In the other the variant embodiment of formula (VII) R 1is morpholinyl. In another variant embodiment of formula (VII) R1represents isoxazolyl. In another variant embodiment of formula (VII) R1is piperidinyl. In another variant embodiment of formula (VII) R1represents alkyl, which is not substituted. In another variant embodiment of formula (VII) R1represents alkyl, which is substituted by one or more R7, SR7N(R7)2, NHC(O)R7or Cl.

In one variant embodiment of formula (VII) R7represents phenyl. In one variant embodiment of formula (VII) R7represents methyl. In one variant embodiment of formula (VII) R7represents isopropyl. In one variant embodiment of formula (VII) R7is pyrrolidyl. In one variant embodiment of formula (VII) R7is morpholinyl. In one variant embodiment of formula (VII) R7is tetrahydropyranyl.

Another variant of implementation of the present invention relates to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs of such compounds that are useful as inhibitors of anti-apoptotic proteins Bcl-2, these compounds have the formula (VIII)

where each R102 independently represents H or has the meanings given for substituents at R42and the value of A1and Z3shown in the formula (I).

In one variant embodiment of formula (VIII) A1represents furyl, imidazolyl, isothiazolin, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, heteroseksualci or geteroseksualen; each of which is not condensed or fused with benzene, heteroatom or A1A; A1Arepresents geteroseksualen. In another variant embodiment of formula (VIII) A1represents a furyl. In another variant embodiment of formula (VIII) A1is imidazolyl. In another variant embodiment of formula (VIII) A1represents isothiazolin. In another variant embodiment of formula (VIII) A1represents isoxazolyl. In another variant embodiment of formula (VIII) A1represents pyrazolyl. In another variant embodiment of formula (VIII) A1represents pyrrolyl. In another variant embodiment of formula (VIII) A1represents thiazolyl. In another variant embodiment of formula (VIII) A1represents thiadiazolyl. In another variant embodiment of formula (VIII) A1is thienyl. In another variant embodiment of formula (VIII) A1is a Tr is azolyl. In another variant embodiment of formula (VIII) A1is heteroseksualci. In another variant embodiment of formula (VIII) A1represents geteroseksualen. In another variant embodiment of formula (VIII) A1is piperidinyl. In another variant embodiment of formula (VIII) A1is morpholinyl. In another variant embodiment of formula (VIII) A1represents a dihydro-1,3,4-thiadiazole-2-yl. In another variant embodiment of formula (VIII) A1is bestien-2-yl. In another variant embodiment of formula (VIII) A1represents benzothiazol-2-yl. In another variant embodiment of formula (VIII) A1represents [1,2,4]triazolo[1,5-a]pyrimidine-2-yl. In another variant embodiment of formula (VIII) A1is tetrahydrothieno-3-yl. In another variant embodiment of formula (VIII) A1represents [1,2,4]triazolo[1,5-a]pyrimidine-2-yl. In another variant embodiment of formula (VIII) A1represents imidazo[2,1-b][1,3]thiazol-5-yl.

In one variant embodiment of formula (VIII) A1not substituted. In another variant embodiment of formula (VIII) A1substituted with one, or two, or three, or four, or five independently selected substituents R1, OR1C(O)OR1, Other1N(R1)2C(N)C(O)R1C(O)other1, NHC(O)R1N 1C(O)R1, (O), NO2, F, Cl, Br, I or CF3. In one variant embodiment of formula (VIII) A1not substituted. In another variant embodiment of formula (VIII) A1substituted with other1. In another variant embodiment of formula (VIII) A1substituted with other1and NO2. In another variant embodiment of formula (VIII) A1substituted with other1. In another variant embodiment of formula (VIII) A1replaced NR1C(O)R1. In another variant embodiment of formula (VIII) A1substituted N(R1)2. In another variant embodiment of formula (VIII) A1replaced by C(N)C(O)R1and R1. In another variant embodiment of formula (VIII) A1substituted NHC(O)R1and R1. In another variant embodiment of formula (VIII) A1substituted R1. In another variant embodiment of formula (VIII) A1substituted with two independently selected R1. In another variant embodiment of formula (VIII) A1substituted Cl. In another variant embodiment of formula (VIII) A1substituted CF3. In another variant embodiment of formula (VIII) A1substituted F. In another variant embodiment of formula (VIII) A1substituted with three independently selected R1and C(O)OR1. In another variant embodiment of formula (VIII) A1represents a substituted R1and C(O)OR1. In another variant embodiment of formula (VIII) A1substituted R1and Cl. In another variant of the embodiment the Oia of the formula (VIII) A 1substituted R1and Br. In another variant embodiment of formula (VIII) A1substituted with three independently selected R1. In another variant embodiment of formula (VIII) A1substituted C(O)other1. In another variant embodiment of formula (VIII) A1substituted with two independently selected R1and Cl. In another variant embodiment of formula (VIII) A1substituted R1and NO2. In another variant embodiment of formula (VIII) A1substituted with other1and NO2. In another variant embodiment of formula (VIII) A1replaced by (O). In another variant embodiment of formula (VIII) A1substituted OR1.

In one variant embodiment of formula (VIII) R1represents phenyl. In another variant embodiment of formula (VIII) R1represents pyrazolyl. In another variant embodiment of formula (VIII) R1is morpholinyl. In another variant embodiment of formula (VIII) R1represents isoxazolyl. In another variant embodiment of formula (VIII) R1is piperidinyl. In another variant embodiment of formula (VIII) R1represents alkyl, which is not substituted. In another variant embodiment of formula (VIII) R1represents alkyl, which is substituted by one or more R7, SR7N(R7)2, NHC(O)R7or Cl.

In one variant embodiment of formula (VIII) R7predstavljaet a phenyl. In one variant embodiment of formula (VIII) R7represents methyl. In one variant embodiment of formula (VIII) R7represents isopropyl. In one variant embodiment of formula (VIII) R7is pyrrolidyl. In one variant embodiment of formula (VIII) R7is morpholinyl. In one variant embodiment of formula (VIII) R7is tetrahydropyranyl.

Another variant implementation of the present invention relates to compounds having the formula VIII, which are

tert-butyl (2S)-2-{[(5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-({2-[(4-Porterage-2H-Piran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)benzamide;

and their therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites.

The pharmaceutical compositions, combination therapy, methods of treatment and methods of administering drugs

Another variant of implementation of the present invention relates to therapeutic compositions comprising compounds having the formula (I), and an inert filler.

Another option is sushestvennee the present invention relates to a method of treating cancer in a mammal, which includes the introduction of the specified mammal a therapeutically acceptable amount of a compound having the formula (I).

Another variant of implementation of the present invention relates to a method of treating autoimmune disease in a mammal, which includes an introduction to the specified mammal a therapeutically acceptable amount of a compound having the formula (I).

Another variant implementation of the present invention relates to compositions for treating diseases during which is expressed anti-apoptotic proteins Bcl-2, these compositions include excipient and a therapeutically effective amount of the compounds having formula (I).

Another variant implementation of the present invention relates to methods of treating diseases during which is expressed anti-apoptotic proteins Bcl-2, these compositions include excipient and a therapeutically effective amount of the compounds having formula (I).

Another variant implementation of the present invention relates to compositions for treating bladder cancer, brain cancer, breast cancer, cancer, bone marrow cancer, cervical region, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, fall is circular lymphoma, of leukemia, called T-lymphocytes or b-cells, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, lung cancer, prostate cancer, small-cell lung cancer or cancer of the spleen in a patient, the composition includes an inert filler and a therapeutically effective amount of the compounds having formula (I).

Another variant of implementation of the present invention relates to a method of treating bladder cancer, brain cancer, breast cancer, cancer, bone marrow cancer, cervical region, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, leukemia, called T-lymphocytes or b-cells, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, lung cancer, prostate cancer, small-cell lung cancer or cancer of the spleen in a patient, while these methods include assigning the patient a therapeutically effective amount of the compounds having the formula (I).

Another variant implementation of the present invention relates to compositions for treating diseases during which is expressed anti-apoptotic proteins Bcl-2, these compositions include excipient and a therapeutically effective the active amount of an additional therapeutic agent or more than one additional therapeutic agent.

Another variant implementation of the present invention relates to methods of treating diseases during which is expressed anti-apoptotic proteins Bcl-2, while these methods include assigning the patient a therapeutically effective amount of the compounds having formula (I) and a therapeutically effective amount of an additional therapeutic agent or more than one additional therapeutic agent.

Another variant implementation of the present invention relates to compositions for treating bladder cancer, brain cancer, breast cancer, cancer, bone marrow cancer, cervical region, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, leukemia, called T-lymphocytes or b-cells, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small-cell lung cancer or cancer of the spleen in a patient, these compositions include an excipient and a therapeutically effective amount of the compounds having formula (I) and a therapeutically effective amount of an additional therapeutic agent or more than one additional t is repetitsionnogo tools.

Another variant implementation of the present invention relates to methods of treating bladder cancer, brain cancer, breast cancer, cancer, bone marrow cancer, cervical region, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, leukemia, called T-lymphocytes or b-cells, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small-cell lung cancer or cancer of the spleen in a patient, these methods include assigning the patient a therapeutically effective amount of the compounds of formula (I) and a therapeutically effective amount of an additional therapeutic agent or more than one additional therapeutic agent.

Metabolites of compounds of formula (I) formed in the process of exchange in terms ofin vitroorin vivomay also be suitable for treatment of diseases associated with anti-apoptotic protein Bcl-2.

Some precursor compounds, which are subject to currency in terms ofin vitroorin vivowith the formation of compounds having the formula (I) may also be suitable for treatment of diseases associated antiapoptotic protein Bcl-2.

With the organisations of the formula (I) can exist as an acid additive salt, basically additive salt or zwitterion. Salts of the compounds get when released or in the process of cleaning compounds. Acid additive salts of such compounds are salts that get the reaction of the compounds with an acid. For example, it is assumed that acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, benzosulfimide, bisulfate, butyrate, comparatie, camphorsulfonate, digluconate, formiate, fumaric, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate, cleaners containing hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate, maleate, mesitylenesulfonic, methansulfonate, naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate, tartrate, thiocyanate, trichloracetate, triptoreline, pair-toolswhat and undecanoate salt compounds and their prodrugs are included in the scope of the present invention. Basically additive salts of such compounds are salts that get the reaction of the compounds with hydroxide, carbonate or bicarbonate such cations such as lithium, sodium, potassium, calcium and magnesium.

The compounds of formula (I) can be entered, for example, buccal, ophthalmically, orally, osmotically, parenterally (ADAP is remisen, IPR, nutrigrain, intravenously, subcutaneously), rectally, topically, transdermally, or vaginally.

Therapeutically effective amounts of compounds having the formula (I), depend on recipient of treatment, disorder, treatment is carried out, and the severity of the disorder, the composition containing the compound, time of administration, route of administration, duration of treatment, the effectiveness of the compounds, the rate of its excretion from the body and from being used or not used in conjunction with other medicines. The amount of the compounds of formula (I) according to the present invention, which is used for the preparation of compositions intended for daily introduction to the patient in a single dose or in divided doses is from about 0.03 to about 200 mg per kg of body weight. Compositions in the form of a single dose contain the specified number or combination of partial doses.

The compounds of formula (I) can be entered together with the inert filler or without an inert filler. Inert fillers include, for example, encapsulating substances or additives such as agents, accelerating the absorption, antioxidants, binders connection, buffer additives, coatings for tablets, pigments, diluents, disintegrating agents, emulsifiers, dry diluents, fillers, flavorings, HC is anitli, lubricants, flavorings, preservatives, propellants, contributing to the release of substances, sterilizing agent, sweeteners, soljubilizatory, wetting agents and mixtures thereof.

Inert excipients for preparation of compositions comprising the compounds of formula (I), which are intended for oral administration in solid dosage form include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butyleneglycol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethylcellulose, tillaart, etiloleat, esters of fatty acids, gelatin, oil of wheat germ, glucose, glycerin, oil of groundnuts, the hypromellose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate, potato starch, povidone, propylene glycol, ringer's solution, safflower oil, sesame oil, sodium carboxymethylcellulose, phosphate salts of sodium, sodium lauryl sulfate, sodium derivative of sorbitol, soybean oil, stearic acid, fumarate, sucrose, surfactants, talc, tragakant, t is traditionally alcohol, triglycerides, water and their mixtures. Inert excipients for preparation of compositions comprising the compounds of formula (I), which are intended for ophthalmic or oral administration in liquid dosage forms include, for example, 1,3-butyleneglycol, castor oil, corn oil, cottonseed oil, ethanol, esters of fatty acids with sorbitane, oil of wheat germ, peanut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycols, sesame oil, water and mixtures thereof. Inert excipients for preparation of compositions comprising the compounds of formula (I), which are designed for osmotic injection include, for example, chlorofluorocarbons, ethanol, water and mixtures thereof. Inert excipients for preparation of compositions comprising the compounds of formula (I), which are intended for parenteral administration include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, wheat, oil groundnuts, liposomes, oleic acid, olive oil, peanut oil, ringer's solution, safflower oil, sesame oil, soybean oil, saline solution according to the US Pharmacopoeia or isotonic sodium chloride solution, water and their mixtures. Inert excipients for preparation of compositions comprising compounds is ormula (I), intended for rectal or vaginal administration, include, for example, cocoa butter, polyethylene glycol, wax and mixtures thereof.

It is expected that compounds having formula (I), shall be suitable for use with alkylating agents, inhibitors of the development of blood vessels, antibodies, antimetabolites, agents inhibiting the process of cell division, antiproliferative agents, antiviral agents, inhibitors euroracing, other inhibitors and accelerators of apoptosis (for example, Bcl-xL, Bcl-w and Bfl-I), activators of the metabolic pathways of the death receptor, inhibitors of Bcr-Abl kinase, BiTE antibodies (bespecifically activators of T-cells) loaded with drugs antibodies, biological response modifiers, inhibitors of cyclin-dependent kinases, inhibitors of the cell cycle by inhibitors of cyclooxygenase-2, DVD, inhibitors of receptor homologue of the viral oncogene leukemia (ErbB2), inhibitors of growth factor inhibitors, heat shock protein (HSP)-90, inhibitors distantiation (HDAC), hormonal therapy, immunological agents, inhibitors of inhibitors of apoptosis proteins (IAP), intercalating antibiotics, kinase inhibitors, inhibitors of kinesin, Jak2 inhibitors, inhibitors of the target of rapamycin in cells mlec the supply, microRNA inhibitors of mitogen-activated kinase, which is regulated by external signals, multispecificity binding proteins, non-steroidal anti-inflammatory drugs (NSAID), inhibitors of poly-ADP-ribosomally (PARP), chemotherapeutics platinum-based inhibitors of Polo-like kinase (Plk) inhibitors phosphoinositide-3-kinase (PI3K) inhibitors calpaine, purine analogues, and pyrimidine analogues, inhibitors of receptor tyrosine kinase, minigame/alkaloids deltoidea plants, small inhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors, inhibitors of ubiquitinate etc., or in combination with one or more of these agents.

BiTE antibodies are bespecifically antibodies that direct T cells to attack cancer cells, simultaneously connecting both of these cells. Then the T-cells attacking a cancer cell target. Examples of BiTE antibodies include adetomyrma (Micromet MT201), blinatumomab (Micromet MT 103), etc. are Not limiting ourselves to any theory, the authors present invention believe that one of the mechanisms by which T-lymphocytes induce apoptosis in cancerous target cells, is the exocytosis of cytolytic granules components, which include perforin and Grasim Century In this regard, it has been shown that Bcl-2 attenuates the induction of apoptosis under perforin, and granzyme B. These data suggest that inhibition of Bcl-2 may enhance the cytotoxic effect of T-lymphocytes, when they target cancer cells (V. R. Sutton, D. L. Vaux and J. A. Trapani,J. of Immunology1997, 158 (12), 5783).

siRNA represent molecules with endogenous reasons RNA or chemically modified nucleotides. Modifications do not eliminate cellular activity, but rather give the substances enhanced stability and/or increase their intracellular effectiveness. Examples of chemical modifications include phosphorothioate group, 2'-deoxynucleotides, 2'-OCH3-containing ribonucleotides, 2'-F-ribonucleotides, 2'-methoxyethylamine, combinations thereof, etc., siRNA can have a different length (e.g., 10-200 base pairs) and structure (for example, take the form of a stud having one/two spirals, loops, contain single-strand breaks/double-strand breaks, incorrectly paired bases) and are processed in the cells, promoting active suppression of gene transcription. Double-stranded siRNA (dsRNA) can have the same number of nucleotides in each helix (blunt ends) or to have an asymmetric ends (“labeled” ends). 1-2 nucleotide on the “labeled” ends may be present on the sense and/or antisense of the spiral, and to be present at the 5' and/or 3'-ends of this spiral. For example, p is shown, that siRNA, targeting Mcl-I, enhanced the activity of ABT-263 (i.e., N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-EN-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)-3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzosulfimide) or ABT-737 (i.e., N-(4-(4-((4'-chloro-(1,1'-biphenyl)-2-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide) in many lines of tumor cells (Tse et al.,Cancer Research2008, 68(9), 3421 and are there links).

Multispecific binding proteins are binding proteins that comprise two or more binding sites of the antigen. Multispecific binding proteins designs so that they had three or more binding sites of the antigen and in General they are antibodies that are not found in nature. The term "multispecific binding protein" means a binding protein that can bind two or more related or unrelated targets. Proteins that bind dual variable domain (DVD) represent a tetravalent or multivalent binding proteins that comprise two or more binding sites of the antigen. Similar DVD can be monospecificity (i.e., able to bind one antigen) or multispecificity (i.e., capable of binding two or more antigen is). Proteins that bind DVD, which includes two heavy polypeptide chains DVD and two light polypeptide chains DVD, referred to as DVD-Ig. Each half of the DVD-Ig polypeptide includes the heavy chain DVD polypeptide light chain DVD and two-binding site of the antigen. Each binding site includes the variable domain of the heavy chain variable domain and a light chain, with a total of 6 CDR participate in the process of antigen binding of one binding site of the antigen. Multispecific DVD include proteins that bind DVD that bind DLL4 and VEGF, or C-met and EFGR, or ErbB3 and EGFR.

Alkylating agents include altretamin, AMD-473, AP-5280, apaziquone, bendamustine, brostallicin, busulfan, carbocol, carmustin (BCNU), chlorambucil, CLORETAZINE®(laromustine, VPN 40101M), cyclophosphamide, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustin (CCNU), mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, N-oxide nitrogen mustard, ranimustine, temozolomide, thiotepa, TREANDA®(very weak), treosulfan, rotspeed etc.

Inhibitors of the development of blood vessels include inhibitors endothelialization receptor kinase (Tie-2) inhibitors of the receptor for epidermal growth factor (EGFR), a receptor inhibitors of the insulin growth factor-2 (IGFR-2) inhibitors of matrix metalloproteinase-2 (MMP-2) inhibitors of matrix metal is proteinase-9 (MMP-9), inhibitors of growth factor receptor platelet (DERIVED), the analogues of thrombospondin, inhibitors of receptor kinase growth factor vascular endothelial (VEGFR), etc.

Antimetabolites include ALIMTA®(pemetrexed disodium, LY231514, MTA), 5-azacytidine, XELODA®(capecitabine), carmofur, LEUSTAT®(cladribine, Clofarabine, cytarabine, tsitarabina ocfosfate, cytosine arabinoside, decitabine, deferoxamine, doxifluridine, eflornithine, EICAR (5-ethinyl-1-β-D-ribofuranosylthiazole-4-carboxamide), enocitabine, ethnicities, fludarabine, 5-fluorouracil inside the body, either alone or in combination with leucovorin, GEMZAR®(gemcitabine, hydroxyurea, ALKERAN (melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mycophenolate acid, nelarabine, nolatrexed, ocfosfate, political, pentostatin, raltitrexed, ribavarin, triapin, trimetrexate, S-1, tianfuan, tegafur, TS-1, vidarabine, UFT, etc.

Antiviral agents include ritonavir, hydroxychloroquine, etc.

Inhibitors euroracing ABT-348, AZD-1152, MLN-8054, VX-680, inhibitors of Aurora-A-specific kinase, inhibitors of Aurora-B-specific kinases and inhibitors pan-euroracing etc.

Inhibitors of protein Bcl-2 include AT-101 ((-)hossipole), GENASENSE®(G3139 or oblimersen (Bcl-2-targeting antisense oligonucleotide)), IPI-194, IPI-565, N-(4-(4-((4'-chloro-(1,1'-biphenyl)-2-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((f is ylsulphonyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide) (ABT-737), N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-EN-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)-3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzosulfimide (ABT-263), GX-070 (obatoclax) and so on

Inhibitors of Bcr-Abl-kinase include DASATINIB®(BMS-354825), GLEEVEC®(imatinib), etc.

The CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopiridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202, R-roscovitine), ZK-304709 and so on

COX-2 inhibitors include ABT-963, ARCOXIA®(etoricoxib), BEXTRA®(valdecoxib), BMS347070, CELEBREX®(celecoxib), a COX-189 (lumiracoxib), CT-3, DERAMAXX®(deracoxib), JTE-522, 4-methyl-2-(3,4-dimetilfenil)-1-(4-sulfamoyl-1H-pyrrole), MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016, S-2474, T-614, VIOXX®(rofecoksib), etc.

The EGFR inhibitors include ABX-EGF, immunoliposome against EGFR, EGF-vaccine, EMD-7200, ERBITUX®(cetuximab), HR3, IgA antibodies IRESSA®(gefitinib), TARCEVA®(erlotinib or OSI-774), TP-38, EGFR protein, TYKERB®(lapatinib), etc.

Inhibitors of ErbB2 receptor include CP-724-714, CI-1033 (canertinib), HERCEPTIN®(trastuzumab), TYKERB®(lapatinib), OMNITARG®(2C4, pertuzumab), TAK-165, GW-572016 (inferni), GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine), APC-8024 (vaccine HER-2), bispecific antibodies against HER/2neu, B7.her2IgG3, trifunctionally bespecifically antibodies AS HER2, mAB AR-209, mAB 2B-1, etc.

Inhibitors of g is stantially include depsipeptide, Lunar abyss-824, MS-275, trioxin, suberoylanilide acid (SAHA), TSA, valproate acid, etc.,

Inhibitors of HSP-90 include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB®(recombinant human antibody to HSP-90), NCS-683664, PU24FC1, PU-3, radicial, SNX-2112, STA-9090 VER49009 etc.

Inhibitors inhibitors of apoptotic proteins include HGS1029, GDC-0145, GDC-0152, LCL-161, LBW-242, etc.

Antibodies, loaded drugs include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE, anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC MEDI-547, SGN-19Am SGN-35, SGN-75, etc.,

Activators metabolic pathways of death receptors include antibodies or other agents that target TRAIL or death receptors (in particular, DR4 and DR5), such as apomab, conatumumab, ETR2-ST01, GDC0145, (lexatumumab), HGS-1029, LBY-135, PRO-1762 and trastuzumab.

Inhibitors include kinesin Eg5 inhibitors, such as AZD4877, ARRY-520; inhibitors CENPE, such as GSK923295A etc.

Inhibitors of JAK-2 include CEP-701 (resourcelib), XL019 and INCB018424, etc.

The MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059, etc.

The mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, inhibitors of ATP-competitive TORC1/TORC2, including PI-103, PP242, PP30, Torin 1 and so on

Non-steroidal anti-inflammatory drugs include AMIGESIC®(salsalate), DOLOBID®(diflunisal), MOTRIN®(ibuprofen), ORUDIS®(Ketoprofen), RELAFEN®(nabumetone), FLDENE ®(piroxicam), cream ibuprofen, ALEVE®(naproxen and NAPROSYN®(naproxen), VOLTAREN®(diclofenac), INDOCIN®(indomethacin), CLINORIL®(sulindac), TOLECTIN®(tolmetin), LODINE®(etodolac), TORADOL®(Ketorolac), DAYPRO®(oxaprozin), etc.

Inhibitors DERIVED include C-451, CP-673, CP-868596 etc.

Chemotherapeutic drugs based on platinum include cisplatin, ELOXATIN®(oxaliplatin), heptaplatin, lobaplatin, nedaplatin, PARAPLATIN®(carboplatin), satraplatin, picoplatin etc.

Inhibitors of Polo-like kinases include BI-2536, etc.

Inhibitors phosphoinositide-3-kinase (PI3K) include wortmannin, LY294002, XL-147, CAL-120, H-21, AEZS-127, ETP-45658, PX-866, GDC-0941, BGT226, BEZ235, XL765, etc.

Analogues of thrombospondin include ABT-510, ABT-567, ABT-898, TSP-1, etc.

