Apoptosis-inducing agents for treating cancer and immune and autoimmune diseases

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to specific compounds or their therapeutically acceptable salts presented in the patent claim and representing sulphonyl benzamide derivatives. Besides, the invention refers to a pharmaceutical composition and a method of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, stomach cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, T-cell or B-cell lymphoid process, melanoma, myelogenic leukaemia, myeloma, oral cancer, ovarian cancer, non-small-cell lung cancer, prostate cancer, small-cell lung cancer, spleen cancer with the above composition containing an excipient and a therapeutically effective amount of the sulphonyl benzamide derivative or its therapeutically acceptable salt.

EFFECT: preparing the new pharmaceutical composition.

5 cl, 45 ex

 

This application claims the priority of provisional patent application U.S. 61/145627, filed January 19, 2009, which is fully incorporated into the present description by reference.

The SCOPE of the INVENTION

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

The LEVEL of TECHNOLOGY

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

Overexpression of proteins Bcl-2 correlates with resistance to chemotherapy, clinical consequences, the development of the disease, General predictions, or their combinations in different types of cancer and immune system disorders.

Involvement of protein Bcl-2 in bladder cancer, brain cancer, breast cancer, cancer of the bone marrow, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, gastric cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of the processes of T-cell or b-cell origin, melanoma, myelogenous leukemia, myeloma, cancer of the oral cavity, cancer of the ovary, non-small cell lung cancer is easily the th, prostate cancer, small cell lung cancer, cancer of the spleen, etc. described in the joint application PCT US 2004/36770, published as WO2005/049593, and PCT US 2004/37911, published as WO2005/024636.

Involvement of protein Bcl-2 in immune and autoimmune diseases are described in theCurrent Allergy and Asthma Reports2003, 3, 378-384;British Journal of Haematology2000, 110(3), 584-90;Blood2000, 95(4), 1283-92; andNew England Journal of Medicine2004, 351(14), 1409-1418. Involvement of protein Bcl-2 in arthritis disclosed in the joint provisional application for U.S. patent 60/988479. Involvement of protein Bcl-2 in the rejection of bone marrow transplant disclosed in the joint application for U.S. patent 11/941196.

The INVENTION

One way of implementing this invention pertains to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs that can be used as inhibitors of anti-apoptotic proteins Bcl-2, and these compounds have the Formula I

in which

A1denotes N or C(A2);

A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A; NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R 1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

E1and Y1together with the atoms to which they are attached, are benzene, naftilan, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

A2B1and D1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

Y1and B1together with the atoms to which they are attached, are benzene, naftilan, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

A2D1and E1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(ONHOR 1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

A2and B1together with the atoms to which they are attached, are benzene, naftilan, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

A2and D1together with the atoms to which they are attached, are benzene, naphthalene, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

B1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1 , SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

R1oboznachaet R2, R3, R4or R5;

R1Adenotes cycloalkyl, cycloalkenyl or cycloalkenyl;

R2denotes phenyl, which is not condensed or fused with benzene, heteroatom or R2A; R2Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R3denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R3A; R3Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R4denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R4A; R4Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R5denotes alkyl, alkenyl or quinil, each of which is unsubstituted or substituted 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)NH2,C(O)other7C(O)N(R7)2, NHC(O)R7, NR7C(O)R7, NHSO2R7, NHC(O)R 7, 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, (O), N3, CN, NH2, CF3, CF2CF3, F, Cl, Br or I;

R6indicatesC2-C5-spiralcell, each of which is unsubstituted or substituted by OH, (O), N3CN, CF3, CF2CF3, F, Cl, Br, I, NH2, NH(CH3) or N(CH3)2;

R6Aand R6Brepresent independently selected alkyl or, together with the N to which they are attached, R6C;

R6Cindicates aziridine-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidine-1-yl, each of which has one group CH2, nezamenimoy or replaced by the groups O, C(O), CNOH, CNOCH3, S, S(O), SO2or NH;

R7means R8, R9, R10or R11;

R8denotes phenyl, which is not condensed or fused with benzene, heteroatom or R8A; R8Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R9denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R9A; R9Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R10denotes cycloalkyl, cycloalkenyl, g is therotically or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R10A; R10Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R11denotes alkyl, alkenyl or quinil, each of which is unsubstituted or substituted one, or two, or three independently selected substituents R12, OR12, SR12, S(O)R12, SO2R12C(O)R12, CO(O)R12, 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;

R12means R13, R14, R15or R16;

R13denotes phenyl, which is not condensed or fused with benzene, heteroatom or R13A; R13Aindicates cycloalkane, cycloalkene, geteroseksualen is whether geteroseksualen;

R14denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R14A; R14Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R15indicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R15A; R15Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R16denotes alkyl, alkenyl or quinil;

Z1means R26or R27;

Z2means R28, R29or R30;

Z1Aand Z2Aboth are absent, or together form CH2CH2CH2or Z12A;

Z12AindicatesC2-C6-alkylen with one or two groupsCH2replaced by a group NH, N(CH3), S, S(O) or SO2;

L1means R37, OR37, SR37, S(O)R37, SO2R37C(O)R37, CO(O)R37, OC(O)R37, OC(O)OR37, Other37C(O)NH, C(O)NR37C(O)NHOR37C(O)NHSO2R37, SO2NH, SO2Other37C(N)NH, C(N)other37;

R26denotes phenylene, which is not condensed or condensed with benzene or heteroatom or R26A; R26Aindicates cycloalkane, cycloalkene, heteros who cycloalkane or geteroseksualen;

R27indicates heteroaryl that is not condensed or condensed with benzene or heteroatom or R27A; R27Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R28denotes phenylene, which is not condensed or fused with benzene, heteroatom or R28A; R28Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R29indicates heteroaryl that is not condensed or condensed with benzene or heteroatom or R29A; R29Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R30denotes cycloalkyl, cycloalkenyl, heterocyclochain or heterocyclization, each of which is not condensed or fused with benzene, heteroatom or R30A; R30Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R37means a connection or R37A;

R37Adenotes alkylene, albaniles or akinyan, each of which is unsubstituted or substituted by one or two or three substituents, independently selected from R37B, OR37B, SR37B, S(O)R37B, SO2R37BC(O)R37B, CO(O)R37B, OC(O)R37B, OC(O)OR37B, NH2, Other37BN(R37B)2, NHC(O)R37B, NR37BC(O)R37B NHS(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;

R37Bdenotes alkyl, alkenyl, quinil, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen;

Z3means R38, R39or R40;

R38denotes phenyl, which is not condensed or fused with benzene, heteroatom or R38A; R38Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R39denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R39A; R39Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R40denotes cycloalkyl, cycloalkenyl, heteroseksualci, or geteroseksualen, each of which is not condensed or condensed with Ben who I, heteroatom or R40A; R40Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

and groups represented by 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)R41, CO(O)R41, 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, OCF2CF3, F, Cl, Br or I;

R41means R42, R43, R44or R45;

R42denotes phenyl, which is not condensed or fused with benzene, heteroatom or R42A; R42Aindicates cyclea the Kang, cycloalken, geteroseksualen or geteroseksualen;

R43denotes heteroaryl that is not condensed or condensed with benzene or R43A; R43Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R44denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R44A; R44Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R45denotes alkyl, alkenyl or quinil, each of which is unsubstituted or substituted by one or two substituents, independently selected from R46, OR46, SR46, S(O)R46, SO2R46C(O)R46, CO(O)R46, 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;

R46denotes alkyl, alkenyl, quinil, R47, R48or R49;

R47denotes phenyl, which is not condensed or fused with benzene, heteroatom or R47A; R47Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R48denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R48A; R48Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R49denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R49A; R49Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

moreover, the cyclic group represented by E1and Y1together, Y1and B1together, A2and B1together, A2and D1together, R1A, R2, R2A, R3, R3A, R4, R4A, R6, R6C, R8, R8A, R9, R9A, R10, R10A, R13, R13A, R14, R14A, R15, R15A, R28, R28A, R29, R29A, R30, R30A, R37B, R38, R38A, R39, R39A , R40and R40Ano not substituted, is not further substituted, substituted or optionally substituted by one or more substituents independently selected from R57, OR57, SR57, S(O)R57, SO2R57C(O)R57, CO(O)R57, 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;

R57means R58, R59, R60or R61;

R58denotes phenyl, which is not condensed or fused with benzene, heteroatom or R58A; R58Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R59denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R59A; R59Aindicates the cycle of the alkane, cycloalken, geteroseksualen or geteroseksualen;

R60denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R60A; R60Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R61denotes alkyl, alkenyl or quinil, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R62, OR62, SR62, S(O)R62, SO2R62C(O)R62, CO(O)R62, 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;

R62means R63, R64, R65or R66;

R63indicates the dryer is l, which is not condensed or fused with benzene, heteroatom or R63A; R63Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R64denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R64A; R64Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R65denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R65A; R65Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R66denotes alkyl, alkenyl or alkenyl, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R67, OR67, SR67, S(O)R67, SO2R67C(O)R67, CO(O)R67, 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, SO2NH 2, 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;

R67denotes alkyl, alkenyl, quinil, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen;

moreover, the cyclic groups represented by R58, R59, R60, R63, R64, R65and R67not substituted or substituted by one or more substituents independently selected from R68, OR68, SR68, S(O)R68, SO2R68C(O)R68, CO(O)R68, 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;

R68the seat is t R 69, R70, R71or R72;

R69denotes phenyl, which is not condensed or fused with benzene, heteroatom or R69A; R69Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R70denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R70A; R70Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R71denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R71A; R71Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R72denotes alkyl, alkenyl or alkenyl, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R73, OR73, SR73, S(O)R73, SO2R73C(O)R73, CO(O)R73, 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)NHOR 73C(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;

R73denotes alkyl, alkenyl, alkenyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; and

groups represented by R69, R70and R71not substituted or substituted by one or more substituents, independently selected from 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)

A1denotes N or C(A2);

A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3or NO2;

or

E1and Y1together with the atoms to which they are attached, are benzene, or heteroaryl, and

A2B1and D1independently selected from H;

or

Y1and B1together with the atoms to which they are attached, are benzene, and

A2D1and E1independently selected from H;

or

A2Yves 1together with the atoms to which they are attached, represent heteroaryl, cycloalkyl, geteroseksualen or geteroseksualen; and

D1E1and Y1independently selected from H, F, Cl, Br, I or NO2;

Z1means R26;

Z2means R30;

Z1Aand Z2Aboth are absent;

L1means R37;

R26denotes phenylene;

R30denotes heterocyclochain;

R37means R37A;

R37Adenotes alkylene or albaniles, each of which is unsubstituted or substituted R37B;

R37Bdenotes phenyl;

Z3means R38or R40;

R38denotes phenyl;

R40means cycloalkenyl;

and groups represented by 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, SO2R41or other41;

R41means R42or R45;

R42denotes phenyl, which is not condensed or condensed with heteroatom;

R45denotes alkyl, which is unsubstituted or substituted by one or two independently in the abusive R 46;

R46means R47;

R47denotes phenyl;

moreover, the cyclic group represented by E1and Y1together, Y1and B1together, A2and B1together, R30, R30A, R37B, R38and R40no not substituted, is not further substituted, substituted or optionally substituted by one or more substituents independently selected from R57, OR57, NR57C(O)R57or (O);

R57means R58or R61;

R58denotes phenyl,

R61denotes alkyl, which is unsubstituted or substituted one, or two, or three substituents, independently selected from N(R62)2or F, Cl, Br or I;

R62means R66;

R66denotes alkyl; and

moreover, a cyclic group represented by R58, unsubstituted or substituted by one or more substituents, independently selected from F, Cl, Br or I.