The VEGFR inhibitors include AVASTIN®(bevacizumab), ABT-869, AEE-788, ANGIOZYME™ (ribosome, which inhibits the growth of blood vessels (producers - company Ribozyme Pharmaceuticals (Boulder, CO.) and Chiron, (Emeryville, CA), axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptanib), NEXAVAR®(sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib (PTK-787, ZK-222584), SUTENT®(sunitinib, SU-11248), VEGF trap, ZACTIMA™ (vandetanib, ZD-6474), GA101, ofatumumab, ABT-806 (mAb-806), ErbB3-specific antibodies, BSG2-specific antibodies, DLL4-specific antibodies and C-met-specific antibodies, etc.,

Antibiotics include intercalating antibiotics is carubicin, actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE®(bleomycin), daunorubicin, CAELYX®or MYOCET®(liposomal doxorubicin), elsamitrucin, airboren, parboil, ZAVEDOS®(idarubitsin), mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimulater, streptozocin, VALSTAR®(valrubicin), zinostatin etc.

The topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, bicategory, belotecan, BN-80915, CAMPTOSAR®(irinotecan hydrochloride), camptothecin, CARDIOXANE®(dexrazoxane), diflomotecan, edotecarin, ELLENCE®or PHARMORUBICIN®(epirubicin, etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan, mitoxantrone, oracin, parabolin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluprost, topotecan, etc.,

Antibodies include AVASTIN®(bevacizumab), CD40-specific antibodies, chTNT-1/B, denosumab, ERBITUX®(cetuximab), HUMAX-CD4®(zanolimumab), IGF1R-specific antibodies, lintuzumab, PANOREX®(edrecolomab), RENCAREX®(WX G250), RITUXAN®(rituximab), ticilimumab, trastuzumab, CD20 antibodies type I and II, etc.

Hormonal therapeutic agents include ARIMIDEX®(anastrozole), AROMASIN®(exemestane), arzoxifene, CASODEX®(bikalutamid), CETROTIDE®(cetrorelix), degarelix, deslorelin, DESOAN ®(trilostane), dexamethasone, DROGENIL®(flutamide), EVISTA®(raloxifene), AFEMA™ (fadrozole), FARESTON®(toremifene), FASLODEX®(fulvestrant), FEMARA®(letrozole), formestane, glucocorticoids, HECTOROL®(doxercalciferol), RENAGEL®(sevelamer carbonate), lasofoxifene, leuprolide acetate MEGACE®(megestrol), MIFEPREX®(mifepristone), NILANDRON™ (nilutamide), NOLVADEX®(tamoxifen citrate), PLENAXIS™ (abarelix), prednisone, PROPECIA®(finasteride), elastan, SUPREFACT®(buserelin), TRELSTAR®(releasing factor, luteinizing hormone (LHRH)), VANTAS®(implant histrelin), VETORYL®(trilostane or morestan), ZOLADEX®(forlin, goserelin), etc.

Deltoids and retinoids include seocalcitol (EB 1089, CB 1093), lexicality (KH1060), phenetidine, PANRETIN®(alitretinoin), ATRAGEN®(liposomal tretinoin), TARGRETIN®(bexarotene), LGD-1550, etc.

PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231, etc.

Plant alkaloids include, but are not agrarias, vincristine, vinblastine, vindesine, vinorelbine, etc.,

Inhibitors calpaine include VELCADE®(bortezomib), MG132, NPI-0052, PR-171, etc.,

Examples of immunological drugs include interferon and other products, strengthen the immune system. Interferons include interferon alpha,interferon alpha-2a, interferon Alfa-2b, interferon beta, interferon gamma-1a, ACTIMMUNE®(interferon gamma-1b) or interferon gamma-n1, combinations thereof, etc., Other agents include ALFAFERONE®, (IFN-α), BAM-002 (oxidized glutathione), BEROMUN®(tasonermin), BEXXAR®(tositumomab), CAMPATH®(alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), dacarbazin, denileukin, epratuzumab, GRANOCYTE®(lenograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010 (anti-CTLA-4), melanoma vaccine, mitooma, molgramostim, MYLOTARG™ (gemtuzumab ozogamicin), NEUPOGEN®(filgrastim), OncoVAC-CL, OVAREX®(oregovomab), pemtumomab (Y-muHMFGl), PROVENGE®(sipuleucel-T), sargramostim, sizofiran, azelastin, THERACYS®(Bacillus Calmette-guérin (BCG), ubenimex, VIRULIZIN®(immunotherapy drug company Lorus Pharmaceuticals), Z-100 (specific substance of Murayama (SSM)), WF-10 (tetrachlorodecaoxide (TCDO)), PROLEUKIN®(aldesleukin), ZADAXIN®(thymalfasin), ZENAPAX®(daclizumab), ZEVALIN®(90Y-ibritumomab tiuxetan), etc.

The biological reaction modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth or differentiation of tissue cells to direct them to purchase antitumor activity, and include the christening, lentinan, PPE is firan, picibanil PF-3512676 (CpG 8954), ubenimex etc.

Analogues of pyrimidine include cytarabine (ara C, or arabinoside C), cytosine arabinoside, doxifluridine, FLUDARA®(fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR®(gemcitabine), TOMUDEX®(raytraced), TROXATYL™ (triacetyluridine troxacitabine), etc.

Analogues of purine include LANVIS®(tioguanin) and PURI-NETHOL®(mercaptopurine).

Agents inhibiting the process of cell division, include batubulan, epothilone D (KOS-862), N-(2-((4-hydroxyphenyl)amino)pyridine-3-yl)-4-methoxybenzenesulfonamide, ixabepilone (BMS 247550), paclitaxel, TAXOTERE®(docetaxel), PNU100940 (109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO (synthetic epothilone), etc.

Inhibitors of ubiquitinate include MDM2 inhibitors, such as tested nutlins, inhibitors NEDD8, such as MLN4924, etc.

Compounds of the present invention can also be used as agents, polymagma sensitivity to radioactive substances that enhance the effectiveness of radiotherapy. Examples of radiotherapy include external beam radiation therapy, teletherapy, brachytherapy and radiotherapy with the use of pressurized, unpressurized source etc.

Additionally, compounds having formula (I), can be combined with other chemotherapeutics, such as ABRAXANE™ (ABI-007), ABT-100 (inhibitor farnesyltransferase is), ADVEXIN®(vaccine Ad5CMV-p53), ALTOCOR®or MEVACOR®(lovastatin), AMPLIGEN®(poly I:poly C12U, a synthetic RNA), APTOSYN®(exisulind), AREDIA®(panikanova acid), Arglabin, L-asparaginase, atamestane (1-methyl-3,17-dione-androsta-1,4-diene), AVAGE®(tazarotene), AVE-8062 (derived combretastatin), BEC2 (mutimodal), cachectin or cachectin (tumor necrosis factor), canvaxin (vaccine), CEAVAC®(cancer vaccine), CELEUK®(celmoleukin), CEPLENE®(histamine hydrochloride), CERVARIX®(vaccine human papilloma virus), CHOP®(C: CYTOXAN®(cyclophosphamide); H: ADRIAMYCIN®(hydroxydoxorubicin); O: Vincristine (ONCOVIN®); P: prednisone), CYPAT™ (cyproterone acetate), complestatin A4P, DAB(389)EGF (catalytic and translocation domains of diphtheria toxin fused via a linker His-Ala with epidermal growth factor) or TransMID-107R™ (diphtheria toxins), dacarbazine, dactinomycin, 5,6-dimethylxanthene-4-acetic acid (DMXAA), eniluracil, EVIZON™ (squalamine lactate), DIMERICINE® (liposomal lotion T4N5), discodermolide, DX-8951f (exatecan mesilate), enzastaurin, EPO906 (epitalon B), GARDASIL®(quadrivalent recombinant vaccine against human papillomavirus (types 6, 11, 16, 18)), GASTRIMMUNE®, GENASENSE®, GMK vaccine conjugate ganglioside), GVAX®(the vaccine for prostate cancer), halofuginone, histrelin, hydroxycarbamide, IBAN is Renova acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox), exotoxin IL-13-Pseudomonas, interferon-α, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide), lonafarnib, 5,10-methylenetetrahydrofolate, miltefosine (hexadecylphosphocholine), NEOVASTAT®(AE-941), NEUTREXIN®(trimetrexate the glucuronate), NIPENT®(pentostatin), ONCONASE®(the enzyme ribonuclease), ONCOPHAGE®(therapy with vaccines against melanoma), ONCOVAX®(vaccine IL-2), ORATHECIN™ (rubitecan), OSIDEM®(cell-based therapy antibodies), OVAREX®MAb (mouse monoclonal antibody), paclitaxel, PANDIMEX™ (saponin aglycone of containing ginseng 20(S)protopanaxadiol (aPPD) and 20(S) protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (experimental drug, the cancer vaccine), pegaspargase, PEG interferon A, phenoxodiol, procarbazine, ropemaster, REMOVAB® (catumaxomab), REVLIMID®(lenalidomide), RSR13 (efaproxiral), SOMATULINE®LA (untreated), SORIATANE® (acitretin), staurosporine (Streptomyces staurospores), talabostat (PT100), TARGRETIN®(bexarotene), TAXOPREXIN®(DHA-paclitaxel), TELCYTA®(infospeed, TLK286), timelife, TEMODAR®(temozolomide), tesmilifene, thalidomide, THERATOPE®(STn-KLH), thymitaq (2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)hintline the dihydrochloride), TNFERADE™ (media adenovector: DNA, containing the gene for tumor necrosis factor α), TRACLEER®or ZAVESCA®(bosentan), is tretinoin (retin-A), tetrandrine, TRISENOX®(arsenic trioxide), VIRULIZIN®, Ukraine (provodnye of alkaloids from plants of the great celandine), vitaxin (antibody against alphavbeta3), XCYTRIN®(motexafin gadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex), YONDELIS®(trabectedin), ZD-6126, ZINECARD®(dexrazoxane), ZOMETA®(zolendronate acid), zorubicin etc.

Data

Determining the suitability of the compounds of formula (I) as agents that bind to anti-apoptotic proteins Bcl-2 and inhibit them, are performed using analysis by the method of resonance energy transfer fluorescence time-resolved (TR-FRET). Antibody Tb-anti-GST acquire the company Invitrogen (catalog number PV4216).

Synthesis of probes

All reagents, unless otherwise stated, is used in the form in which they are received from the manufacturer. Reagents for the synthesis of peptides, including diisopropylethylamine (DIEA), dichloromethane (DCM), N-organic (NMP), hexaflurophosphate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (HBTU), N-hydroxybenzotriazole (HOBt) and piperidine obtained from the company Applied Biosystems, Inc. (ABI), Foster City, CA or American Bioanalytical, Natick, MA. Pre-filled cartridges 9-fluorenylmethoxycarbonyl(Fmoc)-amino acid (Fmoc-Ala-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Phe-OH, Fmoc-GIy-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Met-OH, Fmoc-Asn(Trt)-OH, Fmoc-Pro-OH, Fmor-Gln(Trt)-OH, moc-Arg(Pbf)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH) obtained from the ABI or Anaspec, San Jose, CA. Resin for peptide synthesis (resin Fmoc-Rink amide MBHA) and Fmoc-Lys(Mtt)-OH get from Novabiochem, San Diego, CA. Monoitor complex Succinimidyl ether 6-carboxyfluorescein (6-FAM-NHS) are obtained from Anaspec. Triperoxonane acid (TFA) are obtained from Oakwood Products, West Columbia, SC. Thioanisole, phenol, triisopropylsilane (TIS), 3,6-dioxa-1,8-octanedithiol (DODT) and isopropanol receive from the company Aldrich Chemical Co., Milwaukee, WI. Mass spectra of matrix-assisted laser desorption/ionization (MALDI-MS) register in the device Applied Biosystems Voyager DE-PRO MS). Mass spectra when elektrorazpredelenie (ESI-MS) register in the device Finnigan SSQ7000 (Finnigan Corp., San Jose, CA) in either positive or negative ions.

A General method of carrying out solid-phase synthesis of peptides (PPPS)

Peptides are synthesized using no more than 250 mmol. pre-filled resin Wang to the reactor in an automatic peptide synthesizer ABI 433A conducting cycles of condensation in the scale 250 mmol. Fastmoc™. Use pre-filled cartridges containing 1 mmol standard Fmoc-amino acids, except for the position of attachment of fluorophores, where the cartridge is placed 1 mmol Fmoc-Lys (Mtt)-OH, by the control method feedback conductivity. N-terminal acetylon is of spend in the cartridge, using 1 mmol of acetic acid, under standard conditions the condensation reaction.

Remove 4-methyltricyclo (Mtt) of lysine

The pitch of the synthesizer thrice washed with dichloromethane and keep moist. Then through the resin for 30 min insure flow of 150 ml of a mixture of 95:4:1 dichloromethane:triisopropylsilane:triperoxonane acid. The mixture becomes a dark yellow color, and then becomes pale yellow. Through the layer of resin over 15 min pass current 100 ml of N,N-dimethylformamide. Then the resin is washed three times with N,N-dimethylformamide and filtered. Tests using ninhydrin shows a strong signal of the primary amine.

Drawing on resin tag 6-carboxyfluorescein-NHS (6-FAM-NHS)

The resin is treated with 2 equivalents of 6-FAM-NHS in 1% solution of DIEA/N,N-dimethylformamide and stirred or shaken overnight at ambient temperature. After the resin dried, washed three times with N,N-dimethylformamide, washed three more times (1×DCM and 1×methanol) and dried, obtaining a resin orange color, which gives a negative reaction with ninhydrin.

A General method to detach and remove protection from attached to the resin peptide

Peptides otscheplaut from the resin by shaking for 3 h at ambient temperature in the cleavage cocktail for containing 80% TFA, 5% water, 5% thioanisole, 5% of the Enola, a 2.5% TIS and 2.5% TDT (1 ml / 0.1 g resin). The resin is removed by filtration and washed twice TFA. TFA from the filtrate evaporated and the product precipitated with ether (10 ml per 0.1 g resin), is removed by centrifugation, washed twice with ether (10 ml per 0.1 g resin) and dried, obtaining the crude peptide.

A common method of purification of peptides

Crude peptides are purified using HPLC system Gilson company, using the analysis software Unipoint®(Gilson, Inc., Middleton, WI), on a column filled with technology radial compression, which includes two segments 25×100 mm, filled with particles of a Delta-Pak™ C18 15 μm and a pore size 100Å, and elution is performed using one of the following methods for gradient elution. In the process of cleaning one injection take from one to two milliliters of the crude peptide solution (10 mg/ml in 90% DMSO/water). The peaks containing the product(s) from each run, unite and lyophilized. All preparative work cycles carried out with a feed rate of 20 ml/min, using elution buffer A is 0.1% TFA - water and buffer B: acetonitrile.

General methodology for preparative HPLC

Analytical HPLC is carried out in the system Hewlett-Packard 1200 series diode array detector and fluorescence detector Hewlett-Packard 1046A using version A. 03.04 software 3D HPLC ChemStation (Hewlett-Packard, Palo Alto, CA) 4.6×250 mm Colo is ke YMC, filled with particles of ODS-AQ 5 μm and pores 120Å, and elution is performed using one of the following methods gradient elution after pre-elution in the initial conditions for 7 minutes as solvents for elution using buffer A is 0.1% TFA-water and buffer B: acetonitrile. Volumetric flow rate for all gradients is 1 ml/min

F-Bak:Peptide probe acetyl-(SEQ ID NO: 1)GQVGRQLAIIGDK(6-FAM)-(SEQ ID NO: 2) INR-NH2

Resin Fmoc-Rink amide MBHA extend, using the General methods of synthesis of peptides, getting protected is associated with the resin peptide (1,020 g). The Mtt group is removed, enter the label 6-FAM-NHS, otscheplaut and protection is removed, as indicated above, give crude product as a solid orange color (0,37 g). The resulting product was then purified by HPLC (c reversed-phase (RP-HPLC). Fractions from the main peak investigate method analytical RP-HPLC, pure fractions isolated and lyophilized of the main peak gain is indicated in the name of the connection (0,0802 g) as a solid yellow; MALDI-MS m/z=2137,1 [(M+H)+].

Alternative synthesispeptide probe F-Bak: acetyl-(SEQ ID NO: 1)GQVGRQLAIIGDK(6-FAM)-(SEQ ID NO: 2) INR-NH2

Containing the protected peptide is placed on a 0.25 mmol of resin Fmoc-Rink amide MBHA (Novabiochem) in an automatic peptide synthesizer Applied Biosystems 433A and carry out cycles of condensation Fastmoc™, ISOE is isua pre-filled with 1 mmol amino acid cartridges except labeled with fluorescein (6-FAM) lysine where the cartridge is placed 1 mmol Fmoc-Lys(4-methyldecyl). N-terminal acetyl group is administered by placing 1 mmol of acetic acid in the cartridge and carrying out the condensation, as described above. Selective removal of 4-methyltricyclo group carried out using a solution of 95:4:1 DCM:TIS:TFA (about./about./vol.), which is passed through the resin for more than 15 min, and then quenched with a stream of dimethylformamide. Monoitor 6-carboxyfluorescein-NHS enter into interaction with the side chain of lysine in a 1% solution of DIEA in N,N-dimethylformamide, and the end of the process is confirmed by a test with ninhydrin. Peptide otscheplaut from the resin, remove the protection of the side chains by treatment with a mixture of 80:5:5:5:2,5:2,5 TFA/water/phenol/thioanisole/triisopropylsilane: 3,6-dioxa-1,8-octanedithiol (about./about./about./about./about./about), and the crude peptide is extracted by precipitation in diethyl ether. The crude peptide is purified by high-performance liquid chromatography with reversed phase, and its purity and identity confirm analytical high-performance liquid chromatography with reversed phase and mass spectrometry according to the method of matrix-assisted laser desorption/ionization (m/z=2137,1 ((M+H)+)).

Analysis by the method of resonance energy transfer fluorescence time-resolved (TR-FRET)

Individual compounds are serially diluted in d is methylsulfoxide (DMSO), starting with a concentration of 50 μm (2× initial concentration; 10% DMSO) and 10 μl transferred to a 384-well plate. Then to each well add 10 ál of a mixture of protein/probe/antibody to a final concentration shown in table 1. Then the samples are mixed on a shaker for 1 min and incubated for additional 3 h at room temperature. For each analysis is performed adding the probe/antibody and protein/probe/antibody administered at each analytical tablet as negative and positive control, respectively. Fluorescence is measured on the device Envision (Perkin Elmer) using excitation filter 340/35 nm, and emission filters 520/525 (peptide F-Bak) and 495/510 nm (containing Tb-tag antibody against histidine) emission filters. The inhibition constants (Ki) given below in table 2, and they are determined using equation Wang (Wang Z.-X. An Exact Mathematical Expression for Describing Competitive Binding of Two Different Ligands to a Protein Molecule. FEBS Lett.1995, 360:111-4).

Table 1
Protein probe and antibody used in the analysis of the TR-FRET
ProteinProbeProtein (nm)Probe (nm)Ant is a body Antibody (nm)
GST-Bcl-2F-Bak peptide probe acetyl-(SEQ ID NO: 1)GQVGRQLAIIGDK(6-FAM)-(SEQ ID NO: 2 INR-amide)1100Tb-anti-GST1
6-FAM = 6-carboxyfluorescein; Tb = terbium; GST = glutathione-S-transferase

Table 2
TR-FRET binding: Ki (μm) for Bcl-2
Example No.TR-FRET binding: Ki (μm) for Bcl-2Example No.TR-FRET binding: Ki (μm) for Bcl-2
10,051449250,372106
20,082918260,393356
30,051702270,433996
50,176183280,417285
6 0,703735290,339986
70,000084300,269175
80,000064310,138755
90,000307320,43792
100,743178330,000649
110,177064340,001791
120,392534350,002067
130,387693360,293805
140,408575390,020238
150,282112400,000407
160,03785941 0,000053
170,356257420,000039
180,128531430,046497
190,234118440,024776
200,048076450,0067348
220,188226460,0017502
230,447133470,020416
240,3421480,001637

The inhibition constant (Ki) represents the dissociation constant of the complex enzyme-inhibitor or protein molecule/small molecule, small molecule inhibits the binding of one protein with another protein. Thus, a large value of Kiindicates low affinity binding, and a small value of Kiindicates a high affinity of binding.

Table 2 shows data on the constants is ingibirovaniya for inhibition of binding of the peptide probe Bak BH3 protein Bcl-2, and they show that the compounds of the present invention have high affinity binding to the antiapoptotic protein Bcl-2. Thus, assume that these compounds are suitable for treating diseases during which is expressed anti-apoptotic proteins Bcl-2.

It is expected that as the compounds having formula I, are associated with Bcl-2, they are also suitable as binders for anti-apoptotic proteins with close structural homology to Bcl-2, such as, for example, anti-apoptotic proteins Bcl-XL, Bcl-w, Mcl-1 and Bfl-1/A1.

The involvement of the protein Bcl-2 in the development of bladder cancer, brain cancer, breast cancer, cancer, bone marrow cancer, cervical region, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, leukemia, called T-lymphocytes or b-cells, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, lung cancer, prostate cancer, small-cell lung cancer, prostate cancer, cancer of the spleen, etc. described in the concurrently pending application PCT US 2004/36770, published as WO 2005/049593, and PCT application US 2004/37911, published as WO 2005/024636.

The involvement of the protein Bcl-2 in immune and autoimmune diseases are described in theCurrent Allergy and Athma Reports 2003, 3, 378-384;British Journal ofHaematology2000,110(3), 584-90;Blood2000, 95(4), 1283-92; andNew England Journal of Medicine2004, 351(14), 1409-1418.

The involvement of the protein Bcl-2 in the development of arthritis are disclosed in pending provisional patent application U.S. No. 60/988479.

The involvement of the protein Bcl-2 in the rejection of bone marrow transplant disclosed in pending application for U.S. patent No. 11/941196.

Overexpression of proteins Bcl-2 correlates with resistance to chemotherapy and clinical outcome, disease progression, General forecast of the further course of the disease or their combinations with different types of cancer and disorders of the immune system. Cancers include, but are not agrarias, hematological and solid tumor types, such as acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-lymphocytic leukemia, basal cell carcinoma, carcinoma of the bile ducts, bladder cancer, brain cancer, breast cancer (including breast cancer with positive estrogenreceptor status), bronchogenic carcinoma, Burkitt's lymphoma, cancer of the cervical region, chondrosarcoma, chordoma, horiokartsinoma, chronic leukemia, chronic the ski lymphocytic leukemia, chronic miliitary (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, deproliferation changes (dysplasia and metaplasia), the embryonic carcinoma, endometrial cancer, ehotelier.com, ependymoma, carcinoma of the epithelium, erythroleukemia, esophageal cancer, breast cancer with positive estrogenreceptor status, hereditary thrombocythemia, abnormal Ewing tumor, fibrosarcoma, gastric cancer, a tumor of germ cells of the testes caused by pregnancy USSR tumor, glioblastoma, head and neck cancer, disease, heavy chains, hemangioblastoma, hepatoma, hepatocellular cancer, hormone-insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer (including small cell lung cancer and non-small cell lung cancer), lymphangiectasia-sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (lymphoma, including diffuse In both lymphoma, follicular lymphoma, Hodgkin's lymphoma and nahodkinskuju lymphoma), malignant disease and hyperproliferative diseases of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, malignant disease, called T-lymphocytes or b-cells, leukemia, medullar what I carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, peripheral T-lymphocytic lymphoma, pinealoma, polycythemia Vera, prostate cancer (including hormone-insensitive (resistant) prostate cancer), rectal cancer, renal cell cancer, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland cancer, seminoma, skin cancer, small cell carcinoma of the lung, solid tumors (carcinomas and sarcomas), stomach cancer, squamous cell carcinoma, sinovioma, cancer of the sweat glands, testicular cancer (including tumor germ cells of the testes), thyroid cancer, macroglobulinemia waldenstrom, tumors of the testes, uterine cancer, Wilms tumor, etc.