In another embodiment of Formula (I),

A1denotes N or C(A2);

A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3or NO2;

or

E1and Y1together with the atoms to which they are attached, are benzene, or heteroaryl, and

A2B1and D1independently selected from H;

or

Y1and B1/sup> together with the atoms to which they are attached, are benzene, and

A2D1and E1independently selected from H;

or

A2and B1together with the atoms to which they are attached, represent heteroaryl, cycloalkyl, geteroseksualen or geteroseksualen; and

D1E1and Y1independently selected from H, F, Cl, Br, I or NO2;

Z1means R26;

Z2means R30;

Z1Aand Z2Aboth are absent;

L1means R37;

R26denotes phenylene;

R30denotes heterocyclochain;

R37means R37A;

R37Adenotes alkylene or albaniles, each of which is unsubstituted or substituted R37B;

R37Bdenotes phenyl;

Z3means R38or R40;

R38denotes phenyl;

R40means cycloalkenyl;

and groups represented by 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, SO2R41or other41;

R41means R42or R45;

R42denotes phenyl, Kateryna condensed or condensed with heteroatom;

R45denotes alkyl, which is unsubstituted or substituted by one or two independently selected R46;

R46means R47;

R47denotes phenyl;

moreover, the cyclic group represented by E1and Y1together, Y1and B1together, A2and B1together, R30, R30A, R37B, R38and R40no not substituted, is not further substituted, substituted or optionally substituted by one or more substituents independently selected from R57, OR57, NR57C(O)R57or (O);

R57means R58or R61;

R58denotes phenyl,

R61denotes alkyl, which is unsubstituted or substituted one, or two, or three substituents, independently selected from N(R62)2or F, Cl, Br or I;

R62means R66;

R66denotes alkyl; and

moreover, a cyclic group represented by R58, unsubstituted or substituted by one or more substituents, independently selected from F, Cl, Br or I.

Another variant implementation of the invention pertains to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs that can be used as inhibitors of anti-apoptotic proteins Bcl-2, and connect the to have the Formula IV,

in which

A1denotes N or C(A2);

A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A; NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

E1and Y1together with the atoms to which they are attached, are benzene, naftilan, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

A2B1and D1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

Y1and B1together with the atoms to which they are attached, are benzene, naphthas is len, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

A2D1and E1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

A2and B1together with the atoms to which they are attached, are benzene, naftilan, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

A2and D1together with the atoms to which they are attached, are benzene, naphthalene, heteroaryl, recloak is h, cycloalken, geteroseksualen or geteroseksualen; and

B1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

R1means R2, R3, R4or R5;

R1Adenotes cycloalkyl, cycloalkenyl or cycloalkenyl;

R2denotes phenyl, which is not condensed or fused with benzene, heteroatom or R2A; R2Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R3denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R3A; R3Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R4denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R4A; R4Aindicates cycloalkane, cycloalkene, geteroseksualen or heterocycle is Ken;

R5denotes alkyl, alkenyl or quinil, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R6, NC(R6A)(R6B), R7, OR7, SR7, S(O)R7, SO2R7, Other7N(R7)2C(O)R7C(O)NH2,C(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, (O), N3, CN, NH2, CF3, CF2CF3, F, Cl, Br or I;

R6represents C2-C5-spiralcell, each of which is unsubstituted or substituted by OH groups, (O), N3CN, CF3, CF2CF3, F, Cl, Br, I, NH2, NH(CH3) or N(CH3)2;

R6Aand R6Brepresent independently selected alkyl or, together with the N to which they are attached, denote R6C;

R6Cindicates aziridine-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidine-1-yl, each of which has one group CH2, nezamenimoy or replaced by a group of O, C(O), CNOH, CNOCH3, S, S(O), SO2or NH;

R7means R8, R9, R10or R11;

R8denotes phenyl, which secondinterval or fused with benzene, heteroatom or R8A; R8Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R9denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R9A; R9Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R10denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R10A; R10Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R11denotes alkyl, alkenyl or quinil, each of which is unsubstituted or substituted by one or two or three substituents, independently selected from R12, OR12, SR12, S(O)R12, SO2R12C(O)R12, CO(O)R12, 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, (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;

R12means R13, R14, R15or R16;

R13denotes phenyl, which is not condensed or fused with benzene, heteroatom or R13A; R13Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R14denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R14A; R14Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R15indicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R15A; R15Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R16denotes alkyl, alkenyl or quinil;

Z3means R38, R39or R40;

R38denotes phenyl, which is not condensed or fused with benzene, heteroatom or R38A; R38Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R39denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R 39A; R39Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R40denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R40A; R40Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

moreover, the cyclic group represented by E1and Y1together, Y1and B1together, A2and B1together, A2and D1together, R1A, R2, R2A, R3, R3A, R4, R4A, R6, R6C, R8, R8A, R9, R9A, R10, R10A, R13, R13A, R14, R14A, R15, R15A, R28, R28A, R29, R29A, R30, R30A, R37B, R38, R38A, R39, R39A, R40and R40Ano not substituted, is not further substituted, substituted or optionally substituted by one or more substituents independently selected from R57, OR57, SR57, S(O)R57, SO2R57C(O)R57, CO(O)R57, 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;

R57means R58, R59, R60or R61;

R58denotes phenyl, which is not condensed or fused with benzene, heteroatom or R58A; R58Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R59denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R59A; R59Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R60denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R60A; R60Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R61denotes alkyl, alkenyl, or quinil, each of which is unsubstituted or substituted by one or two or three substituents, independently is selected from R 62, OR62, SR62, S(O)R62, SO2R62C(O)R62, CO(O)R62, 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;

R62means R63, R64, R65or R66;

R63denotes phenyl, which is not condensed or fused with benzene, heteroatom or R63A; R63Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R64denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R64A; R64Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R65denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of catharijne condensed or fused with benzene, heteroatom or R65A; R65Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R66denotes alkyl, alkenyl, or alkenyl, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R67, OR67, SR67, S(O)R67, SO2R67C(O)R67, CO(O)R67, 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;

R67denotes alkyl, alkenyl, quinil, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen;

moreover, the cyclic groups represented by R58, R59, R60, R63, R64, R65and R67not substituted or substituted by one or more substituent and, independently selected from R68, OR68, SR68, S(O)R68, SO2R68C(O)R68, CO(O)R68, 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;

R68means R69, R70, R71or R72;

R69denotes phenyl, which is not condensed or fused with benzene, heteroatom or R69A; R69Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R70denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R70A; R70Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R71denotes cycloalkyl, cycloalkenyl, heteroseksualci or heterocy alkenyl, each of which is not condensed or fused with benzene, heteroatom or R71A; R71Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R72denotes alkyl, or alkenyl, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R73, OR73, SR73, S(O)R73, SO2R73C(O)R73, CO(O)R73, 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;

R73denotes alkyl, alkenyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; and

groups represented by R69, R70and R71not substituted or substituted by one or more substituents, the independent is IMO selected from NH 2C(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 implementation of the invention pertains to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs that can be used as inhibitors of anti-apoptotic proteins Bcl-2, and compounds have the Formula V,

in which

A1denotes N or C(A2);

A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A; NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

E1and Y1together with the atoms to which they are attached, are benzene, naftilan, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

A2B1and D1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(ONH 2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

Y1and B1together with the atoms to which they are attached, are benzene, naftilan, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

A2D1and E1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

A2and B1together with the atoms to which they are attached, are benzene, naftilan, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1ANO 2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

A2and D1together with the atoms to which they are attached, are benzene, naphthalene, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

B1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

R1means R2, R3, R4or R5;

R1Adenotes cycloalkyl, cycloalkenyl or cycloalkenyl;

R2denotes phenyl, which is not condensed or fused with benzene, heteroatom or R2A; R2Aindicates cycloalkane, cycloalkene, geteroseksualen or heterocycle is alkene;

R3denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R3A; R3Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R4denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R4A; R4Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R5denotes alkyl, alkenyl or quinil, each of which is unsubstituted or substituted by one or two or three substituents, independently selected from R6, NC(R6A)(R6B), R7, OR7, SR7, S(O)R7, SO2R7, Other7N(R7)2C(O)R7C(O)NH2,C(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, (O), N3, CN, NH2, CF3, CF2CF3, F, Cl, Br or I;

R6represents C2-C5-spiralcell, each of which is unsubstituted or substituted by OH groups, (O), N3CN, CF3, CF2CF3, F, Cl, Br, I, NH2, NH(CH ) or N(CH3)2;

R6Aand R6Brepresent independently selected alkyl or, together with the N to which they are attached, denote R6C;

R6Cindicates aziridine-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidine-1-yl, each of which has one group CH2, nezamenimoy or replaced by a group of O, C(O), CNOH, CNOCH3, S, S(O), SO2or NH;

R7means R8, R9, R10or R11;

R8denotes phenyl, which is not condensed or fused with benzene, heteroatom or R8A; R8Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R9denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R9A; R9Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R10denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R10A; R10Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R11denotes alkyl, alkenyl or quinil, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R12, OR12, SR12, S(O)R12SO 2R12C(O)R12, CO(O)R12, 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;

R12means R13, R14, R15or R16;

R13denotes phenyl, which is not condensed or fused with benzene, heteroatom or R13A; R13Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R14denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R14A; R14Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R15indicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen, each of which is not condensed or fused with benzene,heteroatom or R 15A; R15Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R16denotes alkyl, alkenyl or quinil;

Z3means R38, R39or R40;

R38denotes phenyl, which is not condensed or fused with benzene, heteroatom or R38A; R38Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R39denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R39A; R39Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R40denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R40A; R40Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

moreover, the cyclic group represented by E1and Y1together, Y1and B1together, A2and B1together, A2and D1together, R1A, R2, R2A, R3, R3A, R4, R4A, R6, R6C, R8, R8A, R9, R9A, R10, R10A, R13, R13A, R14, R14A, R15, R15A, R28, R28A, R29, R29A, R30, R30A, R37B , R38, R38A, R39, R39A, R40and R40Ano not substituted, is not further substituted, substituted or optionally substituted by one or more substituents independently selected from R57, OR57, SR57, S(O)R57, SO2R57C(O)R57, CO(O)R57, 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;

R57means R58, R59, R60or R61;

R58denotes phenyl, which is not condensed or fused with benzene, heteroatom or R58A; R58Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R59denotes heteroaryl that is not condensed or fused with benzene, heteroatom is whether R 59A; R59Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R60denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R60A; R60Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R61denotes alkyl, alkenyl, or quinil, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R62, OR62, SR62, S(O)R62, SO2R62C(O)R62, CO(O)R62, 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;

R62means R63, R64, R65Il is R 66;

R63denotes phenyl, which is not condensed or fused with benzene, heteroatom or R63A; R63Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R64denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R64A; R64Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R65denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R65A; R65Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R66denotes alkyl, alkenyl, or alkenyl, each of which is unsubstituted or substituted by one or two or three substituents, independently selected from R67, OR67, SR67, S(O)R67, SO2R67C(O)R67, CO(O)R67, 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)NRsup> 67SO2R67, 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;

R67denotes alkyl, alkenyl, quinil, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen;

moreover, the cyclic groups represented by R58, R59, R60, R63, R64, R65and R67not substituted or substituted by one or more substituents independently selected from R68, OR68, SR68, S(O)R68, SO2R68C(O)R68, CO(O)R68, 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;

R68means R69, R70, R71or R72;

R69denotes phenyl, which is not condensed or fused with benzene, heteroatom or R69A; R69Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R70denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R70A; R70Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R71denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R71A; R71Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R72denotes alkyl or alkenyl, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R73, OR73, SR73, S(O)R73, SO2R73C(O)R73, CO(O)R73, 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)other73, (O)N(R 73)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;

R73denotes alkyl, alkenyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; and

groups represented by R69, R70and R71not substituted or substituted by one or more substituents, independently selected from 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 implementation of the invention pertains to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs that can be used as inhibitors of anti-apoptotic proteins Bcl-2, and these compounds have the Formula VI,

in which

A1denotes N or C(A2);

A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A; NO2, OCF3, CFsub> 2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