It is also expected that compounds having formula (I) inhibit the growth of cells expressing Bcl-2, obtained from the children's cancer or tumor, including the embryonic rhabdomyosarcoma, childhood acute lymphoblastic leukemia, childhood acute myelogenous leukemia, children alveolar rhabdomyosarcoma, childhood the anaplastic ependymoma, childhood both anaplastic lymphoma, baby the anaplastic medulloblastoma, atypical children, teratoid/Palookaville is a tumor of the Central nervous system, children biphenotypic acute leukemia, pediatric Burkitt's lymphoma, childhood cancers from tumors of abnormal Ewing family, such as primitive neuroectodermal tumors, children diffuse anaplastic Wilms tumor, children Wilms tumor with favorable histological structure, pediatric glioblastoma, pediatric medulloblastoma, pediatric neuroblastoma, myelocytomatosis caused pediatric neuroblastoma, childhood pre-B-cell cancers (such as leukemia), children with osteosarcoma, children rhabdoid kidney tumor, pediatric rhabdomyosarcoma, and children's T-lymphocytic cancer, such as lymphoma and skin cancer, etc.,

Autoimmune disorders include acquired immunodeficiency syndrome (AIDS), autoimmune lymphoproliferative syndrome, hemolytic anemia, inflammatory diseases, and thrombocytopenia, acute or chronic immunopathological disease associated with organ transplantation, Addison disease, allergic disease, alopecia, alopecia alopecia, atheromatous disease/arteriosclerosis, atherosclerosis, arthritis (including osteoarthritis, juvenile chronic arthritis, septic arthritis, Lyme arthritis, psoriatic arthritis and reactive arthritis), autoimmune bullous disease, abetalipoproteinemia, diseases, related to the acquired immunodeficiency wired the e organ transplantation acute immunopathological disease purchased acrocyanosis, acute and chronic parasitic or infectious processes, acute pancreatitis, acute renal failure, acute rheumatic fever, acute transverse myelitis, adenocarcinoma, atrial ectopic beats, (acute) respiratory distress syndrome in adults, complex, AIDS-dementia, alcoholic cirrhosis, alcohol-induced liver disease, alcohol-induced hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allergies, asthma, allograft rejection, lack of alpha-1-antitrypsin deficiency, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, angina, associated with ankylosing spondylitis lung disease, degeneration of anterior horn cells of the spinal cord antibody-mediated cytotoxicity, antiphospholipid syndrome, allergic reactions to protivozachatochnye antibodies, aortic aneurysm and peripheral vascular, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, arthropathy, fatigue, asthma, ataxia, atopic Allergy, atrial fibrillation (persistent or paroxysmal AF), atrial flutter, atrioventricular blockade, atrophic autoimmune hypothyroidism, autoimmune hemolytic anemia, autoimmune hepatitis,autoimmune hepatitis type 1 (classical autoimmune or lipoid hepatitis), autoimmune-mediated hypoglycemia, autoimmune neutropenia, autoimmune thrombocytopenia, autoimmune disease of the thyroid gland, b-cell lymphoma, rejection, bone graft rejection of bone marrow transplant (BMT), obliterative bronchiolitis, interventricular blockade, burns, cachexia, cardiac arrhythmia syndrome temporary cardiac arrest, cancer of the heart, cardiomyopathy, inflammatory response in the artificial circulation, graft rejection cartilage, cerebellar cortical degeneration, cerebellar disorder, chaotic or multichrome atrial tachycardia associated with chemotherapy disorders, chlamydia, heliostat, chronic alcoholism, chronic active hepatitis, chronic fatigue syndrome, chronic immune disease associated with organ transplantation, chronic eosinophilic pneumonia, chronic inflammatory pathologies, chronic mucocutaneous candidiasis, chronic obstructive pulmonary disease (COPD), chronic salicylate intoxication, cancer of the colon and rectum, the total transient immunodeficiency (common transient hypogammaglobulinemia), conjunctivitis, associated with a disease of connective tissue, interstitial lung disease, contact dermatitis, positively the Yu hemolytic anemia of Coombs, pulmonary heart disease Creutzfeldt-Jakob disease, cryptogenic autoimmune hepatitis, cryptogenic fibrosing alveolitis, is negative in the culture of sepsis, cystic fibrosis, disorders associated with therapy with cytokines, Crohn's disease, dementia boxers, demyelinating diseases, Dengue hemorrhagic fever, dermatitis, dermatitic scleroderma, dermatological conditions associated with dermatomyositis/polymyositis lung disease, diabetes, diabetic arteriosclerotic disease, diabetes mellitus, a disease with diffuse calves Levi, dilated cardiomyopathy, dilated congestive cardiomyopathy, discoid lupus erythematosus, disorders of the basal ganglia, disseminated intravascular coagulation, down's syndrome in middle age, drug-induced tool interstitial lung disease induced drug hepatitis induced by drugs of movement disorders that are caused by drugs that block dopamine receptors in the Central nervous system, sensitivity to drugs, eczema, encephalomyelitis, endocarditis, endocrinopathy, enteropathic synovitis, epiglottitis, infection with Epstein-Barr, erythromelalgia, extrapyramidal and cerebellar violations, family g is metaforically lymphocytic histiocytosis, rejection of the implant embryonic thymus, ataxia, functional peripheral arterial disorders, female infertility, fibrosis, vibrationthe lung disease, fungal sepsis, gas gangrene, gastric ulcer, giant cell arteritis diagnostics, glomerulonephritis, glomerulonephritides syndrome?, goitrous autoimmune hypothyroidism (Hashimoto's disease), gouty arthritis, graft rejection of any organ or tissue, graft-versus-host, gram-negative sepsis, gram positive sepsis, granulomas caused by intracellular organisms, streptococcal infection group B (GBS), graves ' disease associated with hemosiderosis disease of the lungs, vaccinations leukemia, hairy cell leukemia, a disease of Hallervorden-Spitze, Hashimoto's thyroiditis, hay fever, graft rejection hearts, hemochromatosis, hematopoietic malignant diseases (leukemia and lymphoma), hemolytic anemia, hemolytic uremic syndrome/thrombolytic thrombocytopenic purple, bleeding, disease Seleina's disease, hepatitis A, hepatitis B, hepatitis C, HIV infection/HIV neuropathy, Hodgkin's disease, hypoparathyroidism, horey's disease, hyperkinetic movement disorders, allergic reactions, allergic pneumonitis, hypertonia is, hypokinetic movement disorders, the diagnosis of hypothalamic-pituitary-adrenal axis, idiopathic Addison disease, idiopathic leukopenia, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia, idiosyncratic liver disease, childhood spinal muscular atrophy, infectious diseases, inflammation of the aorta, inflammatory bowel disease, insulin dependent diabetes mellitus, interstitial pneumonitis, iridocyclitis/uveitis/optic neuritis, ischemic/reperfusion injury, ischemic stroke, juvenile pernicious anaemia, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma, Kawasaki disease, transplant rejection of kidney, infection with Mycobacterium Legionella, leishmaniasis, leprosy, damage corticospinal system, IgA-dependent linear dermatosis, lipedema, graft rejection liver, Lyme borreliosis, lymphedema, lymph edema in lung disease, malaria, unidentified or unspecified male infertility, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, microscopic vasculitis of the kidneys, migraine headache, mitochondrial multi-system disorder, disease mixed connective tissue associated with the disease mixed connective the tissue lung disease, the monoclonal gammopathy, multiple myeloma, multiple system degeneration (a disease of Menzel, disease Dejerine-Thomas, disease, Shi-Drager, and disease Machado-Joseph), myalgic encephalitis/chronic fatigue syndrome, heavy pseudoparalysis myasthenia, microscopic vasculitis of the kidneys, Mycobacterium avium complex, tubercle Bacillus, myelodysplasia syndrome, myocardial infarction, ischemic disorders of the myocardium, carcinoma of the nasopharynx, chronic lung disease of the newborn, nephritis, nephrosis, nephrotic syndrome, neurodegenerative diseases, neurogenic I muscular atrophy, neurogenic fever, non-alcoholic steatohepatitis, occlusion of the abdominal aorta and its branches, occlusal blood disorders, transplant rejection bodies, orchitis/epididymitis, post-treatment of orchitis/vasectomy, organomegaly, osteoarthritis, osteoporosis, loss of ovarian function, graft rejection of the pancreas, parasitic diseases, graft rejection parathyroid cancer, Parkinson's disease, an inflammatory disease of the renal pelvis, utricularia vulgaris, the leaf bladderwort, pemphigoid, rhinitis, diseases of the pericardium, peripheral atherosclerotic disease, peripheral vascular disorders, peritonitis, pernici the EIT anemia, phacogenic uveitis, interstitial ploskokletochnyi pneumonia, pneumonia syndrome Crowe-Fukase (POEMS) (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and syndrome with lesion of the skin), postperfusion syndrome, potentiality syndrome, postcardiotomy syndrome after myocardial infarction, post-infectious interstitial lung disease, premature loss of ovarian function, primary biliary cirrhosis, primary sclerosing hepatitis, primary myxedema, primary pulmonary hypertension, primary sclerosing cholangitis, primary vasculitis, progressive supranuclear paralysis, psoriasis, psoriasis type 1, psoriasis type 2, the psoriatic arthropathy, pulmonary hypertension, secondary to connective tissue disease, pulmonary manifestation nadeznogo of polyarteritis, postinflammatory interstitial lung disease, radiation fibrosis, radiation therapy, phenomenon and Raynaud's disease, Raynaud's disease, a disease of Resume, tachycardia with regular narrow QRS complexes-teeth, disease, Reiter, unspecified kidney disease, renovaskulyarnoy hypertension, reperfusion injury, restrictive cardiomyopathy, associated with rheumatoid arthritis interstitial lung disease, rheumatoid spondylitis, sarcoidosis syndrome Schmidt, scleroderma, canopy is inuu horey, senile dementia associated with calves Levi, sepsis syndrome, septic shock, seronegative arthropathies, shock, sickle cell anemia, associated with a disease Sjogren lung disease, Sjogren syndrome, allograft rejection, skin, syndrome with lesion of skin graft rejection of the small intestine, autoimmunity sperm, multiple sclerosis (all subtypes), spinal ataxia, spinal-cerebellar degeneration, spondyloarthropathy, spondyloarthropathy, sporadic pluriglandular failure type I, pluriglandular deficiency type II, of still's disease, streptococcal myositis, stroke, structural damage to the cerebellum, subacute sclerosing panencephalitis, metastatic ophthalmia, fainting, cardiovascular syphilis, systemic anaphylaxis, systemic inflammatory syndrome reactions, systemic juvenile rheumatoid arthritis, systemic lupus erythematosus associated with systemic lupus erythematosus lung disease, systemic sclerosis associated with systemic sclerosis interstitial lung disease, T-cell or acute lymphocytic leukemia (FAB classification), Takayasu's disease/arteritis diagnostics, telangiectasia, Th2 type and Th1 type mediated diseases, obliterating thromboangiitis, thrombocytopenia, thyroiditis, toxicity, toxic syndrome sho is a, transplants, trauma/hemorrhage, autoimmune hepatitis type-2 (hepatitis C antibody against LKM), insulin resistance type with a black acanthosis, allergic reactions type III, type IV allergies, arthropathy, ulcerative colitis, ulcerative colitis, unstable angina, uremia, urosepsis, urticaria, uveitis, valvular heart disease, varicose veins, vasculitis, masculine diffuse lung disease, venous diseases, venous thrombosis, ventricular fibrillation, vitiligo, acute liver disease, viral and fungal infections, acute encephalitis with damage to vital functions/aseptic meningitis, hemophagocytosis syndrome, associated with a high risk of death, Wegener's granulomatosis syndrome Wernicke-Korsakov, Wilson disease, xenograft rejection of any organ or any fabric, Yersinia and associated with the Salmonella arthropathy, etc.

Schemes and experiments

The following abbreviations have the indicated values. ADDP means 1,1'-(azodicarbon)dipiperidino; AD-mix-β means a mixture of (DHQD)2PHAL, K3Fe(CN)6, K2CO3and K2SO4; 9-BBN means 9-borabicyclo(3.3.1)nonan; Boc means tert-butoxycarbonyl; (DHQD)2PHAL means hydroxypyridine 1,4-phthalazinedione diethyl ether; DBU means 1,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL means on Isobutyraldehyde; DIEA means diisopropylethylamine; DMAP means N,N-dimethylaminopyridine; DMF DMF means N,N-dimethylformamide; dmpe means 1,2-bis(dimethylphosphino)ethane; DMSO means dimethylsulfoxide; dppb means 1,4-bis(diphenylphosphino)butane; dppe means 1,2-bis(diphenylphosphino)ethane; dppf means 1,1'-bis(diphenylphosphino)ferrocene; dppm means 1,1-bis(diphenylphosphino)methane; EDAC-HCl means of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; Fmoc means fluorenylmethoxycarbonyl; HATU means hexaphosphate O-(7-asobancaria-1-yl)-N,N',N',N'-tetramethylurea; HMPA means hexamethylphosphoramide; IPS means isopropyl alcohol; MP-BH3means the macroporous triethylammonium metropolitical cyanoborohydride; TEA means triethylamine; TFA means triperoxonane acid; THF means tetrahydrofuran; NCS means N-chlorosuccinimide; NMM means N-methylmorpholine; NMP means N-organic; PPh3means triphenylphosphine.

The following schemes are shown to provide the authors of the present invention, the most useful and the most understandable description of the methodologies and conceptual aspects of the present invention. Compounds of the present invention can be obtained using methods of chemical synthesis, examples of which are given in the present description. It should be understood that the order of stages in the process can b the th different, and that the reagents, solvents and conditions of the reactions can be replaced by those that are specifically listed, and you should also understand that the affected fragments can be, if necessary, protected and exempt from protection.

Scheme 1

The compounds of formula (4) can be obtained as shown in SCHEME 1, and can be used as shown in scheme 8, to obtain the compounds of formula (I), which are representative of compounds of the present invention. The compounds of formula (I), where R represents alkyl, can be converted into compounds of the formula (2) using reagent Z3L1MgX1where X1represents a halogen atom, in this solvent, however, it does not agrarias as a simple ether or tetrahydrofuran. The compounds of formula (3) can be obtained from compounds of the formula (2) using a strong base such as NaH and R57X2where X2represents a halogen atom, and a value of R57described in this description. Once the compounds of formula (3) is treated with an aqueous solution of NaOH or LiOH, get the compounds of formula (4).

Scheme 2

As shown in scheme 2, compounds of formula (5) can interact with the compounds of the formula (6) and a reducing agent to form compounds f is rmula (7). Examples of reducing agents include sodium borohydride, cyanoborohydride sodium, triacetoxyborohydride sodium, grafted to the polymer cyanoborohydride, etc., the Reaction is typically carried out in this solvent, however, it does not agrarias as methanol, tetrahydrofuran and dichloromethane or mixtures thereof. The compounds of formula (8) can be obtained from compounds of formula (7), as indicated in figure 1, and can be used as described in scheme 8, to obtain the compounds of formula I.

Scheme 3

Of the compounds of the formula (9), if they enter into reaction with the compound of the formula (10), where X is a halide or triflate, and the basis on which it is possible to obtain the compounds of formula (11). Bases suitable for the reaction include triethylamine, diisopropylethylamine, etc. of Compounds of formula (13), where the value of Y given in this description for substituents at Z3can be obtained from compounds of formula (11) and compounds of formula (12) under the conditions of condensation Suzuki, renowned experts from the field of technology and readily available from the literature. The compounds of formula (14) can be obtained from compounds of formula (13), as indicated in figure 1, and can be used as described in SCHEME 8, to obtain the compounds of formula I.

Scheme 4

As shown in scheme 4, compounds of formula (17) can be obtained from the joining of the formula (15) and compounds of formula (16), where R is an alkyl, and a value of R38described in this description, the terms condensation Suzuki, renowned experts from the field of technology and readily available from the literature. The compounds of formula (17) can be restored in the compounds of formula (18) using a reductant such as LiAlH4in this solvent, however, it does not agrarias as diethyl ether or THF. The compounds of formula (19) can be obtained from compounds of formula (18) using periodinane dessa-Martin or in the conditions of the oxidation reaction Swarna, well-known experts from the field of technology and readily available from the literature. The compounds of formula (19) can interact with the compound of the formula (5) and a reducing agent to obtain compounds of the formula (20). Examples of reducing agents include sodium borohydride, cyanoborohydride sodium, triacetoxyborohydride sodium, grafted to the polymer cyanoborohydride, etc., the Reaction is usually carried out in this solvent, however, it does not agrarias as methanol, tetrahydrofuran, 1,2-dichloroethane and dichloromethane, or a mixture thereof. The compounds of formula (21) can be obtained from compounds of formula (20), as indicated in figure 1, and can be used as described in SCHEME 8, to obtain the compounds of formula I.

Scheme 5

As shown in scheme 5, compounds of formula (22), where R is sobiecki, can be converted into compounds of formula (23) by the reaction of the first specified connection, where X1represents Cl, Br, I or CF3SO3-and the compounds of formula R41-OH and catalyst in the presence or in the absence of base. Examples of catalysts include complex triftoratsetata copper(I) toluene, PdCl2Pd(OAc)2and Pd2(dba)3. The first examples of the base include triethylamine, N,N-diisopropylethylamine, Cs2CO3, Na2CO3, K3PO4and mixtures thereof.

The compounds of formula (22) can also be converted into compounds of formula (23) by the reaction of the first specified connection, where X1represents Cl, F or NO2and the compounds of formula R41-OH with the first base. The first examples of the base include triethylamine, N,N-diisopropylethylamine, Cs2CO3, Na2CO3, K3PO4and mixtures thereof.

Scheme 6

The compounds of formula (18) can enter into interaction with methylchloride and a base, such as, but not agrarias, triethylamine, followed by treatment of N-tert-butoxycarbonylamino obtaining compounds of formula (24). The compounds of formula (25) can be obtained by the reaction of compounds of formula (24) with triethylsilane and triperoxonane acid. The compounds of formula (25) can be inserted into usaimage is due with the compound of the formula (26) and HK 2PO4and to obtain the compounds of formula (27), in this solvent, however, it does not agrarias as dimethyl sulfoxide. The compounds of formula (28) can be obtained from compounds of formula (27), as indicated in figure 1, and can be used as described in scheme 8, to obtain the compounds of formula I.

Scheme 7

As shown in scheme 7, compounds of formula (1) you can enter into interaction with the corresponding triphenylphosphonium formulas (29) and a base such as, but not agrarias as sodium hydride or n-utility, and to obtain the compounds of formula (30). The reaction is usually conducted in a solvent such as THF or DMSO. The compounds of formula (31) can be obtained from compounds of formula (30), as indicated in figure 1, and can be used as described in scheme 8, to obtain the compounds of formula I.

Scheme 8

As shown in scheme 8, compounds of formula (32), which can be obtained, as specified in this description can be transformed into compounds of formula (33) in the first reaction of the compounds with ammonia. The compounds of formula (33) can be transformed into compounds of formula (I) interaction of the first specified connection with compounds of formula(4), (8), (14), (21), (28), (31) or (37) and a condensing agent in the presence or in the absence of base. Examples of condenser the common agents include hydrochloride, 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide, 1,1'-carbonyldiimidazole and hexaphosphate benzotriazol-1-ilexibility. The first examples of the bases include triethylamine, N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, and mixtures thereof.

Scheme 9

The compounds of formula (33), obtained as described in SCHEME 1, can also be converted into compounds of formula (I) by the reaction of the first specified compounds and compounds of the formula (34) and first base. The first examples of the base include, but are not agrarias, triethylamine, N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, and mixtures thereof.

Scheme 10

As shown in scheme 10, compounds of formula (35), where L represents a simple bond, alkyl, O, S, S(O), S(O)2, NH, and so on, can react with compounds of formula (36) to form compounds of formula (37). The reaction is usually carried out at elevated temperatures in this solvent, however, it does not agrarias as dimethyl sulfoxide, and you may need to use a base, such, however, this is not agrarias as potassium phosphate, potassium carbonate, etc., the compounds of formula (38) can be obtained from compounds of formula (37), as indicated in figure 1, and can be used as described in SCHEME 8, to obtain the compounds of formula I.

Scheme 11

The compounds of formula (39), DG is the value of Y is specified herein for substituents at Z 3can be obtained from compounds of formula (39A), where X is a halide or triflate, and Y-B(OH)2in the conditions of the condensation reaction Suzuki, renowned experts from the field of technology and readily available from the literature. The compounds of formula (39) can enter into interaction with tert-butyl piperazine-1-carboxylate and a reducing agent, such as triacetoxyborohydride sodium, and to obtain the compound of formula (40). The reaction is usually carried out in this solvent, however, it does not agrarias as methylene chloride. The compounds of formula (41) can be obtained from the compounds of formula (40) by reaction of the latter with a compound R57X, where X is a halide, and NaH in a solvent such as N,N-dimethylformamide, and then the resulting material can be treated with triethylsilane and triperoxonane acid in dichloromethane. The compounds of formula (41) can be used, as shown in scheme 10, where L1-Z3shown in the formula (41).

Scheme 12

As shown in scheme 12, a substituted piperazine-2-it, where R57represents alkyl, you can enter into interaction with the compounds of the formula (6) and a reducing agent, such as triacetoxyborohydride sodium in dichloromethane, to obtain the compounds of formula (42). The compounds of formula (42) can be restored in the compounds of formula (43) using this in the of stanovites, however, this is not agrarias as alumalite lithium, in this solvent, however, it does not agrarias as tetrahydrofuran. The compounds of formula (43) can be used, as shown in scheme 10, where L1-Z3shown in the formula (43).

The following examples are given to provide the authors of the present invention, the most useful and the most understandable description of the methodologies and conceptual aspects of the present invention. Separate connections are called in accordance with ACD/ChemSketch Version 5.06 (05 June, 2001, Advanced Chemistry Development Inc., Toronto, Ontario) or ChemDraw®Ver. 9.0.5 (CambridgeSoft, Cambridge, MA). Intermediate compounds referred to in accordance with ChemDraw®Ver. 9.0.5 (CambridgeSoft, Cambridge, MA).

EXAMPLE 1

4-[4-(Cyclohexylmethyl)-4-methoxypiperidine-1-yl]-N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}benzamide

EXAMPLE 1A

(R)-Benzyl 4-(dimethylamino)-1-hydroxy-4-oxobutyl-2-ylcarbamate

A solution of 3-(S)-((carbobenzoxy)amino)-γ-butyrolactone (receive in accordance with the methodology described in McGarvey, G. J.; Williams, J. M.; Hiner, R. N.; Matsubara, Y.; Oh, T., J. Am. Chem. Soc.,1986, 108, 4943-4952, 7,72 g) in THF (100 ml) saturated with gaseous dimethylamine, stirred at room temperature for 16 h and concentrated. The residue is filtered through a layer of silica gel, elwira 50% solution of acetone in hexane, and get the desired product

Example 1V

(R)-Benzyl 4-(dimethylamino)-4-oxo-1-(phenylthio)butane-2-ylcarbamate

A solution of the compound from example 1A (8,45 g) in toluene (15 ml) is treated with tributylphosphine (9,76 ml) and diphenyldisulfide (7.30 g) and heated to 80°C for 16 hours. The reaction mixture was concentrated and purified column chromatography on silica gel, performing a gradient elution in the range of 0-50% ethyl acetate in hexane, and get the desired product.

EXAMPLE 1C

(R)-3-Amino-N,N-dimethyl-4-(phenylthio)butanamide

A suspension of the compound from example 1B (or 10.60 g) in 50 ml of 30% solution of HBr/acetic acid left to mix overnight at room temperature. The obtained homogeneous reaction mixture is concentrated, diluted with water (200 ml) and 5% HCl solution (100 ml) and washed with diethyl ether (3×). the pH of the aqueous phase is brought to a value of about 8-9 solid Na2CO3and extracted with dichloromethane (5×). The combined organic phases, dried (MgSO4), filtered and concentrated, obtaining the desired product.

EXAMPLE 1D

(R)-N1N1-Dimethyl-4-(phenylthio)butane-1,3-diamine

A solution of the compound from example 1C (8,68 g) in THF (200 ml) is treated with a complex BH3-sulfoxide (18.2 ml) at room temperature, left to mix overnight, slowly add methanol (20 ml), and then 2 HCl solution (50 ml), leave much to be mixed on OCI and concentrate. The resulting residue is purified by chromatography on silica gel, elwira 5% 7N NH3/CH3OH in dichloromethane, and get the desired product.

EXAMPLE 1E

(R)-5-(Dimethylamino)-1-(phenylthio)butane-2-ylamino)-4-nitrothiophen-2-sulfonamide

A mixture of 2-chloro-3-nitrothiophene-5-sulfonamida (2,18 g), the compound from Example 1D (1,14 g) and triethylamine (1 g) was stirred in dioxane (30 ml) at 90°C for 24 hours. The solution is diluted with ethyl acetate, washed with a solution of NaH2PO4and saturated salt solution, dried over Na2SO4filter and concentrate. The product obtained by grinding in ethyl acetate.

EXAMPLE 1F

Ethyl 4-(4-(cyclohexylmethyl)-4-hydroxypiperidine-1-yl)benzoate

To a solution of cyclohexylmaleimide (1,90 ml 2M solution in THF) at -78°C is added ethyl 4-(4-oxo-1-piperidinyl)benzoate (produced in accordance with the method described in Synthesis1981, 606-608, of 0.30 g) and left overnight to warm to room temperature. The reaction mixture redistribute between ethyl acetate and saturated aqueous NH4Cl and the aqueous layer was extracted with ethyl acetate (2×). The organic layers are combined, dried (MgSO4), filtered and concentrated. The resulting residue is purified by chromatography on silica gel, elwira 20% ethyl acetate, and receive the product.

EXAMPLE 1G

Ethyl 4-(4-(cyclohexylmethyl)-4-methoxypiperidine-1-yl)benzoe the

To a solution of compound from Example 1F (380 mg) in THF (5 ml) is added NaH (96 mg, 60% dispersion in mineral oil) is heated to 50°C for 2 h and treated with hexamethylphosphoramide (1 ml), and then add MeI (1 ml). The reaction mixture is left overnight to boil under reflux, cooled to 0°C and diluted with saturated aqueous NaHSO4(10 ml). The resulting biphasic mixture was separated, the aqueous phase is twice extracted with ether, the organic extracts are combined, washed with water and saturated salt solution. Dried over MgSO4the mixture was concentrated in vacuo and purified by chromatography on silica gel, elwira 15% solution of ethyl acetate in hexano.