E1and Y1together with the atoms to which they are attached, are benzene, naftilan, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

A2B1and D1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

Y1and B1together with the atoms to which they are attached, are benzene, naftilan, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

A2D1and E1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2 CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

A2and B1together with the atoms to which they are attached, are benzene, naftilan, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

A2and D1together with the atoms to which they are attached, are benzene, naphthalene, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

B1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C()NH 2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

R1means R2, R3, R4or R5;

R1Adenotes cycloalkyl, cycloalkenyl or cycloalkenyl;

R2denotes phenyl, which is not condensed or fused with benzene, heteroatom or R2A; R2Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R3denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R3A; R3Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R4denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R4A; R4Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R5denotes alkyl, alkenyl or quinil, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R6, NC(R6A)(R6B), R7, OR7, SR7, S(O)R7,SO 2R7, Other7N(R7)2C(O)R7C(O)NH2,C(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, (O), N3, CN, NH2, CF3, CF2CF3, F, Cl, Br or I;

R6indicatesC2-C5-spiralcell, each of which is unsubstituted or substituted by OH groups, (O), N3CN, CF3, CF2CF3, F, Cl, Br, I, NH2, NH(CH3) or N(CH3)2;

R6Aand R6Brepresent independently selected alkyl or, together with the N to which they are attached, denote R6C;

R6Cindicates aziridine-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidine-1-yl, each of which has one group CH2, nezamenimoy or replaced by a group of O, C(O), CNOH, CNOCH3, S, S(O), SO2or NH;

R7means R8, R9, R10or R11;

R8denotes phenyl, which is not condensed or fused with benzene, heteroatom or R8A; R8Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R9denotes heteroaryl that is not condensed or Conde is financed with benzene, heteroatom or R9A; R9Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R10denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R10A; R10Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R11denotes alkyl, alkenyl or quinil, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R12, OR12, SR12, S(O)R12, SO2R12C(O)R12, CO(O)R12, 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;

R12means R13, R 14, R15or R16;

R13denotes phenyl, which is not condensed or fused with benzene, heteroatom or R13A; R13Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R14denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R14A; R14Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R15indicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R15A; R15Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R16denotes alkyl, alkenyl or quinil;

Z3means R38, R39or R40;

R38denotes phenyl, which is not condensed or fused with benzene, heteroatom or R38A; R38Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R39denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R39A; R39Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R40denotes cycloalkyl, cycloalkenyl, heteroseksualci or heterocyclic the Nile, each of which is not condensed or fused with benzene, heteroatom or R40A; R40Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

moreover, the cyclic group represented by E1and Y1together, Y1and B1together, A2and B1together, A2and D1together, R1A, R2, R2A, R3, R3A, R4, R4A, R6, R6C, R8, R8A, R9, R9A, R10, R10A, R13, R13A, R14, R14A, R15, R15A, R28, R28A, R29, R29A, R30, R30A, R37B, R38, R38A, R39, R39A, R40and R40Ano not substituted, is not further substituted, substituted or optionally substituted by one or more substituents independently selected from R57, OR57, SR57, S(O)R57, SO2R57C(O)R57, CO(O)R57, 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, SO NH2, 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;

R57means R58, R59, R60or R61;

R58denotes phenyl, which is not condensed or fused with benzene, heteroatom or R58A; R58Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R59denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R59A; R59Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R60denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R60A; R60Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R61denotes alkyl, alkenyl, or quinil, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R62, OR62, SR62, S(O)R62, SO2R62C(O)R62, CO(O)R62, OC(O)R62, OC(O)OR62, NH2, Other62N(R62)2, NHC(O)R62, NR62C(O)R 62NHS(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;

R62means R63, R64, R65or R66;

R63denotes phenyl, which is not condensed or fused with benzene, heteroatom or R63A; R63Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R64denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R64A; R64Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R65denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R65A; R65Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R66oznachaet alkyl or alkenyl, each of which is unsubstituted or substituted by one or two or three substituents, independently selected from R67, OR67, SR67, S(O)R67, SO2R67C(O)R67, CO(O)R67, 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;

R67denotes alkyl, alkenyl, quinil, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen;

moreover, cyclic half, presents R58, R59, R60, R63, R64, R65and R67not substituted or substituted by one or more substituents independently selected from R68, OR68, SR68, S(O)R68, SO2R68C(O)R68, CO(O)R68, OC(O)R68, OC(O)OR68, NH2, Other68N(R6 )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;

R68means R69, R70, R71or R72;

R69denotes phenyl, which is not condensed or fused with benzene, heteroatom or R69A; R69Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R70denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R70A; R70Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R71denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R71A; R71Aindicates cycloalkane, cycloalkene, heterocyclic is or geteroseksualen;

R72denotes alkyl or alkenyl, each of which is unsubstituted or substituted by one or two or three substituents, independently selected from R73, OR73, SR73, S(O)R73, SO2R73C(O)R73, CO(O)R73, 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;

R73denotes alkyl, alkenyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; and

groups represented by R69, R70and R71not substituted or substituted by one or more substituents, independently selected from NH2C(O)NH2C(O)NHOH, SO2NH2, CF3, CF2CF3C(O)H, C(O)OH, C(N)NH2, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF 2CF3, F, Cl, Br or I.

Another variant implementation of the invention pertains to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs that can be used as inhibitors of anti-apoptotic proteins Bcl-2, and these compounds have the Formula VII

in which

A1denotes N or C(A2);

A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A; NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

E1and Y1together with the atoms to which they are attached, represents a benzene, naftilan, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

A2B1and D1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

Y1and B1together with the atoms to which they are attached, represents a benzene, naftilan, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

A2D1and E1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

A2and B1together with the atoms to which they are attached, represents a benzene, naftilan, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2 , NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

A2and D1together with the atoms to which they are attached, represents a benzene, naphthalene, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

B1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

R1means R2, R3, R4or R5;

R1Adenotes cycloalkyl, cycloalkenyl or cycloalkenyl;

R2denotes phenyl, which is not condensed or fused with benzene, heteroatom or R2A; R2Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R3denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R3A; R3Ameans cyclol the Academy of Sciences, cycloalken, geteroseksualen or geteroseksualen;

R4denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R4A; R4Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R5denotes alkyl, alkenyl or quinil, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R6, NC(R6A)(R6B), R7, OR7, SR7, S(O)R7, SO2R7, Other7N(R7)2C(O)R7C(O)NH2,C(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, (O), N3, CN, NH2, CF3, CF2CF3, F, Cl, Br or I;

R6represents C2-C5-spiralcell, each of which is unsubstituted or substituted by OH groups, (O), N3CN, CF3, CF2CF3, F, Cl, Br, I, NH2, NH(CH3) or N(CH3)2;

R6Aand R6Brepresent independently selected alkyl or, together with the N to which they are attached, denote R6C ;

R6Cindicates aziridine-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidine-1-yl, each of which has one group CH2, nezamenimoy or replaced by a group of O, C(O), CNOH, CNOCH3, S, S(O), SO2or NH;

R7means R8, R9, R10or R11;

R8denotes phenyl, which is not condensed or fused with benzene, heteroatom or R8A; R8Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R9denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R9A; R9Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R10denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R10A; R10Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R11denotes alkyl, alkenyl or quinil, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R12, OR12, SR12, S(O)R12, SO2R12C(O)R12, CO(O)R12, OC(O)R12, OC(O)OR12, NH2, Other12N(R12)2, NHC(O)R12, NR12C(O)R12NHS(O)2 12, 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;

R12means R13, R14, R15or R16;

R13denotes phenyl, which is not condensed or fused with benzene, heteroatom or R13A; R13Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R14denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R14A; R14Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R15indicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R15A; R15Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R16denotes alkyl, Alchemilla quinil;

Z3means R38, R39or R40;

R38denotes phenyl, which is not condensed or fused with benzene, heteroatom or R38A; R38Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R39denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R39A; R39Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R40denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R40A; R40Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

moreover, the cyclic group represented by E1and Y1together, Y1and B1together, A2and B1together, A2and D1together, R1A, R2, R2A, R3, R3A, R4, R4A, R6, R6C, R8, R8A, R9, R9A, R10, R10A, R13, R13A, R14, R14A, R15, R15A, R28, R28A, R29, R29A, R30, R30A, R37B, R38, R38A, R39, R39A, R40and R40Ano not substituted, is not further substituted, substituted or additional C is medeni one or more substituents, independently selected from R57, OR57, SR57, S(O)R57, SO2R57C(O)R57, CO(O)R57, 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;

R57means R58, R59, R60or R61;

R58denotes phenyl, which is not condensed or fused with benzene, heteroatom or R58A; R58Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R59denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R59A; R59Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R60denotes cycloalkyl, cycloalkenyl, heteroseksualci or heterocy alkenyl, each of which is not condensed or fused with benzene, heteroatom or R60A; R60Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R61denotes alkyl, alkenyl or quinil, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R62, OR62, SR62, S(O)R62, SO2R62C(O)R62, CO(O)R62, 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;

R62means R63, R64, R65or R66;

R63denotes phenyl, which is not condensed or fused with benzene, heteroatom or R63A; R63Aindicates cycloalkane, cycloalkene, heterocycle is an or geteroseksualen;

R64denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R64A; R64Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R65denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R65A; R65Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R66denotes alkyl or alkenyl, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R67, OR67, SR67, S(O)R67, SO2R67C(O)R67, CO(O)R67, 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, CF2CFsub> 3, OCF3, OCF2CF3, F, Cl, Br or I;

R67denotes alkyl, alkenyl, quinil, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen;

moreover, cyclic half, presents R58, R59, R60, R63, R64, R65and R67not substituted or substituted by one or more substituents independently selected from R68, OR68, SR68, S(O)R68, SO2R68C(O)R68, CO(O)R68, 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,

R68means R69, R70, R71or R72;

R69denotes phenyl, which is not condensed or fused with benzene, heteroatom or R69A; R69Ahereafter which includes cycloalkane, cycloalken, geteroseksualen or geteroseksualen;

R70denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R70A; R70Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R71denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R71A; R71Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R72denotes alkyl or alkenyl, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R73, OR73, SR73, S(O)R73, SO2R73C(O)R73, CO(O)R73, 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;

R73denotes alkyl, alkenyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; and

groups represented by R69, R70and R71not substituted or substituted by one or more substituents, independently selected from 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 refers to compounds having Formula I, which are

4-[4-(3,3-diphenylprop-2-enyl)piperazine-1-yl]-N-[(3-nitrophenyl)sulfonyl]benzamide;

N-[(2-bromophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)cyclohex-1-EN-1-yl]methyl}piperazine-1-yl)benzamide;

N-[(3-bromophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)cyclohex-1-EN-1-yl]methyl}piperazine-1-yl)benzamide;

N-[(4-bromophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)cyclohex-1-EN-1-yl]methyl}piperazine-1-yl)benzamide;

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

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

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

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

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

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

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

4-[4-(1,1'-biphenyl-4-ylmethyl)-3-isopropylpiperazine-1-yl]-N-(phenylsulfonyl)benzamide;

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

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

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

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

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

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

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

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

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

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

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methylpiperazin-1-yl}-N-[(3-forfinal)sulfonyl]-2-phenoxybenzamide;

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

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

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

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

4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)piperazine-1-yl]-2-(1H-indol-4-yloxy)-N-[(3-nitrophenyl)sulfonyl]benzamide;

4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)piperazine-1-yl]-2-(1H-indol-4-yloxy)-N-(phenylsulfonyl)benzamide;

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

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-(phenylsulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(3-cyanophenyl)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-{[3-(trifluoromethyl)phenyl]sulfonyl}benzamide;

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

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1 is the n-1-yl]methyl}piperazine-1-yl)-N-[(3-forfinal)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-(2-naphthylmethyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-(isoquinoline-5-ylsulphonyl)benzamide;

N-[(4-chloro-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indazol-4-yloxy)benzamide;

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(2-chloropyridin-3-yl)sulfonyl]benzamide;

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(7-nitro-1H-benzimidazole-5-yl)sulfonyl]benzamide;

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)sulfonyl]benzamide;

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(6-chloro-1,1-dioxide-2H-1,2,4-benzothiadiazin-7-yl)sulfonyl]benzamide;

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-({5-[ethyl(TRIFLUOROACETYL)amino]-1-naphthyl}sulfonyl)benzamide;

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfonyl]benzamide;

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(2-oxo-2H-chromen-6-yl)sulfonyl]benzamide;

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

Another variant of implementation relates to compositions for treating bladder cancer, brain cancer, breast cancer, bone cancer MoH is a, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, gastric cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or b-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, lung cancer, prostate cancer, small-cell lung cancer, cancer of the spleen, and this composition includes excipient and a therapeutically effective amount of the compounds of Formula (I).