EXAMPLE 1H

4-(4-(Cyclohexylmethyl)-4-methoxypiperidine-1-yl)benzoic acid

A solution of the compound from example 1G (300 mg) in dioxane (5 ml) is treated with 1 N. NaOH solution (2 ml), allowed to mix overnight, acidified with 1 N. HCl solution, extracted with ethyl acetate (3×), dried (MgSO4) and filtered. Concentration of the filtrate get the desired product.

EXAMPLE 1I

4-[4-(Cyclohexylmethyl)-4-methoxypiperidine-1-yl]-N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}benzamide

The compound from example 1E (60 mg), the compound from example 1H (65 mg), the hydrochloride of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (65 mg) and 4-dimethylaminophenyl is in (22 mg) is stirred in CH 2Cl2(4 ml) for 24 hours. The reaction mixture is cooled and purified chromatographically on silica gel, elwira 50-100% solution of ethyl acetate in hexane, and then the mixture 1/10/89 the triethylamine/methanol/ethyl acetate.

1H NMR (400 MHz, DMSO-d6) δ 9,06 (user.s, 1H), to 7.77 (d, 2H), 7,44 (c, 1H), 7,35 (d, 2H), 7,26 (DD, 2H), 7,11 (t, 1H), at 6.84 (d, 2H), 3,60 (m, 1H), of 3.45 (m, 2H), 3,32 (m, 1H), of 3.07 (m, 4H), of 2.97 (m, 2H), 2,77 (m, 1H), 2,66 (m, 1H), 2,43 (c, 6H), was 2.05 (m, 2H), of 1.75 (m, 2H), 1,59 (m, 2H), 1,48 (m, 2H), 1,33 (m, 2H), 1,17 (m, 6H), were 0.94 (m, 2H).

EXAMPLE 2

N-{[5-({(1R)-3-(Dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}-4-[4-methoxy-4-(3-methylbenzyl)piperidine-1-yl]benzamide

EXAMPLE 2A

Ethyl 4-(4-hydroxy-4-(3-methylbenzyl)piperidine-1-yl)benzoate

The specified connection receive, replacing cyclohexylethylamine in example 1F 3-methylbenzylamine.

EXAMPLE 2B

Ethyl 4-(4-methoxy-4-(3-methylbenzyl)piperidine-1-yl)benzoate

The specified connection get by replacing in example 1G connection example 1F to the compound from example 2A.

EXAMPLE 2C

4-(4-Methoxy-4-(3-methylbenzyl)piperidine-1-yl)benzoic acid

The specified connection get by replacing in example 1H, the compound from example 1G connection in example 2B.

EXAMPLE 2D

N-{[5-({(1R)-3-(Dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}-4-[4-methoxy-4-(3-methylbenzyl)piperidine-1-yl]benzamide

The specified connection produces the t, by replacing in example 1I connection example 1H to connect to example 2C.

1H NMR (400 MHz, DMSO-d6) δ 9,00 (user.s, 1H), 7,76 (d, 2H), 7,44 (c, 1H), 7,35 (d, 2H), 7,26 (DD, 2H), 7,16 (m, 2H), 6.89 in (m, 3H), PC 6.82 (d, 2H), of 4.05 (m, 1H), 3,61 (m, 1H), 3,48 (m, 2H), 3,32 (m, 2H), 3.27 to (c, 3H), 3,17 (c, 2H), of 3.07 (m, 1H), 2,92 (m, 2H), 2,74 (c, 6H), and 2.27 (c, 3H), 2,07 (m, 2H), 1,67 (m, 2H), of 1.52 (m, 2H).

EXAMPLE 3

N-{[5-({(1R)-3-(Dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}-4-[4-(3,3-diphenylprop-2-enyl)piperazine-1-yl]benzamide

EXAMPLE 3A

Ethyl 4-(4-(3,3-divanillyl)piperazine-1-yl)benzoate

A suspension of ethyl 4-piperazine-1-eventout (1,36 g) and 3,3-diphenylacetamide aldehyde (1.56 g) in dichloromethane (10 ml) and methanol (10 ml) is treated grafted to the polymer by cyanoborohydride (2,47 mmol/g, 6 g), shaken at room temperature for 24 hours and filtered. The resin is washed with a solution of 1:1 dichloromethane/methanol (10 ml × 3), the filtrates are combined and concentrated. The concentrate is purified by chromatography on silica gel, conducting elution in a gradient of 10-50% ethyl acetate/hexane, and get the desired product.

EXAMPLE 3B

4-(4-(3,3-Divanillyl)piperazine-1-yl)benzoic acid

The specified connection get by replacing in example 1H, the compound from example 1G connection in example 3A.

EXAMPLE 3C

N-{[5-({(1R)-3-(Dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}-4-[4-(3,3-diphenylprop-2-enyl)piperazine-1-yl]Bentham is d

The specified connection get by replacing in example 1I connection example 1H in the connection example 3B.

1H NMR (500 MHz, DMSO-d6) of 10.25 δ (user.s, 1H), remaining 9.08 (user.s, 1H), 7,78 (d, 2H), 7,43 (m, 2H), 7,35 (m, 3H), 7,30 (m, 2H), 7,20-7,29 (m, 5H), 7,16 (m, 3H), at 6.84 (d, 2H), from 6.22 (t, 1H) and 3.59 (m, 1H), of 3.45 (m, 4H), of 3.32 (m, 4H), 3,03 (m, 4H), 2,78 (m, 1H), to 2.65 (m, 1H), 2,42 (c, 6H), 2,07 (m, 2H).

EXAMPLE 4

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-{[2-(phenylthio)ethyl]amino}piperidine-1-yl)sulfonyl]benzamide

Example 4A

Ethyl 4-(piperazine-1-yl)benzoate

A suspension of piperazine (to 129.2 g of 1.5 mol.), ethyl-4-perbenzoate (84 g of 0.5 mol.) and potassium carbonate (103,65 g of 0.75 mol.) in DMSO (200 ml) stirred in an atmosphere of N2at 120°C for 6 hours. Then the reaction mixture is cooled to room temperature, poured into water (800 ml) and stirred for 30 minutes the Desired product are filtered and passed to the next stage without further purification.

EXAMPLE 4B

Ethyl 4-(4-(2-bromobenzyl)piperazine-1-yl)benzoate

A solution of the compound from example 4A ((LK 23: 43 g, 100.0 mmol), 2-bromobenzylamine (26,24 g, 105,0 mmol) and diisopropylethylamine (20,94 ml, 120,0 mmol) in acetonitrile (200 ml) was stirred at room temperature for two hours. The formed precipitate was separated by filtration and receive the desired product which is used without further purification.

EXAMPLE 4C

Ethyl 4-(4-((4'-chlorobiphenyl-2-yl)methyl)PIP the Razin-1-yl)benzoate

A suspension of the compound from example 4B (13,83 g, to 34.3 mmol), 4-Chlorfenvinphos acid (? 7.04 baby mortality g, 45,0 mmol), dichloride bis(triphenylphosphine)palladium(II) (0,481 g, China 0,686 mmol, 2 mol%) and 2M aqueous solution of Na2CO3(22.5 ml, 45,0 mmol) in a mixture of dichloromethane/N2O/ethanol (7:3:2, 200 ml) is heated to a temperature of 90°C for 4.5 hours and diluted with ethyl acetate (200 ml). The layers are separated and the organic phase is dried over MgSO4), filtered and concentrated. The residue is purified by chromatography on silica gel, performing a gradient elution in a mixture of 5%-40% ethyl acetate/hexane, and get the desired product.

EXAMPLE 4D

4-(4-((4'-Chlorobiphenyl-2-yl)methyl)piperazine-1-yl)benzoic acid

A suspension of the compound from example 4C (13,0 g, and 29.9 mmol) and LiOH monohydrate (of 3.78 g of 90.0 mmol) in dioxane (250 ml) and water (100 ml) is heated to 95°C for 16 h, concentrated to dryness, add water (600 ml), heated to a temperature of 80°C and filtered. The filtrate is treated with 1M HCl solution (90 ml) and the formed precipitate was separated by filtration, obtaining the desired product.

EXAMPLE 4E

tert-Butyl 4-oxopiperidine-1-ylsulphonyl

Chlorosulfonylisocyanate (1,044 g 7,353 mmol) are added to dichloromethane (20 ml) and the resulting mixture is cooled to 0°C. Add tert-butanol (544 mg, 7,353 mmol) in dichloromethane (3 ml) and the resulting solution stirred at 0°C for 30 minutes Floor the military solution is then added to a separate flask, containing the hydrochloride of 4-piperidone (1,00 g 7,353 mmol) and triethylamine (3.1 ml, 22,059 mmol) in dichloromethane (20 ml), cooled to 0°C. after addition the solution is allowed to warm to room temperature and stirred for two hours. The mixture is then redistributed between dichloromethane and saturated aqueous ammonium chloride. The aqueous layer was extracted three times with dichloromethane, the organic extracts are combined and dried over anhydrous magnesium sulfate. The solution is concentrated and purified flash column-chromatography on silica gel, elwira in a gradient from 0% of ethyl acetate in dichloromethane to 20% ethyl acetate in dichloromethane.

EXAMPLE 4F

4-Oxopiperidin-1-ylsulphonyl

Connection example 4E (500 mg) is dissolved in 1,4-dioxane (4 ml), treated with 4M HCl solution (4 ml) and stirred at room temperature for three hours. The solution is concentrated and purified flash column-chromatography on silica gel, elwira in a gradient from 0% acetonitrile (in dichloromethane) to 40% acetonitrile (in dichloromethane).

EXAMPLE 4G

4-(4-((4'-Chlorobiphenyl-2-yl)methyl)piperazine-1-yl)-N-(4-oxopiperidin-1-ylsulphonyl)benzamid

The specified connection get by replacing in example 1I connection example 1E compound from example 4F, a compound of example 1H compound from example 4D.

EXAMPLE 4H

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]PI is erasin-1-yl}-N-[(4-{[2-(phenylthio)ethyl]amino}piperidine-1-yl)sulfonyl]benzamide

Connection example 4G (100 mg, 0,176 mmol), 2-(phenylthio)ethanamine (30 mg, 0,194 mmol), triacetoxyborohydride sodium (56 mg, 0,264 mmol) and acetic acid (11 μl, 0,194 mmol) are added to 1,2-dichloroethane (2 ml) and stirred at room temperature for six hours. The solvent is removed in vacuo and to the residue water is added. The precipitate is filtered off, dried, dissolved in a mixture of dimethyl sulfoxide/methanol containing a few drops of triethylamine, and purified by the method of preparative HPLC column Phenomenex Luna C8(2) 5 µm 100Å AXIA column (30×75 mm). Using a gradient of acetonitrile (A) and 0.1% solution triperoxonane acid in water (B) at a flow rate of 50 ml/min (0-0,5 min: 10% A, from 0.5 to 7.0 min linear gradient 10-95% A, 7,0-10,0 min: 95% A, of 10.0 to 12.0 min linear gradient 95-10% A).

1H NMR (400 MHz, DMSO-d6) δ 11,53 (user.s, 1H), 8,92 (user.s, 2H), 7,76 (d, 2H), 7,70 (user.s, 1H), of 7.48 (m, 4H), 7,38-7,26 (m, 7H), 7.24 to 7,17 (m, 1H), 4,18 (user.s, 2H), 3,74 (d, 4H), 3,21-and 3.16 (m, 6H), is 3.08 (user.s, 4H), 2,87 (t, 4H), 2,04 (d, 2H), 1,48 (m, 2H).

EXAMPLE 5

N-[(4-{Acetyl[2-(phenylthio)ethyl]amino}piperidine-1-yl)sulfonyl]-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide

Connection example 4H (30 mg, 0,0426 mmol), acetic anhydride (4.3 mg, 0,0426 mmol) and triethylamine (18 μl, 0,128 mmol) are added to dichloromethane (1 ml) and stirred at room temperature for four hours. The solvent is removed in vacuum, the residue is dissolved in the art dimethyl sulfoxide/methanol and purified by the method of preparative HPLC column Phenomenex Luna C8(2) 5 µm 100Å AXIA column (30×75 mm). Using a gradient of acetonitrile (A) and 0.1% solution triperoxonane acid in water (B) at a flow rate of 50 ml/min (0-0,5 min: 10% A, from 0.5 to 7.0 min linear gradient 10-95% A, 7,0-10,0 min: 95% A, of 10.0 to 12.0 min linear gradient 95-10% A).

1H NMR (400 MHz, DMSO-d6) δ 11,50 (user.s, 1H), 7,82 (d, 2H), 7,74 (user.s, 1H), 7,52 (d, 4H), 7,40 (t, 4H), 7,35-7,25 (m, 3H), 7,18 (dt, 1H), 6,94 (d, 2H), 4.26 deaths (user.s, 2H), 3.96 points (t, 1H, in), 3.75 (d, 4H), of 3.28 (dt, 4H), 3,10-to 2.85 (m, 8H), 2,04 (c, 2H), 1,88 (c, 1H), 1,75-of 1.56 (m, 4H).

EXAMPLE 6

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-{methyl[2-(phenylthio)ethyl]amino}piperidine-1-yl)sulfonyl]benzamide

Connection example 4H (30 mg, 0,0426 mmol), formaldehyde (37% solution in water, 10 ál, 0,128 mmol) and triacetoxyborohydride sodium (14 mg, 0,0639 mmol) are added to acetonitrile (0.8 ml) and water (0.2 ml). The solvent is removed in vacuum, the residue is dissolved in a mixture of dimethyl sulfoxide/methanol and purified by the method of preparative HPLC column Phenomenex Luna C8(2) 5 µm 100Å AXIA column (30×75 mm). Using a gradient of acetonitrile (A) and 0.1% solution triperoxonane acid in water (B) at a flow rate of 50 ml/min (0-0,5 min: 10% A, from 0.5 to 7.0 min linear gradient 10-95% A, 7,0-10,0 min: 95% A, of 10.0 to 12.0 min linear gradient 95-10% A).

1H NMR (400 MHz, DMSO-d6) δ 11,32 (user.s, 1H), 9,84 (user.s, 1H), 7,54 (d, 2H), 7,49 (user.s, 1H), 7,26 (d, 4H), 7,12 (d, 4H), 7,11-7,07 (m, 3H), of 6.99 (t, 1H), 6,69 (d, 2H), 3,98 (user.s, 2H), of 3.56 (d, 2H), 3.33 and-3,11 (m, 4H), 3,09-only 2.91 (m, 7H), 2,68 (t, 4H), 2.49 USD (c, 3H), 1,72 (d, 2H), 1,38 (user.with 2H).

EXAMPLE 7

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}benzamide

EXAMPLE 7A

(R)-Benzyl 4-oxo-1-(phenylthio)butane-2-ylcarbamate

In a three-neck round bottom flask with a capacity of 100 ml was placed compound from example 1B (3.75 g, 10.0 mmol) in an argon atmosphere using a syringe add bis(cyclopentadienyl)zirconium chloride hydride (3,85 g, 15.0 mmol) in 50 ml of anhydrous THF (air from the system, replacing the three cycles of pumping in vacuum and filling with argon). The mixture is stirred at room temperature for 20 min, the solution becomes transparent. Analysis by TLC indicates completion of the reaction, and the mixture concentrated. The residue is placed on a layer of silica gel and washed with a mixture of hexane/ethyl acetate (1:1, 300 ml). After concentrating receive specified in the name of the connection.

EXAMPLE 7B

(R)-Benzyl 4-(isopropyl(methyl)amino)-1-(phenylthio)butane-2-ylcarbamate

In a round bottom flask with a capacity of 250 ml containing compound from example 7A (2,87 g, 8,71 mmol), add 50 ml of 1,2-dichloroethane, metrizability (1.92 g, 26,25 mmol) and triacetoxyborohydride sodium (3.0 g, 14.1 mmol). The mixture in an atmosphere of N2stirred at room temperature for two hours. The mixture is diluted with ethyl acetate (200 ml) and washed with 2 N. NaOH solution, water, saturated salt solution and dried over Na 2SO4. The solvent is removed in vacuum and get listed in the name of the connection.

EXAMPLE 7C

(R)-N1-Isopropyl-N1-methyl-4-(phenylthio)butane-1,3-diamine

The compound from example 7B (0.56 g of 1.47 mmol) dissolved in acetonitrile (10 ml) and add trimethylsilylmethyl (400 µl). The mixture is left overnight to mix at room temperature. Terminate the reaction by adding methanol, concentrated in vacuo, the residue is dissolved in ethyl acetate (200 ml) and washed twice with 1.5% HCl solution (50 ml). The aqueous layers are combined and alkalinized solid NaOH, and then extracted with ethyl acetate (100 ml × 3). The combined extracts washed with saturated salt solution and dried over Na2SO4. After evaporation of the solvent receive specified in the name of the connection.

EXAMPLE 7D

(R)-5-(4-Isopropyl(methyl)amino)-1-(phenylthio)butane-2-ylamino)-4-nitrothiophen-2-sulfonamide

In a flask containing the compound from example 7C (0,43 g, 1,69 mmol) is added 2-chloro-3-nitrothiophene-5-sulfonamide (0,409 g, was 1.69 mmol) and DMSO (5 ml), and then add diisopropylethylamine (1 ml, 5,74 mmol). The mixture is left overnight to mix at a temperature of 60°C, dilute the mixture with ethyl acetate and washed with aqueous solution of NaHCO3, water and saturated salt solution. After drying over Na2SO4and evaporation of the solvent the residue is placed in a column with words is m silica gel and elute with a mixture of ethyl acetate/dichloromethane (saturated with ammonia) and get listed in the name of the connection.

EXAMPLE 7E

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]-propyl}amino)-4-nitration-2-yl]sulfonyl}benzamide

Indicated in the name of the connection receive, as described in example 1I, substituting the compound from example 1E and compound from example 1H in the connection example 7D and connection example 4D, respectively.

1H NMR (300 MHz, DMSO-d6) δ ppm 8,98 (m, 1H), 7,83 (m, 2H), of 7.70 (m, 1H), 7,52 (m, 4H), 7,35 (m, 6H), 7,16 (m, 4H), of 6.96 (m, 2H), of 3.77 (m, 2H) and 3.59 (m, 5H), 3,21 (m, 7H), 2,64 (t, 3H), 2,52 (d, 6H), 1,19 (d, 4H).

EXAMPLE 8

4-(4-{[2-(4-Chlorophenyl)cyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}benzamide

EXAMPLE 8A

Ethyl 2-(tripterocalyx)cyclohex-1-enecarboxylate

To a cooled (0°C.) suspension of NaH (0,983 g 60% dispersion in mineral oil, which was washed with three times with hexane) in ether (50 ml) was added with stirring ethyl 2-oxocyclohexanecarboxylate (3.2 g, of 20.5 mmol). The mixture is stirred at 0°C for 30 min, and then add the anhydride triftormetilfullerenov acid (4,2 ml, 25 mmol). The mixture is left overnight to mix at room temperature. Dilute the mixture with ether (200 ml) and washed with 5% HCl solution, water and saturated salt solution. After drying over Na2SO4and evaporation of the solvent receive what ever got the product, which is used without further purification.

EXAMPLE 8B

Ethyl 2-(4-chlorophenyl)cyclohex-1-enecarboxylate

To a solution of the compound from example 8A (2,88 g, 10 mmol), 4-Chlorfenvinphos acid (1.88 g, 12 mmol) and tetrakis(triphenylphosphine)palladium(0) (0,578 g, 0.5 mmol) in toluene (40 ml) and ethanol (10 ml) is added 2n. a solution of Na2CO3(10 ml). The mixture is left overnight to boil under reflux. Dilute the mixture with ether (300 ml) and washed with water, saturated salt solution and dried over Na2SO4. After evaporation of the solvent the residue is placed in a column and elute with 3% ethyl acetate in hexane, getting listed in the name of the connection.

EXAMPLE 8C

(2-(4-Chlorophenyl)cyclohex-1-enyl)methanol

To a solution of compound from example 8B (1.6 g, 6.38 mmol) in ether (20 ml) is added LiAlH4(1.2 g, 32 mmol). The mixture is stirred at room temperature for four hours. The mixture is carefully acidified with 5% HCl solution, extracted with ethyl acetate (100 ml × 3), washed with water, saturated salt solution and dried over Na2SO4. After evaporation of the solvent the crude product is placed in a column and elute with 10% ethyl acetate in hexane, getting listed in the name of the connection.

EXAMPLE 8D

2-(4-Chlorophenyl)cyclohex-1-interbanded

To a solution of oxalicacid (1.1 g, 8,63 mmol) in dichloromethane (30 ml) at -78°With add is dimethyl sulfoxide (6,12 ml, 86 mmol). The mixture was stirred at -78°C for 30 min, and then add a solution of the compound from example 8C (1.2 g, of 5.75 mmol) in dichloromethane (10 ml). The mixture is stirred at a temperature of -78°C for 2 hours, and then add triethylamine (10 ml). The mixture is left to mix overnight and allow the temperature to rise to room. Dilute the mixture with ether (300 ml) and washed with water, saturated salt solution and dried over Na2SO4. After evaporation of the solvent and purification on column (5% ethyl acetate in hexane) receive specified in the name of the connection.

EXAMPLE 8E

Ethyl 4-(4-((2-(4-chlorophenyl)cyclohex-1-enyl)methyl)piperazine-1-yl)benzoate

Connection example 8D (100 mg, 0,484 mmol) and the compound from example 4A (177 mg, 0,484 mmol) in 1,2-dichloroethane (10 ml) add triacetoxyborohydride sodium (154 mg, 0,726 mmol). The mixture is left to mix overnight at room temperature. Dilute the mixture with ethyl acetate (200 ml) and washed with 2% NaOH solution, water and saturated salt solution. After drying over Na2SO4the solvent was concentrated in vacuo, the residue is placed in a column and elute 30% ethyl acetate in hexane, getting listed in the name of the connection.

EXAMPLE 8F

4-(4-((2-(4-Chlorophenyl)cyclohex-1-enyl)methyl)piperazine-1-yl)benzoic acid

To a solution of compound from example 8E (254 mg, 0,457 mmol) in tetrahydrof the Ana (4 ml), methanol (2 ml) and water (2 ml) is added monohydrate of lithium hydroxide (126 mg, 3 mmol). The mixture is left to mix overnight at room temperature. The mixture is then neutralized with 5% HCl solution and diluted with ethyl acetate (200 ml). After washing with a saturated solution of the salt solution is dried over Na2SO4. By evaporation of the solvent receive specified in the name of the connection.

EXAMPLE 8G

4-(4-{[2-(4-Chlorophenyl)cyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}benzamide

Indicated in the name of the connection receive, as described in example 1I, substituting the compound from example 1E and compound from example 1H compound from example 7D and connection example 8F, respectively.1H NMR (300 MHz, DMSO-d6) δ 8,97 (m, 1H), 7,83 (m, 2H), 7,68 (m, 1H), 7,42 (m, 2H), 7,30 (m, 2H), 7,17 (m, 5H), 6,97 (m, 2H), 3,91 (m, 2H), 3,66 (m, 3H), 3,18 (m, 7H), 2,87 (m, 3H), 2,64 (t, 3H), of 2.51 (d, 6H), 2,24 (m, 4H), 1,72 (m, 3H), of 1.18 (m, 6H).

EXAMPLE 9

4-(4-{[2-(4-Chlorophenyl)-5,5-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}benzamide

EXAMPLE 9A

Methyl 5,5-dimethyl-2-oxocyclohexanecarboxylate

To the suspension is washed with hexane NaH (0,72 g, 60%, 18 mmol) in tetrahydrofuran (30 ml) add a solution of 4,4-dimethylcyclohexanone (2.0 g, 15.6 mmol) in tetrahydrofuran (20 ml The resulting suspension is stirred at room temperature for 30 minutes Then added dropwise with a syringe to add dimethylcarbonate (of 6.31 ml, 75 mmol). The mixture is refluxed for four hours. Acidifying the mixture with 5% HCl solution and extracted with dichloromethane (100 ml × 3), and then washed with water, saturated salt solution and dried over Na2SO4. After concentration the crude product is placed in a column and elute with a 10% solution of ethyl acetate in hexane, getting listed in the name of the connection.

EXAMPLE 9B

Methyl 5,5-dimethyl-2-(tripterocalyx)cyclohex-1-enecarboxylate

Specified in the title compound get analogously to example 8A, replacing ethyl 2-oxocyclohexanecarboxylate compound from example 9A.

EXAMPLE 9C

Methyl 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enecarboxylate

Specified in the title compound get analogously to example 8B, substituting the compound from example 8A compound from example 9B.