Another variant of implementation relates to a method for treating bladder cancer, brain cancer, breast cancer, cancer of the bone marrow, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, gastric cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or b-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, lung cancer, prostate cancer, small-cell lung cancer, cancer of the spleen in a patient, moreover, this method includes the introduction to the patient a therapeutically effective amount of Formula (I).

Another variant of implementation relates to a method of treatment of bladder cancer, the aka cord, breast cancer, cancer of the bone marrow, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, gastric cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or b-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, lung cancer, prostate cancer, small-cell lung cancer, cancer of the spleen in a patient, and this method includes the introduction to the 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

Varying group represented by identifiers (capital letters with numeric and/or alphabetic Superscript notation) and can have special options.

It should be understood that the inherent valency saved for all groups and their combinations, which is a monovalent group having more than one atom are indicated from left to right and is connected through the left ends and that divalent group also indicated from left to right.

Also it should be understood that the specific options of varying groups which can be the same or different in relation to other specific options, having the same identifier.

The term "alkenyl" in the context of the invention means a straight or branched hydrocarbon chain containing from 2 to 10 carbon atoms and containing at least one carbon-carbon double bond. The term “Cx-Cyalkyl” means a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond containing from x to y carbon atoms. The term “C2-C4alkenyl” means alkenylphenol group containing 2-4 carbon atoms. Representative examples of alkenyl include, but are not limited to, 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 hydrocarbons with straight or branched chain, containing from 2 to 4 carbon atoms, and containing at least one carbon-carbon double bond. The term “CxCyalkylene” means a divalent group derived straight or branched hydrocarbon chain containing at least one carbon-carbon double bond and containing from x to y carbon atoms. Representative examples of Alcanena include, but are not limited to, -CH=CH - and-CH2CH=CH-.

The term "alkyl" as part of the image is the shadow means a straight or branched saturated hydrocarbon chain, containing from 1 to 10 carbon atoms. The term “Cx-Cyalkyl” means a straight or branched saturated hydrocarbon chain containing from x to y carbon atoms. For example, “C2-C10alkyl” means a straight or branched saturated hydrocarbon chain containing from 2 to 10 carbon atoms. Examples of alkyl include, but are not limited to, 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 straight or branched saturated carbon chain of 1-10 carbon atoms, for example of 1-4 carbon atoms. The term “Cx-Cyalkylene” means a divalent group derived straight or branched saturated hydrocarbon chain containing from x to y carbon atoms. For example, “C2-C6alkylene” means a straight or branched saturated hydrocarbon chain containing from 2 to 6 carbon atoms. Examples of alkylene include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2- and-CH2CH(CH3)CH2-.

The term "quinil" in the context of the invention means the carbohydrate is native group with a straight or branched chain, containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. The term “Cx-Cyquinil” means a hydrocarbon group with a straight or branched chain, containing from x to y carbon atoms. Representative examples of quinil include, but are not limited to, acetylenyl, 1-PROPYNYL, 2-PROPYNYL, 3-butynyl, 2-pentenyl and 1-butynyl.

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

The term "aryl" in the context of the invention means phenyl.

The term "cyclic group" in the context of the invention means benzene, phenyl, phenylene, cycloalkane, cycloalkyl, cycloalkyl, cycloalkene, cycloalkenyl, cycloalkenyl, cycloalkyl, cycloalkenyl, cycloalkenyl, heteroaryl, heteroaryl, geteroseksualen, heteroseksualci, geteroseksualen, geteroseksualen, spiroheterocyclic, spiroheterocyclic, Spirito and spiralcell.

The term "cycloalkyl", or "cycloalkyl", or "cycloalkane" in the context of the invention means a monocyclic or connected bridge connection hydrocarbon ring system. Monocyclic cycloalkyl is carbocycles the ring system, containing from 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 consists of one, two or three carbon atoms, each of which connects two non-adjacent carbon atom of the ring system. Non-limiting examples of such United bridge connection ring cycloalkyl 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 coupled bridge the communication cycloalkyl can be attached to the parent molecular group via any suitable replacement for the atom contained in the ring system.

The term "cycloalkenyl", or "cycloalkenyl", or “cycloalkene” in the context of the invention means a monocyclic or connected bridge connection hydrocarbon ring system. Monocyclic cycloalkenyl has four-, five-, six-, seven -, or eight carbon atoms and zero heteroatoms. Four-membered ring systems have on the well of the double bond, five - or six-membered ring systems have one or two double bonds, and the seven - or eight-membered ring systems have one, two or three double bonds. Representative examples of monocyclic cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctanol. Monocyclic cycloalkenyl ring may contain one or two alkilinity bridge, each of which consists of one, two or three carbon atoms, each of which connects two non-adjacent carbon atom of the ring system. Representative examples of bicyclic cycloalkenyl groups include, but are not limited to, 4,5,6,7-tetrahydro-3aH-inden, octahydronaphthalene and 1,6-dihydro-pentalene. Monocyclic and bicyclic cycloalkenyl can be attached to the parent molecular group via any suitable replacement for the atom contained in the ring systems.

The term "cycloalkyl", or "cycloalkenyl", or "cycloalkenyl", in the framework of the invention, means a monocyclic or connected bridge connection hydrocarbon ring system. Monocyclic cycloalkenyl has eight or more carbon atoms, and zero heteroatoms and one or more triple bonds. Monocyclic cycloalkenyl ring may contain one or two alkilinity mo is teak, each of them consists of one, two or three carbon atoms, each of which connects two non-adjacent carbon atom of the ring system. Monocyclic and coupled bridge the communication cycloalkenyl can be attached to the parent molecular group via any suitable replacement for the atom contained in the ring systems.

The term "heteroaryl", or "heteroaryl", or "heteroaryl", in the framework of the invention, means a five-membered or six-membered aromatic ring having at least one carbon atom and one or more atoms independently selected from nitrogen, oxygen or sulfur. Heteroarenes according to the invention are connected through any adjacent atoms in the ring, provided that these are inherent valency. Representative examples of heteroaryl include, but are not limited to, furanyl (including, but not limited to, furan-2-yl), imidazolyl (including, but not limited to, 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 limited to, Tien-2-yl, Tien-3-yl), triazolyl and triazinyl.

The term "geteroseksualen", or "heteroseksualci", or "heterocyclochain" under izobreteny is, means monocyclic or United bridging the connection between the three-, four-, five-, six-, seven - or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N and S, and zero double bonds. Monocyclic and coupled bridge connection geteroseksualen related to the parent molecular group via any suitable for replacing a carbon atom or any suitable for substitution of the nitrogen atom contained in the composition of the rings. The heteroatoms nitrogen and sulfur in the ring heterocycle may be oxidized, and the nitrogen atoms can be quaternity. Representative examples geterotsiklicheskikh groups include, but are not limited to, 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, tritional.

The term "geteroseksualen", or "geteroseksualen", or "heterocyclization", in the framework of the invention, means a monocyclic or United bridging the connection between the three-, four-, five-, six-, seven - or eight the fixed ring, containing at least one heteroatom independently selected from the group consisting of O, N and S, and one or more double bonds. Monocyclic and coupled bridge connection geteroseksualen are linked to the parent molecular group via any suitable for replacing a carbon atom or any suitable for substitution of the nitrogen atom contained in the composition of the rings. The heteroatoms nitrogen and sulfur in the ring heterocycle may be oxidized, and the nitrogen atoms can be quaternity. Representative examples geterotsiklicheskikh groups include, but are not limited to, tetrahydrocortisol, 1,4,5,6-tetrahydropyridines, 1,2,3,6-tetrahydropyridine, dihydropyran, imidazolines, isothiazolines, oxadiazolyl, isoxazolyl, oxazolyl, pyranyl, pyrazolyl, pyrrolyl, thiadiazolyl, thiazolyl and tiopronin.

The term "phenylene", in the framework of the invention, means the divalent radical formed by removal of a hydrogen atom of the phenyl.

The term "spirooli", in the framework of the invention, means alkylen, both ends of which are attached to the same carbon atom, and is illustrated by the C2-spiralcell, C3-spiralcell, C4-spiralcell, C5-spiralcell, C6-spiralcell, C7-spiralcell, C8-spiralcell, C9-spiralcell etc.

The term "spirolaterals", within the image is etenia, means spiralcell with one or two groups CH2replaced independently selected groups O, C(O), CNOH, CNOCH3, S, S(O), SO2or NH and one or two CH group, nezamenennymi or replaced by the atom N.

The term "spiroheterocyclic", in the framework of the invention, means serialkey with one or two groups CH2replaced independently selected groups O, C(O), CNOH, CNOCH3, S, S(O), SO2or NH and one or two CH group, nezamenennymi or substituted by N atom, and also means serialkey with one or two groups CH2, nezamenennymi or replaced with independently selected groups O, C(O), CNOH, CNOCH3, S, S(O), SO2or NH and one or two CH group, substituted atom N.

The term "Spirito", in the framework of the invention, means are two substituents on the same carbon atom, which, together with the carbon atom to which they are attached, form cycloalkane, geteroseksualnoe, cycloalkene or geterotsyklicescoe ring.

The term "C2-C5-spiralcell", in the framework of the invention, meansC2-spiralcell, C3-spiralcell, C4-spiralcell and C5-spiralcell.

The term "C2-spiralcell", in the framework of the invention, means et-1,2-ilen, both ends of which replace hydrogen atoms of the same groupCH2.

The term "C3-spiralcell" under the image is the shadow, means prop-1,3-ilen, both ends of which replace hydrogen atoms of the same groupCH2.

The term "C4-spiralcell", in the framework of the invention, means buta-1,4-ilen, both ends of which replace hydrogen atoms of the same groupCH2.

The term "C5-spiralcell", in the framework of the invention, means Penta-1,5-ilen, both ends of which replace hydrogen atoms of the same groupCH2.

The term "C6-spiralcell", in the framework of the invention, means Gex-1,6-ilen, both ends of which replace hydrogen atoms of the same groupCH2.

The term "protective group for a group NH", in the framework of the invention, means trichlorocyanuric, tribromoethanol, benzyloxycarbonyl, para-nitrobenzylamine, ortho-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, TRIFLUOROACETYL, phenylacetyl, formyl, acetyl, benzoyl, tert-aryloxyalkyl, tert-butoxycarbonyl, para-methoxybenzeneboronic, 3,4-dimethoxybenzyl-oxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryl-oxycarbonyl, diphenylcarbinol, 1,1-DIMETHYLPROPANE-carbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantanecarbonyl, 8-hinolincarbonova, benzyl, diphenylmethyl, triphenylmethyl, 2-nitrophenylthio, methanesulfonyl, para-toluensulfonyl, N,N-dimethylaminomethylene, Benz is Liden, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthyl-methylene, 3-hydroxy-4-pyridylmethylene, cyclohexylidene, 2-ethoxycarbonylphenyl, 2-ethoxycarbonylphenyl, 2-acetylcyclohexanone, 3,3-dimethyl-5-axillo-hexylidene, diphenylphosphoryl, dibenzoyltartaric, 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl, trimethylsilyl, and triphenylene.