EXAMPLE 9D

(2-(4-Chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methanol

Specified in the title compound get analogously to example 8C substituting the compound from example 8B compound from example 9C.

EXAMPLE 9F

2-(4-Chlorophenyl)-5,5-dimethylcyclohex-1-interbanded

Specified in the title compound get as in example 8D, substituting the compound from example 8C connect the discharge from example 9D.

EXAMPLE 9F

Ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazine-1-yl)benzoate

Specified in the title compound get analogously to example 8E, replacing the compound from example 8D compound from example 9E.

EXAMPLE 9G

4-(4-((2-(4-Chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazine-1-yl)benzoic acid

Specified in the title compound get analogously to example 8F, replacing the compound from example 8E compound according to example 9F.

EXAMPLE 9H

4-(4-{[2-(4-Chlorophenyl)-5,5-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}benzamide

Indicated in the name of the connection receive, as described in example 1I, substituting the compound from example 1E and compound from example 1H compound from example 7D and connection example 9G, respectively.

1H NMR (300 MHz, DMSO-d6) δ 8,96 (m, 1H), 7,83 (m, 2H), to 7.67 (m, 1H), 7,42 (m, 2H), 7,29 (m, 2H), 7,17 (m, 6H), 6,97 (m, 2H), 3,90 (m, 2H), 3,61 (m, 8H), 3,19 (m, 3H), 2,65 (m, 3H), of 2.23 (m, 5H), 2,04 (m, 2H), 1,48 (m, 2H), to 1.19 (m, 6H), 1.00 m (c, 6H).

EXAMPLE 10

N-{[(5Z)-5-(Acetylamino)-4-methyl-4,5-dihydro-1,3,4-thiadiazole-2-yl]sulfonyl}-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide

The connection in this example receive, replacing in example 1I compound 1H compound from example 4D and choose (Z)-N-(3-methyl-5-sulfamoyl-1,3,4-thiadiazole-2(3H)ilidene)ndimethylacetamide instead of soy is inane in example 1E.

1H NMR (300 MHz, DMSO-d6) δ 7,74 (d, 2H), of 7.48 (m, 5H), 7,38 (m, 2H), 7,24 (m, 1H), 6,83 (d, 2H), 3,84 (c, 2H), 3,17 (m, 4H), 2.40 a (m, 4H), 1,82 (c, 6H).

EXAMPLE 11

N-{[2-(Acetylamino)-4-methyl-1,3-thiazol-5-yl]sulfonyl}-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide

EXAMPLE 11A

N-(4-Methyl-5-sulfamethizole-2-yl)ndimethylacetamide

2-Acetamido-4-methylthiazole-5-sulphonylchloride (0.50 g, a 1.96 mmol) dissolved in THF (7 ml), cooled to 0°C. and add a concentrated solution of NH4OH (0.7 ml). After 3 h the reaction mixture was concentrated, diluted with water and extracted with a mixture of CHCl3/methanol. The organic layer is dried over Na2SO4. After filtration and concentration receive the product, which is used in example 11B.

EXAMPLE 11B

N-{[2-(Acetylamino)-4-methyl-1,3-thiazol-5-yl]sulfonyl}-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide

The connection in this example receive, replacing in example 1I connection example 1H compound from example 4D and choose the connection 11A instead of the compound from example 1E, except that the cleaning method used HPLC on C18 column, 250×50 mm, 10 μm, conducting elution in a gradient of 20-100% CH3CN vs. 0.1% TFA solution in water, you get a product in the form of triptoreline salt.

1H NMR (300 MHz, DMSO-d6) δ 12,60 (c, 1H), 12,30 (very wide.c, 1H), 9,60 (very wide.c, 1H), 7,80 (d, 2H), 7,75 (user.s, 1H), 7,52 (m, 4), 7,40 (d, 2H), was 7.36 (m, 1H), 6,94 (d, 2H), to 4.38 (user.s, 1H), 3,85 (user.s, 1H), 3,40 is 2.80 (envelope, 8H), 2,52 (c, 3H), 2,18 (c, 3H).

EXAMPLE 12

N-({5-[(Benzoylamine)methyl]Tien-2-yl}sulfonyl)-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide

EXAMPLE 12A

N-((5-Allfamilies-2-yl)methyl)benzamide

The connection in this example receive, replacing in example 11A 2-acetamido-4-methylthiazole-5-sulphonylchloride 5-(benzamidomethyl)thiophene-2-sulphonylchloride.

EXAMPLE 12V

N-({5-[(Benzoylamine)methyl]Tien-2-yl}sulfonyl)-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide

The connection in this example receive, replacing in example 1I connection example 1H compound from example 4D and choose the connection 12A instead of the compound from example 1E, except that the cleaning is performed as described in example 11B.

1H NMR (300 MHz, DMSO-d6) δ 12,20 (very wide.c, 1H), 9,60 (very wide.c, 1H), 9,26 (t, 1H), 7,87 (d, 2H), 7,79 (m, 3H), to 7.67 (d, 1H), 7,51 (m, 7H), 7,40 (d, 2H), was 7.36 (m, 1H), to 7.09 (d, 1H), 6.90 to (d, 2H), with 4.64 (d, 2H), to 4.38 (user.s, 1H), 3,85 (user.s, 1H), 3,40 is 2.80 (envelope, 8H).

EXAMPLE 13

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]benzamide

The connection in this example receive, replacing in example 1I connection example 1H compound from example 4D and choose 6 chloroimidazo[2,1-b]thiazole-5-sulfonamide instead of the compound from example 1E, except that clean the ku spend so as described in example 11B.

1H NMR (300 MHz, DMSO-d6) δ 9,60 (very wide.c, 1H), 8,04 (d, 1H), 7,79 (m, 3H), 7,63 (d, 1H), 7,51 (m, 4H), 7,40 (d, 2H), was 7.36 (m, 1H), 6,92 (d, 2H), to 4.38 (user.s, 1H), 3,85 (user.s, 1H), 3,40 is 2.80 (envelope, 8H).

EXAMPLE 14

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-(morpholine-4-ylsulphonyl)benzamid

The connection in this example receive, replacing in example 1I connection example 1H compound from example 4D and choose morpholine-4-sulfonamide instead of the compound from example 1E, except that the cleaning is performed as described in example 11B.

1H NMR (300 MHz, DMSO-d6) δ 11,58 (user.s, 1H), 9,60 (very wide.c, 1H), 7,82 (d, 2H), 7,75 (user.s, 1H), 7,55 (m, 4H), 7,40 (d, 2H), was 7.36 (m, 1H), of 6.96 (d, 2H), to 4.38 (user.s, 1H), 3,85 (user.s, 1H), 3,61 (m, 4H), 3,40 is 2.80 (envelope, 8H), of 3.25 (m, 4H).

EXAMPLE 15

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]benzamide

The connection in this example receive, replacing in example 1I connection example 1H compound from example 4D and choose 2,4-dimethylthiazol-5-sulfonamide instead of the compound from example 1E, except that the treatment in this case is carried out as described in example 11B.

1H NMR (300 MHz, DMSO-d6) δ 12,40 (very wide.c, 1H), 9,60 (very wide.c, 1H), 7,80 (d, 2H), 7,75 (user.s, 1H), 7,55 (m, 4H), 7,40 (d, 2H), was 7.36 (m, 1H), 6,94 (d, 2H), to 4.38 (user.s, 1H), 3,85 (user.s, 1H), 3,40 is 2.80 (envelope, 8H), 2,65 (c, 3H), 2,55 (c, 3H).

EXAMPLE 16

4-{4-[('-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[4-phenyl-5-(trifluoromethyl)Tien-3-yl]sulfonyl]benzamide

EXAMPLE 16A

4-Phenyl-5-(trifluoromethyl)thiophene-3-sulfonamide

The connection in this example get, substituting 2-acetamido-4-methylthiazole-5-sulphonylchloride in example 11A 4-phenyl-5-(trifluoromethyl)thiophene-3-sulphonylchloride.

EXAMPLE 16B

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[4-phenyl-5-(trifluoromethyl)Tien-3-yl]sulfonyl]benzamide

The connection in this example receive, replacing in example 1I connection example 1H compound from example 4D, a compound of example 1E with the compound from example 16A, except that the treatment in this case is carried out as described in example 11B.

1H NMR (300 MHz, DMSO-d6) δ 11,85 (very wide.c, 1H), 9,60 (very wide.c, 1H), 8,80 (c,1H), to 7.77 (user.s, 1H), 7,60 (d, 2H), 7,53 (m, 4H), 7,40 (m, 3H), 7,35 (m, 3H), 7,16 (d, 2H), 6.89 in (d, 2H), to 4.38 (user.s, 1H), 3,85 (user.s, 1H), 3,40 is 2.80 (envelope, 8H).

EXAMPLE 17

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5-fluoro-3-methyl-1-benzothieno-2-yl)sulfonyl]benzamide

Example 17A

5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamide

The connection in this example get, substituting 2-acetamido-4-methylthiazole-5-sulphonylchloride in example 11A 5-fluoro-3-methylbenzo[b]thiophene-2-sulphonylchloride.

EXAMPLE 17B

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5-fluoro-3-methyl-1-benzothieno-2-yl)sulfonyl]benzamide

The connection in this example receive, replacing in example 1I connection note the ru 1H compound from example 4D, a compound of example 1E with the compound from example 17A, except that the treatment in this case is carried out as described in example 11B.

1H NMR (300 MHz, DMSO-d6) δ 12,60 (very wide.c, 1H), 9,60 (very wide.c, 1H), 8,12 (DD, 1H), a 7.85 (d, 1H) 7,80 (m, 3H), 7,52 (m, 4H), 7,46 (DD, 1H), 7,40 (d, 2H), was 7.36 (m, 1H), 6,92 (d, 2H), to 4.38 (user.s, 1H), 3,85 (user.s, 1H), 3,40 is 2.80 (envelope, 8H), 2,66 (c, 3H).

EXAMPLE 18

N-(1,3-Benzothiazol-2-ylsulphonyl)-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide

EXAMPLE 18A

Benzo[d]thiazole-2-sulfonamide

Benzo[d]thiazole-2-sulfonamide receive, as described in Roblin, Jr, R. O.; Clapp, J. W.,J. Am. Chem. Soc.1950, 72, 4890-4892.

EXAMPLE 18B

N-(1,3-Benzothiazol-2-ylsulphonyl)-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide

The connection in this example receive, replacing in example 1I connection example 1H compound from example 4D, a compound of example 1E with the compound from example 18A, except that the treatment in this case is carried out as described in example 11B.

1H NMR (500 MHz, DMSO-d6) to 11.79 δ (user.s, 1H), 8,17 (d, 1H), 8,03 (d, 1H), 7,78 (d, 2H), 7,74 (user.s, 1H), 7,55 (m, 6H), 7,40 (d, 2H), 7,34 (d, 1H), 6.87 in (d, 2H), 4,36 (m, 2H), 3,80 (m, 2H), 3,42 (m, 2H), 3,05 (m, 2H), 2,90 (m, 2H).

EXAMPLE 19

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-(Tien-2-ylsulphonyl)benzamid

The connection in this example receive, replacing in example 1I connection example 1H in connection p. the example 4D, a compound of example 1E in thiophene-2-sulfonamide, except that the treatment in this case is carried out as described in example 11B.

1H NMR (500 MHz, DMSO-d6) δ of 12.33 (user.s, 1H), 8,02 (DD, 1H), 7,82 (DD, 1H), 7,78 (d, 2H), 7,75 (user.s, 1H), 7,54 (m, 4H), 7,39 (d, 2H), 7,34 (m, 1H), 7,20 (DD, 1H), 6,94 (d, 2H), 4,33 (m, 2H), with 3.89 (m, 2H), 3,25 (m, 2H), 3,12 (m, 2H), 2.91 in (m, 2H).

EXAMPLE 20

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]benzamide

EXAMPLE 20A

5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonamide

The connection in this example get, substituting 2-acetamido-4-methylthiazole-5-sulphonylchloride in example 11A for 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulphonylchloride.

EXAMPLE 20B

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]benzamide

The connection in this example receive, replacing in example 1I connection example 1H compound from example 4D, a compound of example 1E with the compound from example 20A, except that the treatment in this case is carried out as described in example 11B.

1H NMR (300 MHz, DMSO-d6) δ 9,60 (very wide.c, 1H), 7,81 (d, 2H), 7,75 (user.s, 1H), 7,55 (m, 4H), 7,40 (d, 2H), 7,39 (c, 1H), was 7.36 (m, 1H), 6,94 (d, 2H), to 4.38 (user.s, 1H), 3,85 (user.s, 1H), 3,40 is 2.80 (envelope, 8H), 2,78 (c, 3H), 2,62 (c, 3H).

EXAMPLE 21

Ethyl 4-{[(4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}b is soil)amino]sulfonyl}-5-methyl-1,2-diphenyl-1H-pyrrole-3-carboxylate

EXAMPLE 21A

Ethyl 5-methyl-1,2-diphenyl-4-sulfamoyl-1H-pyrrole-3-carboxylate

The connection in this example get, substituting 2-acetamido-4-methylthiazole-5-sulphonylchloride in example 11A on methyl 5-(chlorosulfonyl)-1-methyl-1H-pyrrole-2-carboxylate.

EXAMPLE 21B

Ethyl 4-{[(4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzoyl)amino]sulfonyl}-5-methyl-1,2-diphenyl-1H-pyrrole-3-carboxylate

The connection in this example receive, replacing in example 1I connection example 1H compound from example 4D, a compound of example 1E with the compound from example 21A, except that the treatment in this case is carried out as described in example 11B.

1H NMR (300 MHz, DMSO-d6) δ 11,70 (user.s, 1H), 9,60 (very wide.s, 1H), of 7.90 (d, 2H), to 7.77 (user.s, 1H), 7,53 (m, 4H), 7,40 (m, 6H), 7,27 (m, 2H), 7,20 (m, 3H), to 7.09 (m, 2H), 6,92 (d, 2H), to 4.38 (user.s, 1H), 4.00 points (kV, 2H), 3,85 (user.s, 1H), 3,40 is 2.80 (envelope, 8H), 2,35 (c, 3H), of 0.90 (t, 3H).

EXAMPLE 22

Methyl 5-{[(4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzoyl)amino]sulfonyl}-1-methyl-1H-pyrrole-2-carboxylate

EXAMPLE 22A

Methyl 1-methyl-5-sulfamoyl-1H-pyrrole-2-carboxylate

The connection in this example get, substituting 2-acetamido-4-methylthiazole-5-sulphonylchloride in example 11A on methyl 5-(chlorosulfonyl)-1-methyl-1H-pyrrole-2-carboxylate.

EXAMPLE 22B

Methyl 5-{[(4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzoyl)amino]sulfonyl}-1-methyl-1H-p is rol-2-carboxylate

The connection in this example receive, replacing in example 1I connection example 1H compound from example 4D, a compound of example 1E with the compound from example 22A, except that the treatment in this case is carried out as described in example 11B.

1H NMR (300 MHz, DMSO-d6) δ 11,90 (user.s, 1H), 9,60 (very wide.c, 1H), a 7.85 (d, 1H), 7,78 (m, 3H), 7,55 (m, 4H), 7,40 (d, 2H), was 7.36 (m, 1H), 7,15 (d, 1H), 7,92 (d, 2H), to 4.38 (user.s, 1H), 3,90 (c, 3H), 3,85 (user.s, 1H), 3,78 (c, 3H), 3,40 is 2.80 (envelope, 8H).

EXAMPLE 23

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[5-(1,3-dimethyl-1H-pyrazole-5-yl)isoxazol-4-yl]sulfonyl}benzamide

EXAMPLE 23A

5-(1,3-Dimethyl-1H-pyrazole-5-yl)isoxazol-4-sulfonamide

The connection in this example get, substituting 2-acetamido-4-methylthiazole-5-sulphonylchloride in example 11 5-(1,3-dimethyl-1H-pyrazole-4-yl)isoxazol-4-sulphonylchloride.

EXAMPLE 23C

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[5-(1,3-dimethyl-1H-pyrazole-5-yl)isoxazol-4-yl]sulfonyl}benzamide

The connection in this example receive, replacing in example 1I connection example 1H compound from example 4D, a compound of example 1E with the compound from example 23A, except that the treatment in this case is carried out as described in example 11B.

1H NMR (300 MHz, DMSO-d6) δ 11,90 (user.s, 1H), 9,60 (very wide.c, 1H), 8,90 (c, 1H), 8,56 (c, 1H), 7,78 (m, 3H), 7,55 (m, 4H), 7,40 (d, 2H), was 7.36 (m, 1H), 7,92 (d, 2), to 4.38 (user.s, 1H), 3,85 (user.s, 1H), 3,83 (c, 3H), 3,40 is 2.80 (envelope, 8H), 2,37 (c, 3H).

EXAMPLE 24

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-chloro-3-metalization-5-yl)sulfonyl]benzamide

The connection in this example receive, replacing in example 1I connection example 1E 4-chloro-3-metalization-5-sulfonamide, a compound of example 1H in the connection example 4D.

1H NMR (300 MHz, DMSO-d6) δ 2,36 (c, 3H), 2,87-3,10 (m, 4H), 3,71-3,90 (m, 4H), 4,33-4,50 (m, 2H), for 6.81-6,91 (m, 2H), 7,35-7,46 (m, 3H), 7,47-7,63 (m, 4H), 7,72-to 7.84 (m, 3H), 9,45 (c, 1H).

EXAMPLE 25

N-[(5-Bromo-3-methyl-1-benzothieno-2-yl)sulfonyl]-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide

The connection in this example receive, replacing in example 1I connection example 1H compound from example 4D, a compound of example 1 5-bromo-3-methylbenzo[b]thiophene-2-sulfonamide, except that the treatment in this case is carried out as described in example 11B.

1H NMR (300 MHz, DMSO-d6) δ 12,60 (very wide.c, 1H), 9,60 (very wide.c, 1H), 8,19 (d, 1H), with 8.05 (d, 1H), 7,80 (m, 3H), of 7.70 (DD, 1H), 7,52 (m, 4H), 7,40 (d, 2H), was 7.36 (m, 1H), 6,92 (d, 2H), to 4.38 (user.s, 1H), 3,85 (user.s, 1H), 3,40 is 2.80 (envelope, 8H), 2,66 (c, 3H).

EXAMPLE 26

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-({5-[(E)-2-(1,2,4-oxadiazol-3-yl)vinyl]Tien-2-yl}sulfonyl)benzamide

The connection in this example receive, replacing in example 1I connection example 1 5-(2-[1,2,4]oxadiazol-3-illini is)thiophene-2-sulfonamide, a compound of example 1H in the connection example 4D.

1H NMR (300 MHz, DMSO-d6) δ 2,73-to 2.99 (m, 2H), 3.00 and-up 3.22 (m, 2H), of 3.73-a 4.03 (m, 4H), 4,23-of 4.49 (m, 2H), 6.89 in-6,99 (m, 2H), 7,26 was 7.45 (m, 4H), of 7.48-7,58 (m, 4H), to 7.61 (d, 1H), 7,71-7,83 (m, 5H), 7,83-a 7.92 (m, 1H), 9,62 (c, 1H).

EXAMPLE 27

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[1-(2-chloroethyl)-3,5-dimethyl-1H-pyrazole-4-yl]sulfonyl}benzamide

The connection in this example receive, replacing in example 1I connection example 1E 1-(2-chloroethyl)-3,5-dimethyl-1H-pyrazole-4-sulfonamide, a compound of example 1H in the connection example 4D.

1H NMR (300 MHz, DMSO-d6) δ 2,02-of 2.09 (m, 3H), 2,29 to 2.35 (m, 3H), 2.77-to of 2.97 (m, 2H), 2,98-3,17 (m, 2H), 3,81-4,00 (m, 6H), 4,28 is 4.45 (m, 4H), 6,86-of 6.99 (m, 2H), 7,32-7,44 (m, 3H), of 7.48-of 7.60 (m, 4H), 7,71-of 7.82 (m, 3H), 9,52 (c, 1H), 12,01 (c, 1H).

EXAMPLE 28

5-{[(4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzoyl)amino]sulfonyl}-N-(1-ethylpropyl)-1,3,4-thiadiazole-2-carboxamide

The connection in this example receive, replacing in example 1I connection example 1 5-(1-ethylpropylamine)-[1,3,4]thiadiazole-2-sulfonamide, a compound of example 1H in the connection example 4D.

1H NMR (300 MHz, DMSO-d6) δ to 0.80 (t, 6H), 1,36-1,71 (m, 4H), 2,37 at 2.45 (m, 1H), 2,84-3,11 (m, 4H), 3,44 of 3.56 (m, 2H), 3,71-to 3.92 (m, 2H), 4,30-to 4.46 (m, 2H), 6,80-to 6.95 (m, 2H), 7,29-7,44 (m, 3H), 7,47-the 7.65 (m, 4H), 7,69-7,89 (m, 3H), 9,45 (c, 1H), 12,59-12,83 (m, 1H).

EXAMPLE 29

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5-chloro-1,3-dimethyl-1H-pyrazole-4-yl)sulfonyl]benthami the

The connection in this example receive, replacing in example 1I connection example 1 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide, a compound of example 1H in the connection example 4D.

1H NMR (300 MHz, DMSO-d6) δ 2,36 (c, 3H), 2,79 are 2.98 (m, 2H), 3.00 and-3,19 (m, 2H), 3,51-3,59 (m, 2H), of 3.77 (c, 3H), 3,84-a 4.03 (m, 2H), 4,28-4,56 (m, 2H), 6,86-7,02 (m, 2H), 7,30 was 7.45 (m, 3H), of 7.48-to 7.64 (m, 4H), 7,71-7,88 (m, 3H), at 9.53 (c, 1H).

EXAMPLE 30

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-nitro-5-piperidine-1-Illian-2-yl)sulfonyl]benzamide

EXAMPLE 30A

4-Nitro-5-(piperidine-1-yl)thiophene-2-sulfonamide

The connection in this example receive, replacing in example 1E connection example 1D piperidine.

EXAMPLE 30V

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-nitro-5-piperidine-1-Illian-2-yl)sulfonyl]benzamide

The connection in this example receive, replacing in example 1I connection example 1H compound from example 4D, a compound of example 1E with the compound from example 30A, except that the treatment in this case is carried out as described in example 11B.

1H NMR (500 MHz, DMSO-d6) to 11.79 δ (user.s, 1H), 7,93 (c, 1H), 7,80 (d, 2H), 7,74 (m, 1H), 7,52 (m, 4H), 7,39 (d, 2H), 7,34 (m, 1H), 6,94 (d, 2H), 4,25 (m, 2H), of 3.56 (m, 4H), to 3.35 (m, 4H), of 3.25 (m, 2H), 2.91 in (m, 2H), 1,7 (m, 4H), to 1.61 (m, 2H).

EXAMPLE 31

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5-isoxazol-5-yl-2-furyl)sulfonyl]benzamide

EXAMPLE 31A

5-(Isoxazol-5-yl)fu is an-2-sulfonamide

The connection in this example get, substituting 2-acetamido-4-methylthiazole-5-sulphonylchloride in example 11 5-(isoxazol-5-yl)furan-2-sulphonylchloride.

EXAMPLE V

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5-isoxazol-5-yl-2-furyl)sulfonyl]benzamide

The connection in this example receive, replacing in example 1I connection example 1H compound from example 4D, a compound of example 1E with the compound from example 31A, except that the treatment in this case is carried out as described in example 11B.

1H NMR (300 MHz, DMSO-d6) δ 9,60 (very wide.c, 1H), 8,76 (d, 1H), 7,80 (d, 2H), to 7.75 (m, 1H), 7,55 (m, 4H), 7,40 (d, 2H), 7,42 (user.s, 1H), was 7.36 (m, 2H), of 7.96 (d, 1H), 7,92 (d, 2H), to 4.38 (user.s, 1H), 3,85 (user.s, 1H), 3,40 is 2.80 (envelope, 8H).

EXAMPLE 32

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3,5-dimethylisoxazol-4-yl)sulfonyl]benzamide

The connection in this example receive, replacing in example 1I connection example 1H compound from example 4D, a compound of example 1E 3,5-dimethylisoxazol-4-sulfonamide, except that the treatment in this case is carried out as described in example 11B.

1H NMR (500 MHz, DMSO-d6) δ of 12.33 (user.s, 1H), 7,80 (d, 2H), 7,74 (m, 1H), 7,53 (m, 4H), 7,40 (m, 2H), 7,34 (m, 1H), 6,94 (d, 2H), 4,27 (m, 2H), 3,84 (m, 2H), 3,55 (m, 2H), 3,25 (m, 2H), 2,96 (m, 2H), 2,68 (c, 3H), 2,38 (c, 3H).

EXAMPLE 33

4-(4-{[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-the l)-2-(1H-indol-5-yloxy)-N-({4-nitro-5-[(3-pyrrolidin-1-ylpropyl)amino]Tien-2-yl}sulfonyl)benzamide

EXAMPLE 33A

Ethyl 2-(1H-indol-5-yloxy)-4-perbenzoate

Ethyl 2,4-differentat (was 12.75 g), K3RHO4(14,54 g) and 5-hydroxyindole (9,12 g) is stirred at 110°C in diglyme (125 ml) for 24 hours. The reaction mixture is cooled and poured into ether. Solution three times washed with 1M NaOH solution, saturated salt solution and dried. Then the solution is concentrated and the crude product is poured into hexane, stirred and filtered, obtaining the target product.

EXAMPLE 33B

Methyl 4,4-dimethyl-2-(tripterocalyx)cyclohex-1-enecarboxylate

To the suspension is washed with hexane NaH (17 g) in dichloromethane (700 ml) added dropwise 5,5-dimethyl-2-methoxycarbonylamino (38,5 g) at 0°C. Stirred for 30 min, and then the mixture is cooled to a temperature of -78°C and add the anhydride triftormetilfullerenov acid (40 ml). The reaction mixture is allowed to warm to room temperature and then stirred for another 24 hours. The organic layer was washed with saturated salt solution, dried and concentrated, obtaining the target product.

EXAMPLE 33C

Methyl 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate

Connection example 33B (62,15 g), 4-Chlorfenvinphos acid (32,24 g), CsF (64 g) and tetrakis(triphenylphosphine)palladium(0) (2 g) in a mixture of dimethoxyethane/methanol (600 ml) is heated to a temperature of 70°C for 24 hours. mesh concentrate. Add ether (4 x 200 ml) and the mixture is filtered. The ether solutions are combined and condensed, obtaining the target product.

EXAMPLE 33D

(2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol

To a mixture of LiBH4(13 g), compounds in example 33C (53,8 g) and ether (400 ml) slowly via syringe add methanol (25 ml). The resulting mixture was stirred at room temperature for 24 hours. The reaction is interrupted by adding 1 HCl solution under ice cooling. Dilute the mixture with water and extracted with ether (3×100 ml). The extracts are combined, dried and concentrated. The crude product chromatographic on silica gel, elwira mixture of 0-30% ethyl acetate/hexane.

EXAMPLE A

Tert-butyl 4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate

To a mixture of compound from example 33D (10.0 g) and TEA (12,2 ml) in CH2Cl2(300 ml) at 0°C by means of a syringe add methylchloride (3,11 ml) and the resulting mixture stirred for one minute. Add N-tert-butoxycarbonylmethyl (8,17 g) and the reaction mixture was stirred at room temperature for 24 hours. The resulting suspension was washed with saturated salt solution, dried and concentrated. The crude product chromatographic on silica gel, elwira a mixture of 10-20% ethyl acetate/hexane.

EXAMPLE 33F

1-((2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine

Obedinenie for example A (2.0 g) and triethylsilane (0.3 ml) is stirred for one hour at 40 ml triperoxonane acid. The solution is concentrated and transferred into a solution of Na2CO3and the resulting mixture was twice extracted with CH2Cl2. The extracts are combined, washed with saturated salt solution, dried and concentrated.

EXAMPLE 33G

Ethyl 2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-yl)benzoate

The compound from example 33A (225 mg), the compound from example 33F (240 mg) and n2RHO4(131 mg) was stirred in dimethyl sulfoxide (4 ml) at a temperature of 135°C for 24 hours. The reaction mixture was diluted with ethyl acetate, washed three times with water, washed with saturated salt solution, dried and concentrated. The crude product chromatographic on silica gel, elwira a mixture of 30% ethyl acetate/hexane.

Example 33H

2-(1H-Indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-yl)benzoic acid

The connection in this example receive, replacing the compound from example 1G in example 1H to the connection example 33G.

EXAMPLE 33I

4-Nitro-5-(3-pyrrolidin-1-yl)propylamino)thiophene-2-sulfonamide

The connection in this example receive, replacing the compound from example 1D in example 1E 1-(3-aminopropyl)pyrrolidin.

EXAMPLE 33J

4-(4-{[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-({4-nitro-5-[(3-pyrrolidin-1-ylpropyl)amino]Tien-2-yl}sulfonyl)benzamide

With the unity in this example get by replacing in example 1I connection example 1E to the connection example 33I, a compound of example 1H in the connection example 33H.

1H NMR (400 MHz, DMSO-d6) δ 11,12 (c, 1H),9,50 (user.s, 1H), 9.28 are (t, 1H), 7,80 (c, 1H), 7,58 (d, 1H), 7,40-7,35 (m, 4H), to 7.15 (d, 1H), was 7.08 (d, 2H), 6,85 (DD, 1H), of 6.71 (DD, 1H), 6,37 (t, 1H), 6,24 (d, 1H), 3,52 (m, 4H), 3,35 is 3.23 (m, 4H), 3,17 (m, 4H), of 2.97 (m, 4H), to 2.18 (t, 2H), 2,00 (m, 8H), of 1.84 (m, 2H), 1,44 (t, 2H), 0,93 (c, 6H).

EXAMPLE 34

4-(4-{[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(5-{[3-(dimethylamino)propyl]amino}-4-nitration-2-yl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

EXAMPLE 34A

5-(3-(Dimethylamino)propylamino)-4-nitrothiophen-2-sulfonamide

The connection in this example receive, replacing the compound from example 1D in example 1E, 3-(dimethylamino)-1-Propylamine.

EXAMPLE 34B

4-(4-{[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(5-{[3-(dimethylamino)propyl]amino}-4-nitration-2-yl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

The connection in this example receive, replacing in example 1I connection example 1E to the connection example 34A, a compound of example 1H in the connection example 33H.

1H NMR (400 MHz, DMSO-d6) δ 10,95 (c, 1H), 9,15 (user.s, 1H), 7,58 (d, 1H), 7,43 (c, 1H), 7,35-7,27 (m, 4H), 7,03 (d, 2H), 7,01 (DD, 1H), 6,74 (DD, 1H), 6,53 (DD, 1H), of 6.31 (t, 1H), x 6.15 (d, 1H), 2,94 (m, 6H), 2,72 (c, 2H), 2.63 in (m, 6H), 2,20-2,12 (m, 8H), of 1.94 (m, 4H), to 1.37 (t, 2H), 0,91 (c, 6H).

EXAMPLE 35

4-(4-{[2-(4-Chlorophenyl)-4,4-dimethylcyclohex the C-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-({5-[(3-morpholine-4-ylpropyl)amino]-4-nitration-2-yl}sulfonyl)benzamide

EXAMPLE 35A

5-(3-Morpholinopropan)-4-nitrothiophen-2-sulfonamide

The connection in this example receive, replacing the compound from example 1D in example 1E, 3-(4-morpholino)-1-Propylamine.

EXAMPLE 35V

4-(4-{[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-({5-[(3-morpholine-4-ylpropyl)amino]-4-nitration-2-yl}sulfonyl)benzamide

The connection in this example receive, replacing in example 1I connection example 1E to the connection example 35A, a compound of example 1H in the connection example 33H.

1H NMR (400 MHz, DMSO-d6) δ 11,04 (c, 1H), 9,45 (user.s, 1H), to 7.61 (c, 1H), 7,56 (d, 1H), 7,35-7,30 (m, 4H), to 7.09 (DD, 1H),? 7.04 baby mortality (d, 2H), 6,80 (DD, 1H), is 6.61 (DD, 1H), 6,34 (t, 1H), 6,16 (d, 1H), 3,62 (t, 4H), 3,30 (m, 2H), to 3.02 (t, 4H), 2,78 (user.s, 2H), 2,54 (m, 6H), of 2.25 (m, 4H), and 2.14 (t, 2H), 1,95 (c, 2H) and 1.83 (m, 2H), 1,38 (t, 2H), 0,91 (c, 6H).

EXAMPLE 36

N-{[5-({(1R)-3-(Dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}-4-{4-[2-(trifluoromethyl)benzylidene]piperidine-1-yl}benzamide

EXAMPLE 36A

Ethyl 4-(4-(2-(trifluoromethyl)benzylidene)piperidine-1-yl)benzoate

A suspension of 2-(trifluoromethyl)benzyl of triphenylphosphorane (produced by the method described in J. Chem. Soc., Perkin Trans. 11995, 18, 2293-2308) (0,737 g) in THF (10 ml) is treated with n-butyllithium (724 μl, 1.6 M solution in hexane) at 0°C, add ethyl 4-(4-oxo-1-piperidinyl)benzoate (produced by the method described in Synthesis1981606-608, 0.32 g) and leave overnight to gradually warm to room temperature. The reaction mixture redistribute between ethyl acetate and saturated aqueous NH4Cl and the aqueous layer was extracted with ethyl acetate (2×). The organic layers are combined, dried over MgSO4), filtered and concentrated. The resulting residue is purified by chromatography on silica gel, elwira 10% ethyl acetate in hexane, and get the desired product.

EXAMPLE 36V

4-(4-(2-(Trifluoromethyl)benzylidene)piperidine-1-yl)benzoic acid

The connection in this example receive, replacing the compound from example 1G in example 1H to the compound from example 36A.

EXAMPLE 36C

N-{[5-({(1R)-3-(Dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}-4-{4-[2-(trifluoromethyl)benzylidene]piperidine-1-yl}benzamide

The connection in this example receive, replacing in example 1I connection example 1H in the connection example 36V.

1H NMR (400 MHz, DMSO-d6) δ 9,40 (user.s, 1H), 8,91 (d, 1H), 7,79 (d, 2H), 7,72 (d, 1H), to 7.64 (DD, 1H), 7,46 (m, 2H), 7,35 (m, 3H), 7,26 (m, 2H), 7,17 (t, 1H), to 6.88 (d, 2H), of 6.49 (c, 1H), 3,60 (m, 1H), 3,25-3,50 (m, 5H), 2,99 (m, 1H), only 2.91 (m, 1H), 2,74 (c, 6H), 2,64 (c, 6H), 2,44 (m, 2H), and 2.27 (m, 2H), 2,11 (m, 2H).

EXAMPLE 37

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methylene]piperidine-1-yl}-N-[(1,1-dioxymethamphetamine-3-yl)sulfonyl]benzamide

EXAMPLE 37A

(4'-Chlorobiphenyl-2-yl)methanol

A mixture of 2-identiable alcohol (11,0 g), 4-horfe is eventview acid (8.5 g) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (800 mg) in Na 2CO3(2M solution, 94 ml) and dioxane (300 ml) is heated to a temperature of 80°C for 24 hours. The mixture is cooled, the layers separated and the organic layer concentrated. The resulting residue is purified by chromatography on silica gel, elwira 20% ethyl acetate in hexane, and get the desired product.

EXAMPLE 37V

2-(methyl bromide)-4'-chlorobiphenyl

To a mixture of compound from example 37A (7.9 g) and LiBr (3,45 g) in DMF (100 ml) at 0°With add PBr3(3.77 ml) and the reaction mixture is stirred for 1 hour. The reaction mixture was poured into water (400 ml) and extracted with ether (3×200 ml). Combine the ether extracts, washed 3 times with water, saturated salt solution, dried over Na2SO4and concentrate, getting listed in the name of the connection.

EXAMPLE S

[(4'-Chloro-1,1'-biphenyl-2-yl)methyl](triphenyl)phospholipase

The mixture of compounds from example 37V (8,05 g) and triphenylphosphine (7.5 g) in xylene (100 ml) is heated to a temperature of 110°C for one hour. The reaction mixture is cooled and filtered, and the solid is washed with toluene and dried in vacuum, obtaining mentioned in the name of the connection.

EXAMPLE 37D

Ethyl 4-(1,4-dioxa-8 azaspiro[4.5]Decan-8-yl)benzoate

Ethyl 4-perbenzoate (36,16 g, 215 mmol), 1,4-dioxa-8 azaspiro[4.5]decane (35,40 g, 247 mmol) and potassium carbonate (29,72 g, 215 mmol) are added to N,N-dimethylacetamide (500 ml) and heated to temperature is 100°C for 16 hours. The solution is cooled, filtered, added to a 2M solution of HCl and extracted with 50% solution of ethyl acetate (hexano). The organic layers washed with water, saturated salt solution and dried over anhydrous sodium sulfate. The solution is concentrated and purified flash chromatography on silica gel, elwira in gradient from 20% ethyl acetate (in hexano) up to 30% ethyl acetate (in hexano).

EXAMPLE A

Ethyl 4-(4-oxopiperidin-1-yl)benzoate

Connection example 37D (16,23 g, 55,71 mmol) dissolved in toluene (85 ml) and added dropwise 1M solution of HCl (85 ml). The solution is heated to a temperature of 95°C for three hours and cooled. Add 50% ethyl acetate (solution in hexano) and the phases are separated. The organic phase is washed with water, saturated salt solution and dried over anhydrous sodium sulfate. The solvent is removed and the resulting material is used without further purification.

EXAMPLE 37F

Ethyl 4-(4-((4'-chlorobiphenyl-2-yl)methylene)piperidine-1-yl)benzoate

Sodium hydride (60% in mineral oil, to 1.617 g of 40.4 mmol) are added to a dimethylsulfoxide (265 ml) and heated to 80°C for 30 minutes while Continuing the heating to a temperature of 80°C, add connection example C, and then the connection example E. Temperatures up to 80°C continued for another 45 minutes the Solution is cooled, poured into water and extracted three times with diethyl ether. Broadcasting EXT the acts are combined and washed with water, saturated salt solution and dried over anhydrous sodium sulfate. The solution is concentrated and purified flash chromatography on silica gel, elwira in gradient from 10% ethyl acetate (in hexano) up to 20% ethyl acetate (in hexano).

EXAMPLE 37G

4-(4-((4'-Chlorobiphenyl-2-yl)methylene)piperidine-1-yl)benzoic acid

The connection in this example receive, replacing the compound from example 4C in example 4D in the connection example 37F.

EXAMPLE 37H

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methylene]piperidine-1-yl}-N-[(1,1-dioxymethamphetamine-3-yl)sulfonyl]benzamide

The connection in this example receive, replacing in example 1I connection example 1E 1,1-dioxide of the tetrahydrothiophene-3-sulfonamida, a compound of example 1H in the connection example 37G.

1H NMR (400 MHz, DMSO-d6) δ 7,79 (d, 2H), of 7.48 (dt, 2H), 7,42-7,33 (m, 4H), 7,31-of 7.23 (m, 2H), 6,85 (d, 2H), 6,13 (c, 1H), 4,33 (m, 1H), 3,35-up 3.22 (m, 4H), 3,20-of 3.06 (m, 4H), 2,30 (m, 6H).

EXAMPLE 38

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methylene]piperidine-1-yl}-N-[(5-chloro-3-methyl-1-benzothieno-2-yl)sulfonyl]benzamide

The connection in this example receive, replacing in example 1I connection example 1 5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide, a compound of example 1H in the connection example 37G.

1H NMR (400 MHz, DMSO-d6) δ of 8.09 (d, 1H), of 7.90 (c, 1H), to 7.77 (d, 2H), 7,58-7,52 (m, 2H), 7,47 (dt, 2H), 7,41-7,33 (m, 4H), 7,28 (m, 1H), 6,91 (d, 2H), 6,13 (c, 1H), 3,42 (m, 2H), 3,26 (m, 2H), 2,62 (c, 3H), 2,28 (m, 4H).

<> EXAMPLE 39

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5-chloro-3-methyl-1-benzothieno-2-yl)sulfonyl]-2-phenoxybenzamide

EXAMPLE 39A

Ethyl 4-fluoro-2-phenoxybenzoate

The connection in this example get, substituting 5-hydroxyindole in example 33A on the phenol.

EXAMPLE 39B

4'-Chlorobiphenyl-2-carbaldehyde

2-Bromobenzaldehyde (25,05 ml, 40,0 g, 216 mmol) are added to toluene, Tegaserod and rinsed with nitrogen. Add 4-Chlorfenvinphos acid (43,9 g, 281 mmol), degassed 2M sodium carbonate solution (757 ml, 1513 mmol) and tetrakis(triphenylphosphine)palladium(0) (5,00 g, 4,32 mmol). The mixture is heated under reflux for 2.5 hours, cooled and the phases are separated. The organic layer is extracted with 2M sodium carbonate solution and the aqueous layer was again extracted with ethyl ether. The organic extracts are combined, dried salt, and then anhydrous sodium sulfate. The solution is concentrated and purified flash column-chromatography on silica gel, conducting elution in a gradient of 5% ethyl acetate (in hexano) to 10% ethyl acetate (in hexano).

EXAMPLE 39C

Tert-butyl 4-((4'-chlorobiphenyl-2-yl)methyl)piperazine-1-carboxylate

The connection in this example get, substituting example 7B compound from example 7A in the connection example 39B, and metrizability 1-(tert-butoxycarbonyl)piperazine.

EXAMPLE 39D

1-((4'-Chlorobiphenyl-yl)methyl)piperazine

The connection in this example receive, replacing the compound from example I in example 33F on the compound from example 39C.

EXAMPLE 39E

Ethyl 4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazine-1-yl)-2-phenoxybenzoate

The connection in this example receive, replacing in example 33 G of the compound from example 33A on the compound from example 39A, a compound of example 33F on the connection example 39D.

EXAMPLE 39F

4-(4-((4'-Chlorobiphenyl-2-yl)methyl)piperazine-1-yl)-2-phenoxybenzoic acid

The connection in this example receive, replacing the compound from example 1G in example 1H to the connection example 39E.

EXAMPLE 39G

4-{4-[(4'-Chloro-1,1'-biphenyl-2-yl)methylene]piperidine-1-yl}-N-[(5-chloro-3-methyl-1-benzothieno-2-yl)sulfonyl]benzamide

The connection in this example receive, replacing in example 1I connection example 1 5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide, a compound of example 1H in the connection example 39F.

1H NMR (400 MHz, DMSO-d6) δ of 8.06 (d, 1H), 7,98 (d, 1H), 7,60-7,34 (m, 9H), 7,27-to 7.18 (m, 3H), 6,94 (t, 1H), 6,83 (d, 2H), 6.75 in (DD, 1H), 6,36 (d, 1H), 3,48 (m, 2H), and 3.16 (user.s, 4H), 2,54 (c, 3H), 2,43 (user.s, 4H).

EXAMPLE 40

2-(3-Chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-Ν-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]benzamide

EXAMPLE 40A

Ethyl 2-(3-chlorophenoxy)-4-perbenzoate

Ethyl 2,4-differentat (6.0 g), K3RHO4(7.5 g) and 3-chlorine is phenol (4.1 g) is stirred at 110°C in diglyme (25 ml) for 24 hours. The mixture is cooled and poured into ether. Solution three times washed with 1M NaOH solution, then with saturated salt solution and dried. The solution concentrate. Concentrate chromatographic on silica gel, elwira a mixture of 10% ethyl acetate/hexane.

EXAMPLE 40B

Methyl 4,4-dimethyl-2-(tripterocalyx)cyclohex-1-enecarboxylate

To the suspension is washed with hexane NaH (17 g) in dichloromethane (700 ml) at 0°C. are added dropwise 5,5-dimethyl-2-methoxycarbonylamino (38,5 g). The mixture is stirred for 30 min, then cooled to a temperature of -78°C and add triperoxonane anhydride (40 ml). Heat the mixture to room temperature and stirred for 24 hours. The extract is washed with saturated salt solution, dried and concentrated.

EXAMPLE 40C

Methyl 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate

Connection example 40B (62,15 g), 4-Chlorfenvinphos acid (32,24 g), CsF (64 g) and tetrakis(triphenylphosphine)palladium(0) (2 g) in a mixture of 2:1 dimethoxyethane/methanol (600 ml) is heated to a temperature of 70°C for 24 hours. The mixture is concentrated. Add ether, the mixture is filtered and concentrated.

EXAMPLE 40D

(2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol

To a mixture of LiBH4(13 g), compounds in example 40C (53,8 g) and ether (400 ml) slowly via syringe add methanol (25 ml). The mixture is stirred at room temperature during the course the e 24 hours. Terminate the reaction by adding 1 HCl solution under ice cooling. The mixture is diluted with water and extracted with ether (3×100 ml). The extracts are dried and concentrated. Concentrate chromatographic on silica gel, elwira mixture of 0-30% ethyl acetate/hexane.

EXAMPLE 40E

Tert-butyl 4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate

Methylchloride (7.5 ml) with a syringe type connection, example 40D (29.3 g) and triethylamine (30 ml) in CH2Cl2(500 ml) at 0°C, and then the mixture is stirred for 1 min. Add N-tert-butoxycarbonylmethyl (25 g) and the resulting mixture was stirred at room temperature for 24 hours. The suspension is washed with saturated salt solution, dried and concentrated. Concentrate chromatographic on silica gel, elwira a mixture of 10-20% ethyl acetate/hexane.

EXAMPLE 40F

1-((2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine

Connection example 40E (3.0 g) and triethylsilane (1 ml) is stirred in dichloromethane (30 ml) and triperoxonane acid (30 ml) for 2 hours. The mixture is concentrated, dissolved in ether and again concentrated.

EXAMPLE 40G

Ethyl 2-(3-Chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-yl)benzoate

The compound from example 40A (1.2 g), the compound from example 40F (1.4 g) and NK2RHO4(0.9 g) was stirred in DMSO (2 ml) at t is mperature 130°C for 24 hours. Dilute the mixture with ethyl acetate, washed three times with water, washed with saturated salt solution, dried and concentrated. Concentrate chromatographic on silica gel, elwira a mixture of 20% ethyl acetate/hexane.

EXAMPLE N

2-(3-Chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-yl)benzoic acid

Connection example 40G (400 mg) is stirred in 12 ml of a mixture of 5:1 dioxane/2M LiOH at a temperature of 90°C for 7 hours. The solution is cooled and concentrated. Add water to bring the pH to a value of 4 1M HCl solution and extracted with ethyl acetate. The extract is washed with saturated salt solution, dried over Na2SO4) and concentrate.

EXAMPLE 40I

5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonamide

5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulphonylchloride (2.9 g, get in the way described in EP 142152 (A2, A3)) is dissolved in THF (40 ml), cooled to 0°C, concentrate, and add NH4OH (4.0 ml). The reaction mixture upon cooling, stirred for 10 min, and then 30 min at room temperature. The liquid above the precipitate is decanted and the solids redistribute between water and a mixture of CHCl3/isopropyl alcohol (3/1). The aqueous layer was additionally extracted twice with a mixture of CHCl3/isopropyl alcohol (3/1). The organic extracts are combined, dried over Na2SO4) and concentrate.

The EXAMPLE 40J

2-(3-Chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-Ν-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]benzamide

Connection example 40H (170 mg), the compound from example 40I (68 mg), the hydrochloride of 1-ethyl-3-(3-dimethylamino)propyl)carbodiimide (113 mg) and 4-dimethylaminopyridine (72 mg) is stirred in CH2Cl2(3 ml) for 24 hours. Concentrated, re-dissolved in a mixture of DMSO/methanol and carry out cleaning by the method of preparative HPLC using a C18 column, 250×50 mm, 10 μm, and performing elution in a gradient of 20-100% CH3CN vs. 0.1% TFA solution in water. The obtained salt is neutralized, redistributing between CH2Cl2and a saturated solution of NaHCO3.

1H NMR (500 MHz, DMSO-d6) δ of 7.82 (d, 1H), 7,38 (d, 2H), 7,20 (c, 1H), 7,13 (DD, 1H), was 7.08 (d, 2H), 6.87 in (d, 1H), 6,76 (DD, 1H), gold 6.43 (c, 1H), 6.42 per (d, 1H), 6,36 (c, 1H), 3,13(user.s, 4H), 2,80 (user.s, 2H), 2,68 (c, 3H), 2,59 (c, 3H), 2,25 (user.s, 4H), 2,19 (user.m, 2H), 1,98 (c, 2H), 1,40 (t, 2H), 0,93 (c, 6H).

EXAMPLE 41

4-(4-{[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

EXAMPLE 41A

Ethyl 4-fluoro-2-(6-fluoro-1H-indol-5-yloxy)benzoate

The connection in this example get, substituting 3-chlorophenol in example 40A 6-fluoro-5-hydroxyindole (produced by the method described in WO 02/12227).

EXAMPLE 41C

Ethyl 4-(4-((2-(4-harfe who yl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-yl)-2-(6-fluoro-1H-indol-5-yloxy)benzoate

The connection in this example receive, replacing in example 40G compound from example 40A on the compound from example 41A.

EXAMPLE 41P

4-(4-((2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-yl)-2-(6-fluoro-1H-indol-5-yloxy)benzoic acid

The connection in this example receive, replacing in example 40H connection example 40G connection for example 41B.

EXAMPLE 41D

4-(4-{[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide

The connection in this example receive, replacing in example 40J connection example 40H on the compound from example 41C.