The term "protective group for a group C(O)HE", in the framework of the invention, means methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl, naphthyl, benzyl, diphenylmethyl, triphenylmethyl, para-nitrobenzyl, para-methoxybenzyl, bis(para-methoxyphenyl)methyl, acetylethyl, benzoylmethyl, para-nitrobenzoyl, para-bromobenzoyl, para-methanesulfonylaminoethyl, 2-tetrahydropyranyl 2-tetrahydropyranyl, 2,2,2-trichloro-ethyl, 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, triphenylsilane, triisopropylsilyl, diethylenediamine, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilane and tert-butylperoxyisopropyl.

The term "protecting the health of the group for the group HE or SH", in the framework of the invention, means benzyloxycarbonyl, 4-nitrobenzenesulfonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzenesulfonyl, 3,4-dimethoxyphenylacetone, methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropanolamine, isopropoxycarbonyl, isobutylacetate, 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-benzyltoluene, 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-trichloro-ethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methanesulfonyl, para-toluensulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylenediamine, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, di is enigmatically and tert-butylperoxyisopropyl.

Connection

The compounds according to the invention may exist as geometric isomers. Compounds according to the invention may contain carbon-carbon double bond or carbon-nitrogen double bond in the E or Z configuration, and the term “E” represents substituents of higher order on opposite sides of the carbon-carbon or carbon-nitrogen double bond, and the term “Z” represents substituents of higher order on the same side of the carbon-carbon or carbon-nitrogen double bond, as defined according to the Cahn-Ingold-Prelog Priority Rules. Compounds according to the invention may also exist as a mixture of E and Z isomers. Deputies around cycloalkyl or geterotsiklicheskie are defined as having a configuration TRANS or CIS. In addition, the invention covers various isomers and mixtures thereof resulting from the removal of the substituents around the ring system adamantane. The two Vice-around individual rings within the ring system adamantane are defined as having a relative configuration Z or e). as examples, see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le NobleJ. 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 according to the invention can contain asymmetrically substituted carbon atoms in the R configuration is Lee S, moreover, the terms "R" and "S" is defined in accordance with the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10. Compounds having asymmetrically substituted carbon atoms with equal amounts of R and S configurations are racemic in respect of these carbon atoms. Atoms with an excess of one configuration to another is designated as having a configuration that is present in a higher quantity, preferably an excess of about 85%-90%, more preferably, an excess of approximately 95%-99%, and more preferably, an excess of more than about 99%. Accordingly, this invention includes racemic mixtures, relative and absolute stereoisomers and a mixture of relative and absolute stereoisomers.

Compounds according to the invention containing group NH, C(O)OH, OH or SH, can be attached forming a prodrug group. Forming a prodrug groups are removed by metabolic processes and release the connection with the selected hydroxyl, amino or carboxylic acid in vivo. Prodrugs are useful in order to regulate such pharmacokinetic properties of compounds, such as solubility and/or hydrophobicity, absorption in the gastrointestinal tract, bioavailability, penetration into the tissue and the rate of excretion.

Enriched or labeled with isotopes with the organisations

Compounds according to the invention can exist in the isotope-labeled or enriched isotope form, containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most widespread in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorus (3), sulfur, fluorine, chlorine, and iodine include, but are not limited to,2H,3H,13C,14C,15N18O,32P,35S18F,36Cl125I. Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention.

In another embodiment, isotope-labeled compounds contain isotopes deuterium (2H), tritium (3H) or14C. isotope-Labeled compounds according to the invention can be obtained by conventional methods known to the expert. Such isotope-labeled compounds can be obtained by carrying out the procedures disclosed in the Examples disclosed here, and Schemes by replacing its reagent readily available isotope-labeled reagent. In some cases, the compounds may be processed isotope-labeled reagents to replace the normal atom by its isotope, for example, hydrogen may be replaced by deuterium action deuterium to the slots, such asD2SO4/D2O. In addition to the above, the relevant procedures and intermediate compounds disclosed, for example, Lizondo, J et al.,Drugs Fut, 21(11), 1116 (1996); Brickner, S Jet al.,J Med Chem, 39(3), 673 (1996); Mallesham, B et al.,Org Lett, 5(7), 963 (2003); the PCT publications WO1997010223, WO2005099353, WO1995007271, WO2006008754; U.S. patents 7538189; 7534814; 7531685; 7528131; 7521421; 7514068; 7511013; and publications of patent applications U.S. 20090137457; 20090131485; 20090131363; 20090118238; 20090111840; 20090105338; 20090105307; 20090105147; 20090093422; 20090088416; and 20090082471, which are included by reference.

Labeled isotope compounds according to the invention can be used as standards to determine the effectiveness of inhibitors of Bcl-2 in tests of binding. Isotopomeres compounds are used in pharmaceutical research to study the metabolic fate of compounds in vivo by assessing the mechanism of action and metabolic pathways are not isotope-labeled parent compound (Blake et al.J. Pharm. Sci.64, 3, 367-391 (1975)). Such metabolic studies are important in the development of safe, effective therapeutic drugs, as becausein vivothe active compound is administered to the patient, and because the metabolites, which are derivatives of the parent compounds may be 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 (1999).

In addition, containing a non-radioactive isotope of the medicinal product, such as datarecovery medicines called “hard drugs” can be used to treat diseases and conditions associated with the activity of Bcl-2. Increasing the amount of isotope present in the compound above its natural prevalence is known as enrichment. A number of examples 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.%. Replace approximately 15% of normal heavy atom isotope was produced and supported within days to weeks in mammals, including rodents and dogs, with 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 found that acute replacement, such as 15%-23% in human fluids by deuterium, does not cause toxicity (Blagojevic N et al. in "Dosimetry &Treatment Planning for Neutron Capture Therapy", Zamenhof R, Solares G and Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp.125-134; Diabetes Metab. 23: 251 (1997)).

Introduction tracer stable isotope in medicine may alter its physico-chemical properties such as pKa and solubility in lipids. These effects and changes in sodeistvovat on the pharmacodynamic response of the molecule drugs, if the isotopic substitution affects the area included in the interaction of the receptor with the ligand. While some of the physical properties of stable isotope-labeled molecules differ from those of its chemical and biological properties are the same, with one important exception: due to the increased mass of the heavy isotope, any communications involving heavy isotope and the other atom is stronger than the same relationship between the light isotope and this atom. Accordingly, the inclusion of isotope at the site of metabolism or enzymatic transformation will slow these reactions, potentially altering the pharmacokinetic profile or efficacy relative to non-isotropic connections.

Amides,esters and prodrugs

Prodrugs are derivatives of the active medicinal agent intended to improve some of the identified undesirable physical or biological properties. The physical properties are usually related to solubility (excessive or insufficient jirorastvorimogo or water solubility or stability, while problematic biological properties include too quick metabolism or low bioavailability, which directly can be associated with a physicist who-chemical property.

Prodrugs are usually obtained: a) formation of ester, complex profirov, carbonate esters, nitrofuran, amides, hydroxamic acids, carbamates, Iminov, Mannich bases, phosphates, phosphate esters, and enamines active drugs, b) functionalization of drugs azo-, glycoside, peptide and ether functional groups, c) the use of aminolink, pollinating, polymer, salt, complex, phosphoramide, acetylenic, polyacetylene and katalinich forms of medicines. For example, see andrejus on Korolkovas's, "Essentials of Medicinal Chemistry", John Wiley-Interscience Publications, John Wiley and Sons, New York (1988), pp. 97-118, which is fully incorporated into the present description by reference.

Esters can be obtained from the substrates of formula (I) containing or hydroxyl group, or carboxyl group, conventional methods known to the expert. Typical reactions of these compounds are replacing one of the heteroatoms to another atom, for example:

Scheme 1

Amides can be obtained from the substrates of formula (I) containing either the amino group or carboxyl group in a similar fashion. Esters can also react with amines or ammonia with the formation of amides.

Scheme 2

Another way of obtaining the amides of the C compounds of formula (I) is to heat together carboxylic acids and amines.

Scheme 3

In the above Schemes 2 and 3, R and R' are independently substrates of formula (I), the alkyl or hydrogen.

Suitable groups for A1B1D1E1, Y1L1, Z1A, Z2A, Z1, Z2and Z3in the compounds of Formula (I) are chosen independently. Described embodiments of the present invention can be combined. This combination is considered in the framework of the present invention. For example, embodiments of any of the A1B1D1E1, Y1L1, Z1A, Z2A, Z1, Z2and Z3can be combined with options for the implementation defined for any other of the A1B1D1E1, Y1L1, Z1A, Z2A, Z1, Z2and Z3.

One way of implementing this invention pertains to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs that can be used as inhibitors of anti-apoptotic proteins Bcl-2, and compounds have the Formula (I)

in which

A1denotes N or C(A2);

A2B1D1E1and Y1ezavisimo selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A; NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

E1and Y1together with the atoms to which they are attached, are benzene, naftilan, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

A2B1and D1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

Y1and B1together with the atoms to which they are attached, are benzene, naftilan, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

A2D1and E1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

A2and B1together with the atoms to which they are attached, are benzene, naftilan, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

A2and D1together with the atoms to which they are attached, are benzene, naphthalene, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

B1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A , NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

R1oboznachaet R2, R3, R4or R5;

R1Adenotes cycloalkyl, cycloalkenyl or cycloalkenyl;

R2denotes phenyl, which is not condensed or fused with benzene, heteroatom or R2A; R2Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R3denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R3A; R3Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R4denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R4A; R4Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R5denotes alkyl, alkenyl or quinil, each of which is unsubstituted or substituted by one or two or three independently selected substituents R 6, NC(R6A)(R6B), R7, OR7, SR7, S(O)R7, SO2R7, Other7N(R7)2C(O)R7C(O)NH2,C(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, (O), N3, CN, NH2, CF3, CF2CF3, F, Cl, Br or I;

R6indicatesC2-C5-spiralcell, each of which is unsubstituted or substituted by OH, (O), N3CN, CF3, CF2CF3, F, Cl, Br, I, NH2, NH(CH3) or N(CH3)2;

R6Aand R6Brepresent independently selected alkyl or, together with the N to which they are attached, R6C;

R6Cindicates aziridine-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidine-1-yl, each of which has one group CH2, nezamenimoy or replaced by the groups O, C(O), CNOH, CNOCH3, S, S(O), SO2or NH;

R7means R8, R9, R10or R11;

R8denotes phenyl, which is not condensed or fused with benzene, heteroatom or R8A; R8Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R9putting the AET heteroaryl, which is not condensed or fused with benzene, heteroatom or R9A; R9Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R10denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R10A; R10Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R11denotes alkyl, alkenyl or quinil, each of which is unsubstituted or substituted one, or two, or three independently selected substituents R12, OR12, SR12, S(O)R12, SO2R12C(O)R12, CO(O)R12, 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/sub> , F, Cl, Br or I;

R12means R13, R14, R15or R16;

R13denotes phenyl, which is not condensed or fused with benzene, heteroatom or R13A; R13Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R14denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R14A; R14Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R15indicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R15A; R15Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R16denotes alkyl, alkenyl or quinil;

Z1means R26or R27;

Z2means R28, R29or R30;

Z1Aand Z2Aboth are absent, or together form CH2CH2CH2or Z12A;

Z12AindicatesC2-C6-alkylen with one or two groupsCH2replaced by a group NH, N(CH3), S, S(O) or SO2;

L1means R37, OR37, SR37, S(O)R37, SO2R37C(O)R37, CO(O)R37, OC(O)R37, OC(O)OR37, Other 37C(O)NH, C(O)NR37C(O)NHOR37C(O)NHSO2R37, SO2NH, SO2Other37C(N)NH, C(N)other37;