1H NMR (500 MHz, DMSO-d6) δ 11,07 (c, 1H), 7,78 (d, 1H), was 7.36 (d, 2H), 7,30 (m, 1H), 7,24 (d, 1H), 7,20 (c, 1H), was 7.08 (d, 3H), 6,59 (DD, 1H), 6.30-in (c, 1H), 6,05 (c, 1H), 2.95 and (OSiR.s, 4H), 2,75 (user.s, 2H), 2,68 (c, 3H), 2,59 (c, 3H), 2,22 (user.s, 4H), 2,17 (user.m, 2H), 1,95 (c, 2H), 1,40 (t, 2H), 0,93 (c, 6H).

EXAMPLE 42

4-(4-{[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-[(6,7-debtor-1H-indol-5-yl)oxy]-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]benzamide

EXAMPLE 42A

Ethyl 2-(6,7-debtor-1H-indol-5-yloxy)-4-perbenzoate

The connection in this example get, substituting example 40A 3-chlorophenol 6.7-debtor-5-hydroxyindole (produced by the method described in WO 02/12227).

EXAMPLE 42

Ethyl 4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-enyl)methyl)piperazine-1-yl)-2-(6,7-debtor-1H-indol-5-yloxy)benzoate

The connection in this example receive, replacing in example 40G compound from example 40A on the compound from example 42A.

EXAMPLE 42S

4-(4-((2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-yl)-2-(6,7-debtor-1H-indol-5-yloxy)benzoic acid

The connection in this example receive, replacing in example 40H connection example 40G on the compound from example 42B.

EXAMPLE 42D

4-(4-{[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-[(6,7-debtor-1H-indol-5-yl)oxy]-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]benzamide

The connection in this example receive, replacing in example 40J connection example 40H on connection example 42C.

1H NMR (500 MHz, DMSO-d6) δ 11,58 (c, 1H), 7,80 (d, 1H), 7,33 (d, 2H), 7,31 (c, 1H), 7,17 (c, 1H), 7,03 (d, 2H), 6,70 (d, 1H), 6,65 (DD, 1H), 6.35mm (m, 1H), to 6.19(c, 1H), 3.00 and (OSiR.s, 4H), 2,71 (user.s, 2H), 2,68 (c, 3H), 2,59 (c, 3H), 2,20 (user.s, 4H), 2,17 (user.m, 2H), 1,95 (c, 2H), 1.39 in (t, 2H), 0,93 (c, 6H).

EXAMPLE 43

Tert-butyl (2S)-2-{[(5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate

EXAMPLE 43A

5-Bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine

To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (15,4 g) in tetrahydrofuran (250 ml) is added 1M solution hexamethyldisilazide lithium in tetrahydrofuran (86 ml), and after 10 minutes add the keys TIPS-Cl (triisopropylchlorosilane) (18.2 ml). The resulting mixture was stirred at room temperature for 24 hours. Dilute the reaction mixture with ether and the resulting solution washed twice with water. The extracts are dried (Na2SO4), filtered and concentrated. The crude product chromatographic on silica gel, elwira a mixture of 10% ethyl acetate/hexane.

EXAMPLE V

1-(Triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-ol

To a mixture of compound from example 43A (24.3 g) in tetrahydrofuran (500 ml) at a temperature of -78°C. add 2.5 M solution of n-utility (30,3 ml). After 2 minutes add trimethylboron (11.5 ml) and allow to mix for 1 hour to warm to room temperature. Pour the reaction mixture into water, extracted three times with ethyl acetate, the organic extracts are combined, washed with saturated salt solution and concentrated. The crude product is dissolved in tetrahydrofuran (200 ml) at 0°C, add 1M NaOH solution (69 ml), and then 30% aqueous solution of N2About2(8,43 ml) and the resulting solution was stirred for 1 hour. Add Na2S2O3(10 g), adjusted pH to a value of 4-5 with concentrated HCl and the solid NaH2PO4. The solution is extracted twice with ethyl acetate, the extracts combined, washed with saturated salt solution, dried over Na2SO4), filtered and concentrated. The crude product chromatographic on silica gel, elwira mixture of 5-25% ethyl acetate/is exany.

EXAMPLE and 43C

Methyl 2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)-4-perbenzoate

The mixture of compounds from example V (8.5 g), methyl 2,4-differentiate (7,05 g) and K3RHO4(to 9.32 g) in diglyme (40 ml) is stirred at a temperature of 115°C for 24 hours. The reaction mixture is cooled, diluted with ether (600 ml) and washed twice with water, saturated salt solution and concentrated. The crude product chromatographic on silica gel, elwira mixture 2-50% ethyl acetate/hexane.

EXAMPLE 43D

Methyl 2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-yl)benzoate

A mixture of compound in example 43C (1.55 g), compounds in example 43F (2,42 g) and NK2RHO4(1.42 g) in dimethyl sulfoxide (20 ml) at a temperature of 135°C and stirred for 24 hours. The reaction mixture is cooled, diluted with ether (400 ml) and three times washed with 1M NaOH solution, saturated salt solution and concentrated. The crude product chromatographic on silica gel, elwira a mixture of 10-50% ethyl acetate/hexane.

EXAMPLE 43E

2-(1H-Pyrrolo[2,3-b]pyridine-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-yl)benzoic acid

Connection example 43D (200 mg) in dioxane (10 ml) and 1M aqueous NaOH solution (6 ml) at a temperature of 50°C and stirred for 24 hours. The reaction mixture is cooled, add a solution of NaH2PO4and three times extra is irout with ethyl acetate. The extracts are combined, washed with saturated salt solution and concentrated, obtaining a pure product.

EXAMPLE 43F

2-Chloro-4-methylthiazole-5-sulfonamide

A solution of 2-chloro-4-methylthiazole-5-sulphonylchloride (1.0 g) in isopropyl alcohol (10 ml) is cooled in a bath with ice. Then slowly add ammonium hydroxide (2,89 ml). The resulting solution was left to mix overnight at room temperature. The solution is concentrated and the residue is mixed with water (10 ml) and extracted with ethyl acetate (2×20 ml). The crude product is purified on a column of silica gel, elwira a mixture of 60% ethyl acetate-hexane.

EXAMPLE 43G

(S)-Tert-butyl 2-((4-methyl-5-sulfamethizole-2-yloxy)methyl)morpholine-4-carboxylate

To a solution of (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (123 mg) in anhydrous tetrahydrofuran (5 ml) is added sodium hydride (60% dispersion in mineral oil, 94 mg). Stir the mixture at room temperature for 30 min, and then add the connection example 43F (100 mg). The mixture is left overnight to mix at room temperature. Terminate the reaction by adding water (15 ml) and extracted with ethyl acetate. The crude product is purified on a column of silica gel, elwira a mixture of 60% ethyl acetate in hexane, and get listed in the name of the connection.

EXAMPLE 43H

Tert-butyl (2S)-2-{[(5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methylpiperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate

The connection in this example receive, replacing in example 1I connection example 1H in the connection example 43E, a compound of example 1E in the connection example 43G.

1H NMR (500 MHz, pyridine-d5) δ 13,00 (c, 1H), 8,43 (d, 1H), 8,11 (d, 1H), 7,68 (d, 1H), to 7.67 (t, 1H), 7,45 (d, 2H), was 7.08 (d, 2H), 6,76 (DD, 1H), is 6.54 (d, 1H), 6,50 (DD, 1H), to 4.52 is 4.45 (m, 2H), 3,90-3,70 (m, 4H), 3,47 (dt, 1H), of 3.07 (m, 4H), 2,98-2,84 (m, 2H), 2,77 (c, 2H), was 2.76 (c, 3H), and 2.26 (m, 2H), and 2.14 (m, 4H), 1,97 (c, 2H), 1,52 (c, 9H), 1.39 in (t, 2H), 0,94 (c, 6H).

EXAMPLE 44

Tert-butyl (2S)-2-{[(5-{[2-(1H-benzimidazole-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate

EXAMPLE 44A

Methyl 4-fluoro-2-(3-fluoro-2-nitrophenoxy)benzoate

To a solution of methyl 4-fluoro-2-hydroxybenzoate (3.0 g) in tetrahydrofuran (65 ml) was added in several portions of tert-piperonyl potassium (1,979 g). The resulting solution was stirred at ambient temperature for 30 min and then added dropwise a solution of 1,3-debtor-2-nitrobenzene (2,338 g) in tetrahydrofuran (15 ml). After 1 hour the reaction mixture is heated to boiling and refluxed for 18 hours. The reaction is quenched with water (10 ml), diluted with saturated salt solution (75 ml) and extracted twice with methylene chloride (75 ml). The crude product are concentrated and purified on silica gel, spending a stepped gradient elution with mixtures of 10, 2, 50% ethyl acetate in hexane.

EXAMPLE 44B

Methyl 2-(3-(bis(4-methoxyphenyl)methylamino)-2-nitrophenoxy)-4-perbenzoate

To a solution of the compound from example 44A (3,82 g) and bis(4-methoxyphenyl)methanamine (4,51 g) in N-methyl-2-pyrrolidinone (65 ml) is added N-ethyl-N-isopropylparaben-2-amine (4,30 ml) and the resulting mixture is heated to a temperature of 100°C for 24 hours. The crude product, which are concentrated, purified on silica gel, spending a stepped gradient elution with mixtures of 10, 25, 65% ethyl acetate in hexane.

EXAMPLE 44C

Methyl 2-(2-amino-3-(bis(4-methoxyphenyl)methylamino)phenoxy)-4-perbenzoate

To a solution of compound from example 44B (2.76 g) in tetrahydrofuran (125 ml) in a steel bottle type Nickel catalyst (2.76 g). The mixture is stirred for 1 hour under hydrogen pressure of 30 pounds per square inch at ambient temperature. The mixture is filtered through a membrane made of nylon, to remove the catalyst, and after evaporation of the solvent receive specified in the title compound (2,54 g).

EXAMPLE 44D

Methyl 2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-perbenzoate

To a solution of compound from example 44C (1.25 g) in triethyl-orthoformate (30 ml) is added concentrated hydrochloric acid (0.75 ml). The resulting mixture was stirred for 18 h, terminate the reaction by slowly adding 50% n is sydeny solution of sodium carbonate (100 ml), and extracted with ethyl acetate (2×100 ml). The crude product are concentrated and purified on silica gel, spending a stepped gradient elution with mixtures of 25, 50, and 70% ethyl acetate in hexane.

EXAMPLE 44E

Methyl 2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-(piperazine-1-yl)benzoate

A solution of the compound in example 44D (500 mg) and piperazine (420 mg) in dimethyl sulfoxide (9 ml) is heated to a temperature of 100°C for 3 hours. The crude product are concentrated and then washed with water and purified on silica gel, spending a stepped gradient elution with mixtures of 5, 10% methanol in methylene chloride.

EXAMPLE 44F

2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-interbanded

The specified connection receive, replacing the compound from example 8C in example 8D connection for example 33D.

EXAMPLE 44G

Methyl 2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-yl)benzoate

To a solution of compound from example 44E (430 mg) and connection example 44F (259 mg) in dichloromethane (13 ml) was added in several portions of triacetoxyborohydride sodium (323 mg). Stirred for 42 h, the reaction is interrupted, slowly adding saturated aqueous sodium bicarbonate solution (80 ml), and extracted with methylene chloride (2×70 ml). The crude product are concentrated and purified on silica gel,spending a stepped gradient elution with mixtures of 0, 2, 10% methanol in methylene chloride.

EXAMPLE 44H

2-(1-(Bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-yl)benzoic acid

To a solution of compound from example 44G (545 mg) in a mixture of methanol (7,50 ml) and tetrahydrofuran (7,50 ml) add a solution of sodium hydroxide (269 mg) in water (3.0 ml). The reaction mixture is heated to a temperature of 50°C for 18 h and concentrated. The residue is mixed with water (100 ml), adjusted pH to a value of approximately 7 1M aqueous solution of hydrochloric acid, and the mixture is then extracted with 10% solution of methanol in methylene chloride (10×50 ml).

EXAMPLE 44I

8-[4-[[2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohex-1-enyl]methyl]-1-piperazinil]-11N-benzo[b]imidazo[1,5,4-ef][1,5]benzoxazepin-11-he

A solution of the compound from example 44G (4.5 g) in anhydrous dichloromethane (100 ml) is cooled in a bath with ice and add a catalytic amount of N,N-dimethylformamide. Then added dropwise a solution of oxalidaceae (1,231 ml) in anhydrous methylene chloride (5 ml). Bath ice is removed and the reaction mixture is stirred for 1 hour. The reaction is interrupted, crushed ice (150 ml) and saturated aqueous sodium bicarbonate solution (100 ml). The mixture is then further diluted with saturated aqueous sodium bicarbonate (200 ml) and methylene chloride (200 ml). The crude product is isolated con is entryowner organic layer, the residue is purified on silica gel, spending a stepped gradient elution with mixtures of 0, 10, 25 and 100% ethyl acetate in methylene chloride.

EXAMPLE 44J

Tert-butyl (2S)-2-{[(5-{[2-(1H-benzimidazole-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate

To a solution of compound from example 43G (35 mg) in anhydrous tetrahydrofuran (4 ml) is added 2,3,4,6,7,8,9,10-octahedroid[1,2-a]azepin (19,95 µl). The resulting mixture was stirred at room temperature for 30 minutes Add connection example 44I (49.2 mg) and the solution left overnight to mix at room temperature. The solution concentrate. The residue is again dissolved in a mixture of dimethyl sulfoxide-methanol and purified by HPLC (Waters Prep LC4000 system, column (C 18), using as mobile phase 10 mm buffered with ammonium acetate a mixture of water-acetonitrile.

1H NMR (500 MHz, pyridine-d5) δ 8,55 (c, 1H), 8,00 (d, 1H), 7,53 (d, 1H), 7,44 (d, 2H), 7,27 (t, 1H), 7,22 (m, 2H), 7,07 (d, 2H), 6.73 x (d, 1H), of 6.71 (DD, 1H), to 4.52 is 4.45 (m, 2H), 3,90-3,70 (m, 4H), 3,47 (dt, 1H), 3.04 from (m, 4H), 2,98-and 2.83 (m, 2H), 2,77 (c, 2H), was 2.76 (c, 3H), and 2.26 (m, 2H), 2,15 (m, 4H), 1,97 (c, 2H), 1,52 (c, 9H), 1.39 in (t, 2H), 0,94 (c, 6H).

EXAMPLE 45

4-(4-{[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-({2-[(4-Porterage-2H-Piran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)benzamide

EXAMPLE 45A

2-((4-Porterage-2H-Piran-4-yl)methoxy)-4-methylthiazole-5-sulfonamide

The connection in this example get, substituting (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate in example 43G 4 Porterage-2H-Piran-4-yl)methanol.

EXAMPLE 45B

4-(4-{[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-({2-[(4-Porterage-2H-Piran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)benzamide

The connection in this example receive, replacing in example 1I connection example 1H in the connection example 43E, a compound of example 1E in the compound from example 45A.

1H NMR (500 MHz, pyridine-d5) δ 13,01 (c, 1H), 8,43 (d, 1H), 8,15 (d, 1H), of 7.70 (d, 1H), 7,65 (t, 1H), 7,45 (d, 2H), was 7.08 (d, 2H), 6,77 (DD, 1H), 6,55 (d, 1H), 6,50 (DD, 1H), to 4.52 (DD, 2H), 3,83-with 3.79 (m, 2H), 3.72 points-3,70 (m, 2H), of 3.07 (m, 4H), 2,80 (c, 3H), 2,78 (c, 2H), and 2.26 (m, 2H), 2,15 (m, 4H), 1,97 (c, 2H), 1,82 is 1.75 (m, 4H), 1.39 in (t, 2H), 0,94 (c, 6H).

EXAMPLE 46

2-(1H-Benzimidazole-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-({2-[(4-Porterage-2H-Piran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)benzamide

The connection in this example receive, replacing in example 44J connection example 43G on the compound from example 45A.

1H NMR (500 MHz, pyridine-d5) δ 8,56 (c, 1H), 8,02 (d, 1H), 7,53 (d, 1H), 7,44 (d, 2H), 7,27 (t, 1H), 7,21 (m, 2H), was 7.08 (d, 2H), 6,74 (d, 1H), of 6.71 (DD, 1H), 4,54 (DD, 2H), 3,84-with 3.79 (m, 2H), of 3.73-3,70 (m, 2H), 3,05 (m, 4H), 2,79 (c,3H), 2,78 (c, 2H), and 2.26 (m, 2H), 2,16 (m, 4H), 1,98 (c, 2H), 1,82 is 1.75 (m, 4H), 1.39 in (t, 2H), 0,94 (c, 6H).

EXAMPLE 47

(S)-Tert-butyl 2-(((5-(N-(2-(1H-indazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-yl)benzoyl)sulfamoyl)-4-methylthiazole-2-yloxy)methyl)morpholine-4-carboxylate

EXAMPLE 47A

Tert-butyl 4-hydroxy-1H-indazol-1-carboxylate and tert-butyl 4-hydroxy-2H-indazol-2-carboxylate

4-Hydroxyindole (3.94 g) are added to a tetrahydrofuran (250 ml) and the resulting mixture is cooled to 0°C in a bath with ice. Add sodium hydride (60% dispersion in mineral oil, 1.23 g) and the mixture was stirred at 0°C for 5 min to Allow the solution to warm to room temperature and stirred for another 20 minutes, Again cooled the solution to 0°C in a bath with ice and add tert-butyldimethylchlorosilane (4,65 g). Allow the solution to warm to room temperature and stirred for 16 hours. Evaporated the solvent in vacuo, the residue was filtered under vacuum through a layer of silica gel and washed with ethyl acetate. The solutions are combined and concentrated. The resulting residue is mixed with acetonitrile (200 ml), di-tert-BUTYLCARBAMATE (7,06 g) and 4-(dimethylamino)pyridine (0,359 g). The resulting solution was stirred at room temperature for three hours and the solvent is removed in vacuum. To the residue add tetrahydrofuran (200 ml), tetrabutylammonium (1M RA the solution in tetrahydrofuran, 82 ml). After stirring at room temperature for four days, the solvent is removed in vacuo, and the residue is dissolved in ethyl acetate. The resulting solution was washed with saturated aqueous ammonium chloride and a saturated saline solution and then dried over anhydrous sodium sulfate. The solution is filtered through silica gel and the solvent is removed in vacuum, obtaining mentioned in the name of the connection.

EXAMPLE 47B

Methyl ester of 4-fluoro-2-(1H-indazol-4-yloxy)benzoic acid

To a solution of the compound from example 47A (5,56 g) diglyme (200 ml) is added tert-piperonyl potassium (1M solution in tetrahydrofuran, 30,8 ml). The solution was stirred at room temperature for 15 minutes Add methyl 2,4-differentat and the solution is stirred at a temperature of 115°C for 16 hours. The solution is cooled and the solvent is removed in vacuum. The residue is dissolved in dichloromethane (100 ml) and add triperoxonane acid (22,6 ml). The resulting solution was stirred at room temperature for 16 hours. The solvent is removed in vacuum, the residue is dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate, the organic layer separated and dried over anhydrous sodium sulfate. Connection purified flash chromatography on silica gel using first a 30% solution of ethyl acetate (hexano), and then increase to 4% ethyl acetate (in hexano).

EXAMPLE 47C

Methyl ester of 2-(1H-indazol-4-yloxy)-4-piperazine-1-eventing acid

The connection in this example receive, replacing in example 44E connection example 44D on the connection example 47B.

EXAMPLE 47D

Methyl ester 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-animetal}piperazine-1-yl)-2-(1H-indazol-4-yloxy)benzoic acid

The connection in this example receive, replacing in example 44G compound from example 44E on the connection example 47C.

EXAMPLE 47E

2-(1H-Indazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-yl)benzoic acid

The connection in this example receive, replacing in example 44H connection example 44G on the connection example 47D.

EXAMPLE 47F

(S)-Tert-butyl 2-(((5-(N-(2-(1H-indazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-yl)benzoyl)sulfamoyl)-4-methylthiazole-2-yloxy)methyl)morpholine-4-carboxylate

The connection in this example receive, replacing in example 1I connection example 1H in the connection example 47E, a compound of example 1E in the connection example 43G.

1H NMR (500 MHz, pyridine-d5) δ at 8.36 (c, 1H), 8,11 (d, 1H), 7,47 (d, 2H), 7,38 (d, 1H), 7,22 (m, 2H), 7,11 (d, 2H), 6,88-to 6.80 (m, 2H), 6,62 (d, 1H), to 4.52 is 4.45 (m, 2H), 3,90-3,70 (m, 4H), of 3.45 (dt, 1H), 3.15 in (m, 4H), 2,98-and 2.83 (m, 2H), 2,82 (c, 2H), 2.63 in (c, 3H), 2,30 (m, 2H), 2,23 (m, 4H), 1,99 (c, 2H), 1,52 (c, 9H), 1.39 in (t, 2H), 0,94 (c, 6H).

EXAMPLE 48

2-(1H-Indazol--yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-yl)-N-(2-((4-Porterage-2H-Piran-4-yl)methoxy)-4-methylthiazole-5-ylsulphonyl)benzamid

The connection in this example receive, replacing in example 1I connection example 1H in the connection example 47E, a compound of example 1E in the compound from example 45A.

1H NMR (500 MHz, pyridine-d5) δ at 8.36 (c, 1H), 8,14 (d, 1H), 7,47 (d, 2H), 7,38 (d, 1H), 7,22 (m, 2H), 7,11 (d, 2H), 6,88-to 6.80 (m, 2H), 6,62 (d, 1H), to 4.52 (DD, 2H), 3,84-of 3.78 (m, 2H), of 3.73-3,70 (dt, 2H), 3.15 in (m, 4H), 2,82 (c, 2H), 2,67 (c, 3H), 2,30 (m, 2H), 2,23 (m, 4H), 1,99 (c, 2H), 1,82 is 1.75 (m, 4H), of 1.41 (t, 2H), 0,96 (c, 6H).

1. The compound of the formula I

or its therapeutically acceptable salts, where
And1represents furyl, imidazolyl, isothiazolin, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, piperidinyl, morpholinyl, dihydro-1,3,4-thiadiazole-2-yl, bestien-2-yl, benzothiazol-2-yl, tetrahydrothieno-3-yl, [1,2,4]triazolo[1,5-a]pyrimidine-2-yl or imidazo[2,1-b][1,3]-thiazol-5-yl;
where a1unsubstituted or substituted one, or two, or three, or four, or five substituents independently selected from R1, OR1C(O)OR1, Other1N(R1)2C(N)C(O)R1C(O)other1, NHC(O)R1, NR1C(O)R1, (O), NO2, F, Cl, Br and CF3;
R1is an R2, R3, R4or R5;
R2represents phenyl;
R3represents pyrazolyl or isoxazolyl;
R4is piperidinyl;
R5is the th C 1-C10alkyl or C2-C10alkenyl, each of which is not substituted or substituted by substituents selected from R7, SR7N(R7)2, NHC(O)R7, F and Cl;
R7is an R8, R9, R10or R11;
R8represents phenyl;
R9represents oxadiazolyl;
R10is morpholinyl, pyrrolidinyl or tetrahydropyranyl;
R11represents a C1-C10alkyl;
Z1represents a phenylene;
Z2represents piperidine, not substituted or substituted OCH3or piperazine;
Z1Aand Z2Aboth are absent;
L1represents a C1-C10alkyl or C2-C10alkenyl, each of which is not substituted or is substituted by R37B
R37Brepresents phenyl;
Z3is an R38or R40;
R38represents phenyl;
R40represents a cyclohexyl or cyclohexenyl;
where the phenylene represented by Z1not substituted or substituted by a group OR41;
R41is an R42or R43;
R42represents phenyl, which is not condensed or condensed with pyrrolidon, imidazolium or pyrazole;
R43represents pyridinyl, which are not condensed or cond is sirawan with pyrrolidon;
where each of the above cyclic fragment represented by R2, R3, R4, R8, R9, R10, R38, R40, R42and R43regardless not substituted or substituted by one or more substituents independently selected from R57, OR57With(O)OR57, F, Cl, CF3and Br;
R57is an R58or R61;
R58represents phenyl;
R61represents a C1-C10alkyl; and
where the phenyl represented by the group R58not substituted or substituted by one or more substituents, independently selected from F and Cl.

2. Connection on p. 1 or its therapeutically acceptable salt, where the compound has formula II
,
where R101represents H or or41.

3. Connection on p. 1 or its therapeutically acceptable salt, where the compound has formula III
,
where R101represents H or or41.

4. Connection on p. 1 or its pharmaceutically acceptable salt, where the specified connection selected from
4-[4-(cyclohexylmethyl)-4-methoxypiperidine-1-yl]-N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}benzamide;
N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}-4-[4-methoxy-4-(3-methylbenzyl)Pieper is DIN-1-yl]benzamide;
N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}-4-[4-(3,3-diphenylprop-2-enyl)piperazine-1-yl]benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-{[2-(phenylthio)ethyl]amino}piperidine-1-yl)sulfonyl]benzamide;
N-[(4-{acetyl[2-(phenylthio)ethyl]amino}piperidine-1-yl)sulfonyl]-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-{methyl[2-(phenylthio)ethyl]amino}piperidine-1-yl)sulfonyl]benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)cyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-{[5-({(1R)-3-[isopropyl(methyl)amino]-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}benzamide;
N-{[(5Z)-5-(acetylamino)-4-methyl-4,5-dihydro-1,3,4-thiadiazole-2-yl]sulfonyl}-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;
N-{[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]sulfonyl}-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;
N-({5-[(benzoylamine)methyl]Tien-2-yl}sulfonyl)-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;
4-{4-[(4'-PI is the p-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-(morpholine-4-ylsulphonyl)benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[4-phenyl-5-(trifluoromethyl)Tien-3-yl]sulfonyl]benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5-fluoro-3-methyl-1-benzothieno-2-yl)sulfonyl]benzamide;
N-(1,3-benzothiazol-2-ylsulphonyl)-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-(Tien-2-ylsulphonyl)benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]benzamide;
ethyl 4-{[(4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzoyl)amino]sulfonyl}-5-methyl-1,2-diphenyl-1H-pyrrole-3-carboxylate;
methyl 5-{[(4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzoyl)amino]sulfonyl}-1-methyl-1H-pyrrole-2-carboxylate;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[5-(1,3-dimethyl-1H-pyrazole-5-yl)isoxazol-4-yl]sulfonyl}benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-chloro-3-metalization-5-yl)sulfonyl]benzamide;
N-[(5-bromo-3-methyl-1-benzothieno-2-yl)sulfonyl]-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-({5-[(E)-2-(1,2,4-oxadi the ol-3-yl)vinyl]Tien-2-yl}sulfonyl)benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-{[1-(2-chloroethyl)-3,5-dimethyl-1H-pyrazole-4-yl]sulfonyl}benzamide;
5-{[(4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzoyl)amino]sulfonyl}-N-(1-ethylpropyl)-1,3,4-thiadiazole-2-carboxamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5-chloro-1,3-dimethyl-1H-pyrazole-4-yl)sulfonyl]benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-nitro-5-piperidine-1-Illian-2-yl)sulfonyl]benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5-isoxazol-5-yl-2-furyl)sulfonyl]benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3,5-dimethylisoxazol-4-yl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-({4-nitro-5-[(3-pyrrolidin-1-ylpropyl)amino]Tien-2-yl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(5-{[3-(dimethylamino)propyl]amino}-4-nitration-2-yl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-({5-[(3-morpholine-4-ylpropyl)amino]-4-nitration-2-yl}sulfonyl)benzamide;
N-{[5-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-4-nitration-2-yl]sulfonyl}-4-{4-[2-(trifluoromethyl)benzylidene]piperidine-1-yl}benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methylene]piperidine-1-yl}-N-[(1,1-diox tetrahydrothieno-3-yl)sulfonyl]benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methylene]piperidine-1-yl}-N-[(5-chloro-3-methyl-1-benzothieno-2-yl)sulfonyl]benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5-chloro-3-methyl-1-benzothieno-2-yl)sulfonyl]-2-phenoxybenzamide;
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-[(6,7-debtor-1H-indol-5-yl)oxy]-N-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-yl)sulfonyl]benzamide;
tert-butyl (2S)-2-{[(5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;
tert-butyl (2S)-2-{[(5-{[2-(1H-benzimidazole-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-({2-[(4-Porterage-2H-Piran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)benzamide;
2-(1H-benzimidazole-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dime cyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-({2-[(4-Porterage-2H-Piran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)benzamide;
tert-butyl (2S)-2-{[(5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indazol-4-yloxy)benzoyl]sulfamoyl}-4-methyl-1,3-thiazol-2-yl)oxy]methyl}morpholine-4-carboxylate;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-({2-[(4-Porterage-2H-Piran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide.

5. 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-({2-[(4-Porterage-2H-Piran-4-yl)methoxy]-4-methyl-1,3-thiazol-5-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)benzamide or its therapeutically acceptable salt.

6. Pharmaceutical composition for treating bladder cancer, brain cancer, breast cancer, cancer, bone marrow cancer, cervical region, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, leukemia, called T-lymphocytes or b-cells, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, lung cancer, prostate cancer, small-cell lung cancer or cancer of the spleen containing the excipient and a therapeutically effective amount of the compound or its therapeutically acceptable salts under item 1 or 5.

7. A method of treating bladder cancer, brain cancer, breast cancer, ricacosta brain, cancer cervical area, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, leukemia, called T-lymphocytes or b-cells, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, lung cancer, prostate cancer, small-cell lung cancer or cancer of the spleen in a patient, comprising the administration to a patient a therapeutically effective amount of the compound or its therapeutically acceptable salts under item 1 or 5.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula IV, VIII-A and X, and to their pharmaceutical acceptable salts possessing the inhibitory activity on PI3-kinase (phosphoinositide-3-kinase). In compounds of formula IV and IX and Wd is specified in a group consisting of, , , and each of which can be substituted. In formula VIII-A, the group Wd represents the group or , wherein Ra is hydrogen, R11 is amino; in compound IV, Wa2 represents CR5; Wa3 represents CR6; Wa4 represents N or CR7; in compound IX, Wa1 and Wa2 independently represent CR5, N or NR4, and Wa4 independently represents CR7 or S, wherein no more than two neighbouring atoms in a ring represent atom or sulphur; Wb5 represents N; B represents a grouping of formula II, as well as in case of compound IV, B means C1-C10alkyl, C3-C10cycloalkyl, C3-C10heterocycloalkyl having one to six ring heteroatoms specified in N, O and S; in case of compound IX, B also means C1-C10alkyl, C3-C10cycloalkyl or 6-merous heterocycloalkyl having nitrogen atom; Wc represents C6-C10aryl or 5-18-merous heteroaryl having one or more ring heteroatoms specified in N, O and S, or phenyl or 6-merous heteroaryl respectively is equal to an integer of 0, 1, 2, 3 or 4; X is absent or represents -(CH(R9))z-, respectively; z is equal to 1; Y is absent. The other radical values are specified in the patent claim.

EFFECT: compounds can be used for treating such diseases, as cancer, bone disorders, an inflammatory or immune disease, diseases of the nervous system, metabolic disorders, respiratory diseases, thrombosis or cardiac diseases mediated by PI3-kinase.

68 cl, 11 dwg, 7 tbl, 55 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new compounds of formula I or their pharmaceutically acceptable salts, wherein R1 means phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen or 5-6-merous heteroaryl; R2 is phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen, halogen-C1-6alkyl, halogen-C1-6alkoxy, C1-6 alkylsulphonyl, nitrile, etc. R3 means H or C1-6 alkyl; X - -O-, -NRa-,-S(O)m- or CRbRc, wherein Ra - H, C1-6 alkyl or C1-6 alkylcarbonyl; Rb and Rc mean H or together with the atom to which they are attached, form 5-merous cycle additionally containing 2 oxygen atoms; m is equal to 0-2; Y means -NRc-, wherein Rc - H or C1-6 alkyl.

EFFECT: compounds can find application in medicine for treating autoimmune and inflammatory diseases related to P2X7 purinoceptor.

15 cl, 1 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to piridazine derivatives of formula II

,

in which radicals and symbols have determinations, given in the invention formula, or to their pharmaceutically acceptable salts.

EFFECT: compounds of formula II demonstrate inhibiting effect with respect to proteinkinases such as c-met, ron, or ALK, or chimeric proteins, and can be useful for treatment of disorders, associated with abnormal activity of proteinkinases, such as cancer.

7 cl, 1 tbl, 30 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the chemical-pharmaceutical industry and represents a compound having a structure according to formula I:

,

compositions containing the compounds of the above formula applicable to stimulate neurogenesis and/or inhibition of neuron degeneration.

EFFECT: invention may be used in treating diseases and conditions characterised by neuron loss and lower neurogenesis, including Alzheimer's disease, stroke, traumatic brain injury, traumatic nerve injury and depression.

8 cl, 2 tbl, 2 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to method of labelling paired helical filaments (PHF), which includes interaction of PHF with compound and detection of said compound presence, where compound has formula , in which -R- stands for , -Q- is selected from: -NHC(O)-, -N=N-, -CH=CH-; -P is selected from: ; -T is selected from: ; X represents N or CH; -W1-6, -G1-4, -P1-5 are such as given in the invention formula. Invention also relates to method of labelling aggregated tau-protein, which includes interaction of aggregated molecules of tau-protein with compounds and detection of said compound presence, and to compounds of formula , in which values of substituents are such as given in the invention formula.

EFFECT: formula compounds as labels of tau-protein and paired helical filaments (PHF).

28 cl, 5 dwg, 225 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of bicyclic heterocyclic compounds of formula (I), which can be applied in prevention or treatment of abnormal or pathological condition, mediated by FGFR kinase, such as cancer. In formula compound, (i) in case when R1 and R2 independently represent hydrogen or C3-8cycloalkyl; A is group Aa, which represents aromatic group, representing phenyl; R3 represents hydrogen or C1-6alkyl; R4 represents group R4a, which represents amino, halogen, C1-6alkyl, -X-R5, phenyl or aromatic heterocyclic group, where said heterocyclic group represents 5- or 6-membered heterocyclyl group and contains 1, 2 or 3 heteroatoms, independently selected from nitrogen, oxygen or sulphur, where said phenyl or said heterocyclyl group can be optionally substituted with one or two Rb groups; or (ii) when R1 represents hydrogen and R2 represents C1-6alkyl or halogenC1-6alkyl; A is group Ab, which represents aromatic 5-membered heterocyclic group; R3 represents hydrogen or C1-6alkyl; R4 is group R4a, which represents halogen; or (iii) when R1 represents hydrogen and R2 represents C1-6alkyl or halogenC1-6alkyl; A is group Ac, which represents aromatic 6-membered heterocyclic group, containing one nitrogen atom as heteroatom; R3 represents hydrogen or C1-6alkyl; R4 is group R4b, which represents halogen, C1-6alkyl, -X-R5 or aromatic heterocyclic group, containing 1, 2 or 3 heteroatoms, independently selected from nitrogen, oxygen and sulphur. Other values of radicals are given in the invention formula.

EFFECT: obtaining novel derivatives of bicyclic heterocyclic compounds.

21 cl, 7 tbl, 250 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein R1 represents an alkoxy group or halogen; each U and V independently represents CH or N; "----" means a bond or is absent; W represents CH or N, or if "----" is absent, then W represents CH2 or NH, provided not all U, V and W represent N; A represents a bond or CH2; R2 represents H, or provided A means CH2, then it also can represent OH; each m and n are independently equal to 0 or 1; D represents CH2 or a bond; G represents a phenyl group that is single or double substituted in meta- and/or para-position(s) by substitutes specified in alkyl, C1-3alkoxy group and halogen, or G represents one of the groups G1 and G2: wherein each Z1, Z2 and Z3 represents CH; and X represents N or CH and Q represents O or S; it should be noted that provided each m and n are equal to 0, then A represents CH2; or a pharmaceutically acceptable salt of such compound. Besides, the invention refers to a pharmaceutical composition for treating a bacterial infection containing an active ingredient presented by a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert additive.

EFFECT: preparing the oxazolidine compounds applicable for preparing a drug for treating and preventing the bacterial infections.

14 cl, 8 dwg, 2 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: invention relates to antibacterial compounds of formula (I), where R1 represents alkoxygroup; U, V and W each represents CH or one of U, V and W represents N, and each other represents CH; A represents CH2 or O; G represents CH=CH-E, where E represents phenyl group, mono- or di-substituted with halogen, or G represents group of one of the formulas given below , , where Z represents CH or N, Q represents O or S and K represents O or S; or salt of such compound. In addition, invention also relates to pharmaceutical composition based on formula (I) compound for prevention or treatment of bacterial infection, as well as to application of claimed compounds for obtaining medication for prevention or treatment of bacterial infection.

EFFECT: novel compounds, which can be applied in treatment of bacterial infection, are obtained and described.

23 cl, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula or , where Ar1 represents phenyl group, optionally substituted with one or several identical or non-identical halogen atoms; R1 represents hydrogen atom; R4, R5, R6a, R6b represent hydrogen atoms; Y, Z independently represent linear C1-4 alkylene group, optionally substituted with one linear C1-4 alkyl group; Ar2 stands for condensed with benzene 5-membered heterocyclic ring, containing one nitrogen atom and one sulphur atom, substituted with one linear C1-4 alkyl group, or derivative of 5- or 6-membered heterocyclic ring, containing one nitrogen atom and one sulphur atom, condensed with heteroaromatic 6-memebered ring, containing one or two nitrogen atoms, substituted with one linear C1-4 alkyl group, linear C1-4 alkoxygroup or group -NR7R8, where R7 and R8 independently stand for hydrogen atom, linear or branched C1-4 alkyl group, or R7 and R8 together with nitrogen atom form group of general formula , where R2, R3 represent linear C1-4 alkyl groups, A stands for group -CHR12, oxygen atom or group -NR9, where R12 and R9 stand for hydrogen atom or linear C1-4 alkyl group, m has value 1 or 2, n has value 1 or 2, o has value 0 or 1, p has value 0 or 1, Q stands for group -O-, group -N--H or group -N--CO-R10, where R10 stands for linear C1-4 alkyl group or -NH-R11 group, where R11 represents linear C1-4 alkyl group; and to their salts. Invention also relates to methods of obtaining therein and to based on them pharmaceutical composition, possessing antagonistic activity with respect to receptor CCR3.

EFFECT: obtained are novel compounds and based on them pharmaceutical compositions, which can be applied in medicine for obtaining medication, intended for treating asthma, allergic rhinitis, atopic dermatitis, eczema, inflammatory intestinal diseases, ulcerous colitis, Crohn's disease, allergic conjunctivitis, multiple sclerosis or HIV-infection and AIDS-associated diseases.

14 cl, 3 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a 2,4-diamino-1,3,5-triazine derivative of general formula I, having protein kinase inhibitor properties, use thereof and a pharmaceutical composition based thereon. In general formula I Y is CH2, CHR', O, S, S(O) or S(O)2; X1, X2, X3 are independently selected from a CH groups or N; R1 is a C1-8 aliphatic group, C3-8 cycloalkyl, C6-10 aryl, ethylene-dioxyphenyl, methylene dioxyphenyl, pyridyl, each of which is optimally substituted with one or more identical or different groups R"; R' is hydrogen, OH, halogen, such as F, Cl, Br, I, or carboxyl or carboxamide, optimally N-substituted with (C1-6)alkyl, or cyano or halo(C1-8)alkyl, (C1-8)alkoxy, piperidinyl, optimally substituted with methyl; R" is R' or RD; R21, R22, R23, R24 are independently selected from groups F, Cl, Br, I, CN, (C1-16)alkyl; furthermore, R21 and R22 and/or R23 and R24 can be combined and represent one oxo (=O) group or together with a carbon atom can form a spirocycle containing 3 to 7 carbon atoms; furthermore, R21 and R24 together with two carbon atoms can form an aliphatic or aromatic ring containing 4 to 8 atoms, optionally substituted with one or more groups R'; RD is an oxo group =O or =S.

EFFECT: invention can be used to treat autoimmune or cancerous diseases, rheumatoid arthritis and non-Hodgkin lymphoma.

13 cl, 12 ex

Jak inhibitors // 2538204

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I wherein R means C1-6alkyl, C1-6halogenalkyl, hydroxy-C1-6alkyl, hydroxygroup or halogen; m, n is equal to 0 or 1; Z1 means CH or NH; Z2 means CH or N; Z3 means CR1, N or NR2; R1 means H, C1-6alkyl, C3-7cycloalkyl, cyanogroup, cyano-C1-6alkyl or halogen; R2 means H or C1-6alkyl; X means CH, CR' or N; X' means CH, CR' or N; r is equal to 1; Y means CH or CR'; R' means R'a or R'b; R'a means a halogen or cyanogroup; R'b means C1-6alkyl, heterocycloalkyl specified in piperazinyl, morpholinyl, piperidinyl, thiomorpholinyl, azetidinyl, pyrrolidinyl, OR", SR", S(=O)2R" or NR"R", optionally substituted by one or more R'c; R'c means a hydroxygroup, oxogroup, cyanogroup, C1-6alkyl, pyridinyl, carboxy-C1-6alkyl, aminocarbonyl-C1-6alkylaminogroup, C1-6alkylaminogroup, C1-6dialkylaminogroup or C1-6alkoxygroup; R" means H, C1-6alkyl, hydroxy-C1-6alkyl, piperidinyl, C3-7cycloalkyl or pyridinyl; Q means S(=O)2Q1, C(=O)Q2, C(=O)OQ3 or Q4; Q1 means C1-6alkyl, C3-7cycloalkyl-C1-6alkyl, C1-6alkylaminogroup or C1-6dialkylaminogroup optionally substituted by one or more Q1'; each Q1' independently means C1-6alkyl or cyanogroup; Q2 means C1-6alkyl optionally substituted by one or more Q2'; each Q2' independently means a cyanogroup; Q3 means C1-6alkyl; Q4 means C1-6alkyl, oxetanyl optionally substituted by one or more Q4'; each Q4' independently means a halogen, cyanogroup, cyano-C1-6alkyl; p is equal to 0, 1 or 2; q is equal to 1 or 2; each means a single bond or a double bond; provided one of Z1 and Z2, and Z3 and Z3 bonds are double and single.

EFFECT: compounds of formula I as JAK inhibitors.

23 cl, 2 tbl, 121 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula IV, VIII-A and X, and to their pharmaceutical acceptable salts possessing the inhibitory activity on PI3-kinase (phosphoinositide-3-kinase). In compounds of formula IV and IX and Wd is specified in a group consisting of, , , and each of which can be substituted. In formula VIII-A, the group Wd represents the group or , wherein Ra is hydrogen, R11 is amino; in compound IV, Wa2 represents CR5; Wa3 represents CR6; Wa4 represents N or CR7; in compound IX, Wa1 and Wa2 independently represent CR5, N or NR4, and Wa4 independently represents CR7 or S, wherein no more than two neighbouring atoms in a ring represent atom or sulphur; Wb5 represents N; B represents a grouping of formula II, as well as in case of compound IV, B means C1-C10alkyl, C3-C10cycloalkyl, C3-C10heterocycloalkyl having one to six ring heteroatoms specified in N, O and S; in case of compound IX, B also means C1-C10alkyl, C3-C10cycloalkyl or 6-merous heterocycloalkyl having nitrogen atom; Wc represents C6-C10aryl or 5-18-merous heteroaryl having one or more ring heteroatoms specified in N, O and S, or phenyl or 6-merous heteroaryl respectively is equal to an integer of 0, 1, 2, 3 or 4; X is absent or represents -(CH(R9))z-, respectively; z is equal to 1; Y is absent. The other radical values are specified in the patent claim.

EFFECT: compounds can be used for treating such diseases, as cancer, bone disorders, an inflammatory or immune disease, diseases of the nervous system, metabolic disorders, respiratory diseases, thrombosis or cardiac diseases mediated by PI3-kinase.

68 cl, 11 dwg, 7 tbl, 55 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically 4-((2-hydroxyethoxy)methyl)-5-methyl-2-methylmercapto-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one of formula (I) . The invention also relates to a method of producing and using said compound to treat West Nile fever.

EFFECT: obtaining a novel compound with useful biological activity.

3 cl, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: described is novel biologically active compound 2-methylsulphanyl-6-nitro-7-oxo-1,2,4-triazolo[5,1-c][1,2,4]triazinide L-argininium dehydrate of formula , which has antiviral action, method of its obtaining and application for prevention and treatment of West Nile fever.

EFFECT: increased efficiency of compound application.

3 cl, 2 tbl, 2 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

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new compounds of formula I or their pharmaceutically acceptable salts, wherein R1 means phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen or 5-6-merous heteroaryl; R2 is phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen, halogen-C1-6alkyl, halogen-C1-6alkoxy, C1-6 alkylsulphonyl, nitrile, etc. R3 means H or C1-6 alkyl; X - -O-, -NRa-,-S(O)m- or CRbRc, wherein Ra - H, C1-6 alkyl or C1-6 alkylcarbonyl; Rb and Rc mean H or together with the atom to which they are attached, form 5-merous cycle additionally containing 2 oxygen atoms; m is equal to 0-2; Y means -NRc-, wherein Rc - H or C1-6 alkyl.

EFFECT: compounds can find application in medicine for treating autoimmune and inflammatory diseases related to P2X7 purinoceptor.

15 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I, possessing a modulating action with respect to the CC chemokine receptor 3 (CCR3), a based on them pharmaceutical composition, versions of treatment methods and a method of controlling the CCR3 activity. In the general formula I R1 and R2 represent halogen or C1-6alkyl; R3 represents cyano or nitro; R4 represents or ; R5 represents oxo; C1-6alkyl, optionally substituted with halogen atoms; or C(O)OR1a; X represents O or S; Y represents -O-, -S-, -N(R1a)-, -C(R1a)(R1d)- or -C(R1a)(NR1bR1c)-; m represents an integer number from 0 to 2; n represents 1; p represents an integer number from 0 to 2; r represents 1 or 2; and each R1a, R1b, R1c and R1d represents (a) hydrogen; (b) C3-7cycloalkyl; or (c) C1-6alkyl, optionally substituted with hydroxyl, or each pair R1b and R1c together with a N atom, which they are bound to, form imidazoimidazolyl, substituted with oxo, butyl or chlorine, or heterocycle, containing 5 or 6 atoms in a cycle.

EFFECT: improvement of the composition properties.

41 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to benzoimidazole derivatives of formula (I), as well as to their enantiomers, diastereoisomers, racemates and pharmaceutically acceptable salts, where n equals from 2 to 4, each of R1 substituents is independently selected from H, halogen, -C1-4alkyl, -C1-4pergaloalkyl, trifluoro-C1-4alkoxy, -NO2, -CN, CO2H, -OC1-4alkyl, -SC1-4alkyl, -S(C1-4alkyl)-Rc, -S(O)2(C1-4alkyl)-Rc, -S(O)-C1-4alkyl, -SO2-C1-4alkyl, -S-Rc, -S(O)-Rc, -SO2-Rc, -SO2-NH-Rc, -O-Rc, -CH2-O-Rc, -C(O)NH-Rc, -NRaRb, benzyloxy, phenyl, optionally substituted with one-two Rd, cyanobiphenyl-4-ylmethylsulpfanyl, cyanobiphenyl-4-ylmethanesulphonyl, or -S-(CH2)2-morpholine and two adjacent groups R1 can bind with formation of an aromatic 5-6-membered ring, optionally substituted with one methyl group or two atoms of halogen, optionally containing one or two S or N; Ra and Rb each independently represents C1-4alkyl, -C(O)C1-4alkyl, -C(O)-Rc, -C(O)CH2-Re, C1-4alkyl-Re, -SO2-Rc, -SO2-C1-4alkyl, phenyl, benzyl; or Ra and Rb together with a nitrogen atom, which they are bound with, form a monocyclic 5-6- membered heterocycloalkyl ring, optionally containing one heteroatom, selected from O; Rc represents -C3-8cycloalkyl, phenyl, optionally substituted with one-two Rd, benzyl, optionally substituted with one-three Rd; morpholine; Rd independently represents halogen, -OH, -C1-4alkyl or -C1-4perhalogenalkyl, trifluorine C1-4alcoxy, -OC1-4alkyl, or -O-benzyl optionally substituted with halogen, Re represents -C6heterocycloalkyl, optionally containing one or two of O or N atoms, optionally substituted with a methyl group; R2 and R3 both represent H, -CF3 or C1-3alkyl; each of Z represents a C or N atom, on condition that simultaneously not more than two Z represent N. The invention also relates to particular compounds, a pharmaceutical composition, based on formula (I) compound or a particular said compound, a method of treating diseases, mediated by propyl hydroxylase activity.

EFFECT: novel derivatives of benzimidazole, possessing an inhibiting activity with respect to PHD are obtained.

11 cl, 1 tbl, 186 ex

FIELD: chemistry.

SUBSTANCE: invention relates to (3aR,6aR)-N-(4-(3-ethylphenylamino)-7-methoxyquinazolin-6-yl)-1-methylhexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide or its pharmaceutically acceptable salt, as well as to a pharmaceutical composition for treatment of the cancer disease, sensible to inhibition of hyper-expression and/or hyperactivity of a receptor of an epidermal growth factor, which contains the claimed compound, a method of the cancer disease treatment, a method of inhibition and to the application of the claimed compound for a drug preparation.

EFFECT: (3aR,6aR)-N-(4-(3-ethylphenylamino)-7-methoxyquinazoline-6-yl)-1-methylhexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide, which shows an inhibition activity to hyperexpression and/or hyperactivity of the epidermal growth factor receptor.

12 cl, 4 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel 5-methyl-6-nitro-7-oxo-4,7-dihydro-1,2,4-triazolo[1,5-α]pyrimidinide l-argininium monohydrate of formula (1) The compound has antiviral activity with respect to group A and B strain viruses in in vitro and in vivo systems.

EFFECT: compound has low toxicity.

4 dwg, 3 tbl, 4 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

Up!