R26denotes phenylene, which is not condensed or condensed with benzene or heteroatom or R26A; R26Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R27indicates heteroaryl that is not condensed or condensed with benzene or heteroatom or R27A; R27Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R28denotes phenylene, which is not condensed or fused with benzene, heteroatom or R28A; R28Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R29indicates heteroaryl that is not condensed or condensed with benzene or heteroatom or R29A; R29Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R30denotes cycloalkyl, cycloalkenyl, heterocyclochain or heterocyclization, each of which is not condensed or fused with benzene, heteroatom or R30A; R30Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R37means a connection or R37A;

R37Adenotes alkylene, alkenyl is or akinyan, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R37B, OR37B, SR37B, S(O)R37B, SO2R37BC(O)R37B, CO(O)R37B, 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;

R37Bdenotes alkyl, alkenyl, quinil, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen;

Z3means R38, R39or R40;

R38denotes phenyl, which is not condensed or fused with benzene, heteroatom or R38A; R38Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R39denotes heteroaryl, which is not condenser is an or fused with benzene, heteroatom or R39A; R39Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R40denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R40A; R40Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

and groups represented by 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)R41, CO(O)R41, 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, OCF2CF3, F, Cl, Br or I;

R41means R42, R43, R44or R45;

R42denotes phenyl, which is not condensed or fused with benzene, heteroatom or R42A; R42Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R43denotes heteroaryl that is not condensed or condensed with benzene or R43A; R43Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R44denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R44A; R44Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R45denotes alkyl, alkenyl or quinil, each of which is unsubstituted or substituted by one or two substituents, independently selected from R46, OR46, SR46, S(O)R46, SO2R46C(O)R46, CO(O)R46, 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) C(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;

R46denotes alkyl, alkenyl, quinil, R47, R48or R49;

R47denotes phenyl, which is not condensed or fused with benzene, heteroatom or R47A; R47Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R48denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R48A; R48Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R49denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R49A; R49Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

moreover, the cyclic group represented by E1and Y1together, Y1and B1together, A2and B1together, A2and D1together, R1A, R2, R2A, R3, 3A, R4, R4A, R6, R6C, R8, R8A, R9, R9A, R10, R10A, R13, R13A, R14, R14A, R15, R15A, R28, R28A, R29, R29A, R30, R30A, R37B, R38, R38A, R39, R39A, R40and R40Aregardless not substituted, is not further substituted, substituted or optionally substituted by one or more substituents independently selected from R57, OR57, SR57, S(O)R57, SO2R57C(O)R57, CO(O)R57, 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;

R57means R58, R59, R60or R61;

R58denotes phenyl, which is not condensed or condensers the n with benzene, heteroatom or R58A; R58Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R59denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R59A; R59Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R60denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R60A; R60Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R61denotes alkyl, alkenyl or quinil, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R62, OR62, SR62, S(O)R62, SO2R62C(O)R62, CO(O)R62, 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)2, (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;

R62means R63, R64, R65or R66;

R63denotes phenyl, which is not condensed or fused with benzene, heteroatom or R63A; R63Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R64denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R64A; R64Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R65denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R65A; R65Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R66denotes alkyl or alkenyl, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R67, OR67, SR67, S(O)R67, SO2R67C(O)R67, CO(O)R67, OC(O)R67, OC(O)OR67, NH2, Other67N(R67)2, NHC(O)R67, NR67C(O)R67NHS(O)2R67, NR67S(O)2R67, NHC(O)OR6 , 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;

R67denotes alkyl, alkenyl, quinil, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen;

moreover, the cyclic groups represented by R58, R59, R60, R63, R64, R65and R67not substituted or substituted by one or more substituents independently selected from R68, OR68, SR68, S(O)R68, SO2R68C(O)R68, CO(O)R68, 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 NH2, 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;

R68means R69, R70, R71or R72;

R69denotes phenyl, which is not condensed or fused with benzene, heteroatom or R69A; R69Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R70denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R70A; R70Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R71denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R71A; R71Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R72denotes alkyl, or alkenyl, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R73, OR73, SR73, S(O)R73, SO2R73C(O)R73, CO(O)R73, OC(O)R73, OC(O)OR73, NH2, Other73N(R73)2, NHC(O)R73, NR73C(O)R73 NHS(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;

R73denotes alkyl, alkenyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; and

groups represented by R69, R70and R71not substituted or substituted by one or more substituents, independently selected fromNH2C(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 implementation of the invention relates to compounds of Formula (I), in which

A1denotes N or C(A2);

A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A; NO2, OCF3, CF2CF32CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

E1and Y1together with the atoms to which they are attached, are benzene, naftilan, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

A2B1and D1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

Y1and B1together with the atoms to which they are attached, are benzene, naftilan, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

A2D1and E1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH 2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

A2and B1together with the atoms to which they are attached, are benzene, naftilan, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR1C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

or

A2and D1together with the atoms to which they are attached, are benzene, naphthalene, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen; and

B1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3C(O)OH, C(O)NH2C(O)OR1A, NO2, OCF3, CF2CF3, OCF2CF3, NH2C(O)NH2, NR C(O)R1, NR1S(O)2R1, NR1C(O)OR1, NHC(O)NH2, NHC(O)other1, NHC(O)N(R1)2C(O)NHOH, C(O)NHOR1C(O)NHSO2R1, SO2NH2C(O)H, C(N)NH2C(N)other1C(N)N(R1)2, CNOH, CNOCH3N3or NHS(O)R1;

R1means R2, R3, R4or R5;

R1Adenotes cycloalkyl, cycloalkenyl or cycloalkenyl;

R2denotes phenyl, which is not condensed or fused with benzene, heteroatom or R2A; R2Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R3denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R3A; R3Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R4denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R4A; R4Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R5denotes alkyl, alkenyl or quinil, each of which is unsubstituted or substituted by one or two or three substituents, independently selected from R6, NC(R6A)(R6B), R7, OR7, SR7, S(O)R7, SO2R7 , Other7N(R7)2C(O)R7C(O)NH2,C(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, (O), N3, CN, NH2, CF3, CF2CF3, F, Cl, Br or I;

R6indicatesC2-C5-spiralcell, each of which is unsubstituted or substituted by OH groups, (O), N3CN, CF3, CF2CF3, F, Cl, Br, I, NH2, NH(CH3) or N(CH3)2;

R6Aand R6Brepresent independently selected alkyl or, together with the N to which they are attached, denote R6C;

R6Cindicates aziridine-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidine-1-yl, each of which has one group CH2, nezamenimoy or replaced by a group of O, C(O), CNOH, CNOCH3, S, S(O), SO2or NH;

R7means R8, R9, R10or R11;

R8denotes phenyl, which is not condensed or fused with benzene, heteroatom or R8A; R8Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R9denotes heteroaryl that is not condensed or condensed to be what SOLOM, heteroatom or R9A; R9Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R10denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R10A; R10Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R11denotes alkyl, alkenyl or quinil, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R12, OR12, SR12, S(O)R12, SO2R12C(O)R12, CO(O)R12, 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;

R12means R13, R 14, R15or R16;

R13denotes phenyl, which is not condensed or fused with benzene, heteroatom or R13A; R13Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R14denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R14A; R14Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R15indicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R15A; R15Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R16denotes alkyl, alkenyl or quinil;

Z1means R26or R27;

Z2means R28, R29or R30;

Z1Aand Z2Aboth are absent, or together form CH2CH2CH2or Z12A;

Z12Arepresents C2-C6-alkylen with one or two groups CH2replaced by a group NH, N(CH3), S, S(O) or SO2;

L1means R37, OR37, SR37, S(O)R37, SO2R37C(O)R37, CO(O)R37, OC(O)R37, OC(O)OR37, Other37C(O)NH, C(O)NR37C(O)NHOR37C(O)NHSO2R37, SO2 NH, SO2Other37C(N)NH, C(N)other37;

R26denotes phenylene, which is not condensed or condensed with benzene or heteroatom or R26A; R26Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R27indicates heteroaryl that is not condensed or condensed with benzene or heteroatom or R27A; R27Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R28denotes phenylene, which is not condensed or fused with benzene, heteroatom or R28A; R28Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R29indicates heteroaryl that is not condensed or condensed with benzene or heteroatom or R29A; R29Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R30denotes cycloalkyl, cycloalkenyl, heterocyclochain or heterocyclization, each of which is not condensed or fused with benzene, heteroatom or R30A; R30Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R37means a connection or R37A;

R37Adenotes alkylene, albaniles or akinyan, each of which is unsubstituted or substituted one or the two, or three substituents independently selected from R37B, OR37B, SR37B, S(O)R37B, SO2R37BC(O)R37B, CO(O)R37B, 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;

R37Bdenotes alkyl, alkenyl, quinil, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen;

Z3means R38, R39or R40;

R38denotes phenyl, which is not condensed or fused with benzene, heteroatom or R38A; R38Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R39denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R39A ; R39Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R40denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R40A; R40Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

and groups represented by R26and R27substituted (i.e., if Z1Aand Z2Aare absent) or further substituted (i.e., if Z1Aand Z2Athere are one or more OR41;

R41means R42;

R42denotes phenyl, which is condensed with heteroatom;

moreover, the cyclic group represented by E1and Y1together, Y1and B1together, A2and B1together, A2and D1together, R1A, R2, R2A, R3, R3A, R4, R4A, R6, R6C, R8, R8A, R9, R9A, R10, R10A, R13, R13A, R14, R14A, R15, R15A, R28, R28A, R29, R29A, R30, R30A, R37B, R38, R38A, R39, R39A, R40and R40Aregardless not substituted, is not further substituted, substituted or optionally substituted by one or more substituents, independently of wybrand the mi of R 57, OR57, SR57, S(O)R57, SO2R57C(O)R57, CO(O)R57, 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;

R57means R58, R59, R60or R61;

R58denotes phenyl, which is not condensed or fused with benzene, heteroatom or R58A; R58Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R59denotes heteroaryl that is not condensed or fused with benzene, heteroatom or R59A; R59Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R60denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of catharijne condensed or fused with benzene, heteroatom or R60A; R60Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R61denotes alkyl, alkenyl or quinil, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R62, OR62, SR62, S(O)R62, SO2R62C(O)R62, CO(O)R62, 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;

R62means R63, R64, R65or R66;

R63denotes phenyl, which is not condensed or fused with benzene, heteroatom or R63A; R63Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R64denotes heteroaryl, to the which is not condensed or fused with benzene, heteroatom or R64A; R64Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R65denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R65A; R65Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R66denotes alkyl or alkenyl, each of which is unsubstituted or substituted one, or two, or three substituents independently selected from R67, OR67, SR67, S(O)R67, SO2R67C(O)R67, CO(O)R67, 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;

R67denotes alkyl, alkenyl, Ala the Nile, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen;

moreover, the cyclic groups represented by R58, R59, R60, R63, R64, R65and R67not substituted or substituted by one or more substituents independently selected from R68, OR68, SR68, S(O)R68, SO2R68C(O)R68, CO(O)R68, 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;

R68means R69, R70, R71or R72;

R69denotes phenyl, which is not condensed or fused with benzene, heteroatom or R69A; R69Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R70means GE is Eroare, which is not condensed or fused with benzene, heteroatom or R70A; R70Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R71denotes cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is not condensed or fused with benzene, heteroatom or R71A; R71Aindicates cycloalkane, cycloalkene, geteroseksualen or geteroseksualen;

R72denotes alkyl or alkenyl, each of which is unsubstituted or substituted by one or two or three substituents, independently selected from R73, OR73, SR73, S(O)R73, SO2R73C(O)R73, CO(O)R73, 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;

R73denotes alkyl, alkenyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; and

groups represented by R69, R70and R71not substituted or substituted by one or more substituents, independently selected fromNH2C(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),

A1denotes N or C(A2);

A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3or NO2;

or

E1and Y1together with the atoms to which they are attached, are benzene, or heteroaryl, and

A2B1and D1independently selected from H;

or

Y1and B1together with the atoms to which they are attached, are benzene, and

A2D1and E1independently selected from H;

or

A2and B1together with the atoms to which they are attached, represent heteroaryl, cycloalkyl, geteroseksualen or geteroseksualen; and

D1E1and Y1independently selected from H, F, Cl, Br, I or NO2;

Z1means R26;

Z2means R30;

p> Z1Aand Z2Aboth are absent;

L1means R37;

R26denotes phenylene;

R30denotes heterocyclochain;

R37means R37A;

R37Adenotes alkylene or albaniles, each of which is unsubstituted or substituted R37B;

R37Bdenotes phenyl;

Z3means R38or R40;

R38denotes phenyl;

R40means cycloalkenyl;

and groups represented by 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, SO2R41or other41;

R41means R42or R45;

R42denotes phenyl, which is not condensed or condensed with heteroatom;

R45denotes alkyl, which is unsubstituted or substituted by one or two independently selected R46;

R46means R47;

R47denotes phenyl;

moreover, the cyclic group represented by E1and Y1together, Y1and B1together, A2and B1together, R30, R30A, R37B, R38and R40regardless not samewe is s, not further substituted, substituted or optionally substituted by one or more substituents independently selected from R57, OR57, NR57C(O)R57or (O);

R57means R58or R61;

R58denotes phenyl,

R61denotes alkyl, which is unsubstituted or substituted one, or two, or three substituents, independently selected from N(R62)2or F, Cl, Br or I;

R62means R66;

R66denotes alkyl; and

moreover, cyclic half, presents R58not substituted or substituted by one or more substituents, independently selected from F, Cl, Br or I.

In one embodiment of Formula (I), A1refers to C(A2); and A2denotes N. In another embodiment of Formula (I), A1, A2denote n

In another embodiment of Formula (I), A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3or NO2. In another embodiment of Formula (I), A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, CN, CF3or NO2. In another embodiment of Formula (I), A1refers to C(A2); A2denotes H; and B1D1E1and Y1independently selected from H, OH, F, Cl, Br, CN, CF3or NO2. In another embodiment of Formula (I) A1refers to C(A2); and A B1D1, Y1and E1denote N. In another embodiment of Formula (I), A1means(A2); A2B1D1and E1denote H; and Y1indicates NO2. In another embodiment of Formula (I), A1means(A2); A2B1D1and E1denote H; and Y1means Br. In another embodiment of Formula (I), A1means(A2); A2B1D1and E1denote H; and Y1means F. In another embodiment of Formula (I) A1means(A2); A2B1D1and E1denote H; and Y1denotes CN. In another embodiment of Formula (I) A1means(A2); A2B1D1and E1denote H; and Y1means CF3. In another embodiment of Formula (I), A1means(A2); A2B1D1and E1denote H; and Y1denotes Cl. In another embodiment of Formula (I), A1means(A2); A2D1and E1denote H; B1denotes Cl, and Y1indicates NO2. In another embodiment of Formula (I), A1means(A2); Y1, A2B1and E1denote H; and D1means Br. In another embodiment of Formula (I), A1means(A2); Y1, A2D1and E1denote H; and B1means Br. Drugom embodiment of Formula (I), A1means(A2); Y1, A2D1and E1denote H; and B1indicates NO2. In another embodiment of Formula (I), A1means(A2); Y1, A2D1and E1denote H; and B1IT denotes. In another embodiment of Formula (I), A1means(A2); Y1, A2D1and E1denote H; and B1means F. In another embodiment of Formula (I), E1and Y1together with the atoms to which they are attached, represent heteroaryl; and A2B1and D1denote N. In another embodiment of Formula (I), Y1and B1together with the atoms to which they are attached, are benzene, and A2D1and E1independently selected from H. In another embodiment of Formula (I), E1and Y1together with the atoms to which they are attached, are benzene and A2B1and D1denote N. In another embodiment of Formula (I), A2and B1together with the atoms to which they are attached, represent heteroaryl; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2. In another embodiment of Formula (I), A2and B1together with the atoms to which they are attached, represent cycloalkyl; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2. In other variations the those of the Formula (I), A2and B1together with the atoms to which they are attached, represent geteroseksualen; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2. In another embodiment of Formula (I), A2and B1together with the atoms to which they are attached, represent geteroseksualen; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2.

Another variant of implementation refers to compounds having Formula I, which are

4-[4-(3,3-diphenylprop-2-enyl)piperazine-1-yl]-N-[(3-nitrophenyl)sulfonyl]benzamide;

N-[(2-bromophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)cyclohex-1-EN-1-yl]methyl}piperazine-1-yl)benzamide;

N-[(3-bromophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)cyclohex-1-EN-1-yl]methyl}piperazine-1-yl)benzamide;

N-[(4-bromophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)cyclohex-1-EN-1-yl]methyl}piperazine-1-yl)benzamide;

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

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

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

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

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

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

4-[4-(1,1'-biphenyl-4-ylmethyl)-3-isopropylpiperazine-1-yl]-N-(phenylsulfonyl)benzamide;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)piperazine-1-yl]-2-(1H-indol-4-yloxy)-N-[(3-nitrophenyl)sulfonyl]benzamide;

4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)piperazine-1-yl]-2-(1H-indol-4-yloxy)-N-(phenylsulfonyl)benzamide;

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

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-(phenylsulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(3-cyanophenyl)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-{[3-(trifluoromethyl)phenyl]sulfonyl} benzamide;

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

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(3-forfinal)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-(2-naphthylmethyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-(isoquinoline-5-ylsulphonyl)benzamide;

N-[(4-chloro-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indazol-4-yloxy)benzamide;

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(2-chloropyridin-3-yl)sulfonyl]benzamide;

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(7-nitro-1H-benzimidazole-5-yl)sulfonyl]benzamide;

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)sulfonyl]benzamide;

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(6-chloro-1,1-dioxide-2H-1,2,4-benzothiadiazin-7-yl)sulfonyl]benzamide;

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-({5-[ethyl (TRIFLUOROACETYL) amino]-1-naphthyl} sulfonyl)benzamide;

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfonyl]benzamide;

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(2-oxo-2H-chromen-6-yl)sulfonyl]benzamide;

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

Another variant implementation of the invention pertains to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs that can be used as inhibitors of anti-apoptotic proteins Bcl-2, p is ICEM compounds have the Formula (II)

in which A1B1D1E1, Y1and Z3have the meanings described for Formula (I), and R101denotes H or has the values described for substituents on R26.

In one embodiment of Formula (II)

A1denotes N or C(A2);

A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3or NO2;

or

E1and Y1together with the atoms to which they are attached, are benzene, or heteroaryl, and

A2B1and D1independently selected from H;

or

Y1and B1together with the atoms to which they are attached, are benzene, and

A2D1and E1independently selected from H;

or

A2and B1together with the atoms to which they are attached, represent heteroaryl, cycloalkyl, geteroseksualen or geteroseksualen; and

D1E1and Y1independently selected from H, F, Cl, Br, I or NO2;

Z3means R38or R40;

R38denotes phenyl;

R40means cycloalkenyl;

and R101denotes the substituents R41, OR41, SR41, S(O)R41, SO2R41or other41;

R41means R42or R45;

R42denotes phenyl which is not condensed or condensed with heteroatom;

R45denotes alkyl, which is unsubstituted or substituted by one or two independently selected R46;

R46means R47;

R47denotes phenyl;

moreover, the cyclic group represented by E1and Y1together, Y1and B1together, A2and B1together, R30, R30A, R37B, R38and R40regardless not substituted, is not further substituted, substituted or optionally substituted by one or more substituents independently selected from R57, OR57, NR57C(O)R57or (O);

R57means R58or R61;

R58denotes phenyl,

R61denotes alkyl, which is unsubstituted or substituted by one or two or three substituents, independently selected from N(R62)2or F, Cl, Br or I;

R62means R66;

R66denotes alkyl; and

moreover, the cyclic groups represented by R58not substituted or substituted by one or more substituents, independently selected from F, Cl, Br or I.

In one embodiment of Formula (II), A1means(A2); and A2denotes N. In another embodiment of Formula (II), A1denotes n

In another embodiment of Formula (II), A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3Il NO 2. In another embodiment of Formula (II), A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, CN, CF3or NO2. In another embodiment of Formula (II), A1means(A2); A2denotes H; and B1D1E1and Y1independently selected from H, OH, F, Cl, Br, CN, CF3or NO2. In another embodiment of Formula (II), A1means(A2); and A2B1D1, Y1and E1denotes N. In another embodiment of Formula (II), A1means(A2); A2B1D1and E1denotes H; and Y1indicates NO2. In another embodiment of Formula (II), A1means(A2); A2B1D1and E1denote H; and Y1means Br. In another embodiment of Formula (II), A1means(A2); A2B1D1and E1denote H; and Y1means F. In another embodiment of Formula (II), A1means(A2); A2B1D1and E1denote H; and Y1denotes CN. In another embodiment of Formula (II), A1means(A2); A2B1D1and E1denote H; and Y1means CF3. In another embodiment of Formula (II), A1means(A2); A2B1D1and E1denote H; and Y1denotes Cl. In another embodiment of Formula (II), A1 means(A2); A2D1and E1denote H; B1denotes Cl, and Y1indicates NO2. In another embodiment of Formula (II), A1means(A2); Y1, A2B1and E1denote H; and D1means Br. In another embodiment of Formula (II), A1means(A2); Y1, A2D1and E1denotes H; and B1means Br. In another embodiment of Formula (II), A1means(A2); Y1, A2D1and E1denote H; and B1indicates NO2. In another embodiment of Formula (II), A1means(A2); Y1, A2D1and E1denote H; and B1IT denotes. In another embodiment of Formula (II), A1means(A2); Y1, A2D1and E1denote H; and B1means F. In another embodiment of Formula (II), E1and Y1together with the atoms to which they are attached, represent heteroaryl, and A2B1and D1denote N. In another embodiment of Formula (II), Y1and B1together with the atoms to which they are attached, are benzene, and A2D1and E1independently selected from H. In another embodiment of Formula (II), E1and Y1together with the atoms to which they are attached, are benzene and A2B1and D1the convoy is achut N. In another embodiment of Formula (II), A2and B1together with the atoms to which they are attached, represent heteroaryl; and D1E1and Y1independently selected from H, F, Cl, Br, I, or NO2. In another embodiment of Formula (II), A2and B1together with the atoms to which they are attached, represent cycloalkyl; and D1E1and Y1independently selected from H, F, Cl, Br, I, or NO2. In another embodiment of Formula (II), A2and B1together with the atoms to which they are attached, represent geteroseksualen; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2. In another embodiment of Formula (II), A2and B1together with the atoms to which they are attached, represent geteroseksualen; and D1E1and Y1independently selected from H, F, Cl, Br, I, or NO2.

Another variant of implementation refers to compounds having the Formula II, which are

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)piperazine-1-yl]-2-(1H-indol-4-yloxy)-N-[(3-nitrophenyl)sulfonyl]benzamide;

4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)piperazine-1-yl]-2-(1H-indol-4-yloxy)-N-(phenylsulfonyl)benzamide;

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

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-(phenylsulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(3-cyanophenyl)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-{[3-(trifluoromethyl)phenyl]sulfonyl}benzamide;

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

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(3-forfinal)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-(2-naphthylmethyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-(isoquinoline-5-ylsulphonyl)benzamide;

N-[(4-chloro-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indazol-4-yloxy)benzamide;

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(2-chloropyridin-3-yl)sulfonyl]benzamide;

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(7-nitro-1H-benzimidazole-5-yl)sulfonyl]benzamide;

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)sulfonyl]benzamide;

4-{4-[(4'-chlorobiphenyl-2-yl)METI is]piperazine-1-yl}-N-[(6-chloro-1,1-dioxide-2H-1,2,4-benzothiadiazin-7-yl)sulfonyl]benzamide;

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-({5-[ethyl(TRIFLUOROACETYL)amino]-1-naphthyl}sulfonyl)benzamide;

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfonyl]benzamide;

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(2-oxo-2H-chromen-6-yl)sulfonyl]benzamide;

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

Another variant implementation of the invention pertains to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs that can be used as inhibitors of anti-apoptotic proteins Bcl-2, and compounds have the Formula (III)

in which A1B1D1E1, Y1and Z3have the meanings described for Formula (I).

In one embodiment of Formula (III),

A1denotes N or C(A2);

A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3or NO2;

or

E1and Y1together with the atoms to which they are attached, are benzene, or heteroaryl, and

A2B1and D1independently selected from H;

or

Y1and B1together with the atoms to which they are attached, are benzene, and

A2 D1and E1independently selected from H;

or

A2and B1together with the atoms to which they are attached, represent heteroaryl, cycloalkyl, geteroseksualen or geteroseksualen; and

D1E1and Y1independently selected from H, F, Cl, Br, I or NO2;

Z3means R38or R40;

R38denotes phenyl;

R40means cycloalkenyl;

moreover, the cyclic group represented by E1and Y1together, Y1and B1together, A2and B1together, R30, R30A, R37B, R38and R40regardless not substituted, is not further substituted, substituted or optionally substituted by one or more substituents independently selected from R57, OR57, NR57C(O)R57or (O);

R57means R58or R61;

R58denotes phenyl,

R61denotes alkyl, which is unsubstituted or substituted by one or two or three substituents, independently selected from N(R62)2or F, Cl, Br or I;

R62means R66;

R66denotes alkyl; and

moreover, the cyclic groups represented by R58not substituted or substituted by one or more substituents, independently selected from F, Cl, Br or I.

In one embodiment of Formula (III), A1means(A2 ); and A2denotes N. In another embodiment of Formula (III), A1denotes n

In another embodiment of Formula (III), A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3or NO2. In another embodiment of Formula (III), A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, CN, CF3or NO2. In another embodiment of Formula (III), A1means(A2); A2denotes H; and B1D1E1and Y1independently selected from H, OH, F, Cl, Br, CN, CF3or NO2. In another embodiment of Formula (III), A1means(A2); and A2B1D1, Y1and E1denote N. In another embodiment of Formula (III), A1means(A2); A2B1D1and E1denote H; and Y1indicates NO2. In another embodiment of Formula (III), A1means(A2); A2B1D1and E1denote H; and Y1means Br. In another embodiment of Formula (III), A1means(A2); A2B1D1and E1denote H; and Y1means F. In another embodiment of Formula (III), A1means(A2); A2B1D1and E1denote H; and Y1denotes CN. In another embodiment of Formula (III), A1means(A2); A2B1D1and E1 denote H; and Y1means CF3. In another embodiment of Formula (III), A1means(A2); A2B1D1and E1denote H; and Y1denotes Cl. In another embodiment of Formula (III), A1means(A2); A2D1and E1denote H; B1denotes Cl, and Y1indicates NO2. In another embodiment of Formula (III), A1means(A2); Y1, A2B1and E1denote H; and D1means Br. In another embodiment of Formula (III), A1means(A2); Y1, A2D1and E1denote H; and B1means Br. In another embodiment of Formula (III), A1means(A2); Y1, A2D1and E1denote H; and B1indicates NO2. In another embodiment of Formula (III), A1means(A2); Y1, A2D1and E1denote H; and B1IT denotes. In another embodiment of Formula (III), A1means(A2); Y1, A2D1and E1denote H; and B1means F. In another embodiment of Formula (III), E1and Y1together with the atoms to which they are attached, represent heteroaryl, and A2B1and D1denote N. In another embodiment of Formula (III), Y1and B1together with the atoms to which they are attached, represents the t of a benzene, and A2D1and E1independently selected from H. In another embodiment of Formula (III), E1and Y1together with the atoms to which they are attached, are benzene and A2B1and D1denote N. In another embodiment of Formula (III), A2and B1together with the atoms to which they are attached, represent heteroaryl; and D1E1and Y1independently selected from H, F, Cl, Br, I, or NO2. In another embodiment of Formula (III), A2and B1together with the atoms to which they are attached, represent cycloalkyl; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2. In another embodiment of Formula (III), A2and B1together with the atoms to which they are attached, represent geteroseksualen; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2. In another embodiment of Formula (III), A2and B1together with the atoms to which they are attached, represent geteroseksualen; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2.

Another variant of implementation refers to compounds having the Formula III, which are

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

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-2-phenoxy-N-(peninsul who were radioactive)benzamide;

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

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

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

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

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

Another variant implementation of the invention pertains to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs that can be used as inhibitors of anti-apoptotic proteins Bcl-2, and compounds have the Formula (IV)

in which A1B1D1E1, Y1and Z3have the meanings described for Formula (I).

In one embodiment of Formula (IV)

A1denotes N or C(A2);

A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3or NO2;

or

E1and Y1together with the atoms to which they are attached, are benzene, or heteroaryl, and

A2B1and D1independently selected from H;

or

Y1and B1together with the atoms which they are attached, represent benzene, and

A2D1and E1independently selected from H;

or

A2and B1together with the atoms to which they are attached, represent heteroaryl, cycloalkyl, geteroseksualen or geteroseksualen; and

D1E1and Y1independently selected from H, F, Cl, Br, I or NO2;

Z3means R38or R40;

R38denotes phenyl;

R40means cycloalkenyl;

moreover, the cyclic group represented by E1and Y1together, Y1and B1together, A2and B1together, R30, R30A, R37B, R38and R40regardless not substituted, is not further substituted, substituted or optionally substituted by one or more substituents independently selected from R57, OR57, NR57C(O)R57or (O);

R57means R58or R61;

R58denotes phenyl,

R61denotes alkyl, which is unsubstituted or substituted by one or two or three substituents, independently selected from N(R62)2, or F, Cl, Br or I;

R62means R66;

R66denotes alkyl; and

moreover, the cyclic groups represented by R58not substituted or substituted by one or more substituents, independently selected from F, Cl, Br or I.

In one Varian is e of the Formula (IV), A1means(A2); and A2denotes N. In another embodiment of Formula (IV), A1denotes n

In another embodiment of Formula (IV), A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3or NO2. In another embodiment of Formula (IV), A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, CN, CF3or NO2. In another embodiment of Formula (IV), A1means(A2); A2denotes H; and B1D1E1and Y1independently selected from H, OH, F, Cl, Br, CN, CF3or NO2. In another embodiment of Formula (IV), A1means(A2); and A2B1D1, Y1and E1denote N. In another embodiment of Formula (IV), A1means(A2); A2B1D1and E1denote H; and Y1indicatesNO2. In another embodiment of Formula (IV), A1means(A2); A2B1D1and E1denote H; and Y1means Br. In another embodiment of Formula (IV), A1means(A2); A2B1D1and E1denote H; and Y1means F. In another embodiment of Formula (IV), A1means(A2); A2B1D1and E1denote H; and Y1denotes CN. In another embodiment of Formula (IV), A1means(A2); A2 B1D1and E1denote H; and Y1means CF3. In another embodiment of Formula (IV), A1means(A2); A2B1D1and E1denote H; and Y1denotes Cl. In another embodiment of Formula (IV), A1means(A2); A2D1and E1denote H; B1denotes Cl, and Y1indicates NO2. In another embodiment of Formula (IV), A1means(A2); Y1, A2B1and E1denote H; and D1means Br. In another embodiment of Formula (IV), A1means(A2); Y1, A2D1and E1denote H; and B1means Br. In another embodiment of Formula (IV), A1means(A2); Y1, A2D1and E1denote H; and B1indicates NO2. In another embodiment of Formula (IV), A1means(A2); Y1, A2D1and E1denote H; and B1IT denotes. In another embodiment of Formula (IV), A1means(A2); Y1, A2D1and E1denote H; and B1means F. In another embodiment of Formula (IV), Y1and B1together with the atoms to which they are attached, represent heteroaryl, and A2B1and D1represent H. In another embodiment of Formula (IV), Y1and B1together with the atoms to which they p is soedinenii, represent benzene, and A2D1and E1independently selected from H. In another embodiment of Formula (IV), E1and Y1together with the atoms to which they are attached, are benzene and A2B1and D1denote N. In another embodiment of Formula (IV), A2and B1together with the atoms to which they are attached, represent heteroaryl; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2. In another embodiment of Formula (IV), A2and B1together with the atoms to which they are attached, represent cycloalkyl; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2. In another embodiment of Formula (IV), A2and B1together with the atoms to which they are attached, represent geteroseksualen; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2. In another embodiment of Formula (IV), A2and B1together with the atoms to which they are attached, represent geteroseksualen; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2.

Another variant of implementation refers to compounds having Formula IV, which are

4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)piperazine-1-yl]-2-(1H-indol-4-yloxy)-N-[(3-nitrophenyl)sulfonyl]benzamide;

4-[4-({4'-chlorine is-3-[2-(dimethylamino) ethoxy]-1,1'-biphenyl-2-yl} methyl)piperazine-1-yl]-2-(1H-indol-4-yloxy)-N-(phenylsulfonyl)benzamide;

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

Another variant implementation of the invention pertains to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs that can be used as inhibitors of anti-apoptotic proteins Bcl-2, and compounds have the Formula (V)

in which A1B1D1E1, Y1and Z3have the meanings described for Formula (I).

In one embodiment of Formula (V),

A1denotes N or C(A2);

A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3or NO2;

or

E1and Y1together with the atoms to which they are attached, are benzene, or heteroaryl, and

A2B1and D1independently selected from H;

or

Y1and B1together with the atoms to which they are attached, are benzene, and

A2D1and E1independently selected from H;

or

A2and B1together with the atoms to which they are attached, represent heteroaryl, cycloalkyl, geteroseksualen or geteroseksualen; and

D1E1and Y1independently selected from H, F, Cl, Br, I or NO2;

Z3the seat is t R 38or R40;

R38denotes phenyl;

R40means cycloalkenyl;

moreover, the cyclic group represented by E1and Y1together, Y1and B1together, A2and B1together, R30, R30A, R37B, R38and R40no not substituted, is not further substituted, substituted or optionally substituted by one or more substituents independently selected from R57, OR57, NR57C(O)R57or (O);

R57means R58or R61;

R58denotes phenyl,

R61denotes alkyl, which is unsubstituted or substituted by one or two or three substituents, independently selected from N(R62)2or F, Cl, Br or I;

R62means R66;

R66denotes alkyl; and

moreover, the cyclic groups represented by R58not substituted or substituted by one or more substituents, independently selected from F, Cl, Br or I.

In one embodiment of Formula (V), A1means(A2); and A2denotes N. In another embodiment of Formula (V), A1denotes n

In another embodiment of Formula (V), A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3or NO2. In another embodiment of Formula (V), A2B1D1E1and Y1independently chosen is from H, OH, F, Cl, Br, CN, CF3or NO2. In another embodiment of Formula (V), A1means(A2); A2denotes H; and B1D1E1and Y1independently selected from H, OH, F, Cl, Br, CN, CF3or NO2. In another embodiment of Formula (V), A1means(A2); and A2B1D1, Y1and E1denote N. In another embodiment of Formula (V), A1means(A2); A2B1D1and E1denote H; and Y1indicates NO2. In another embodiment of Formula (V), A1means(A2); A2B1D1and E1denote H; and Y1means Br. In another embodiment of Formula (V), A1means(A2); A2B1D1and E1denote H; and Y1means F. In another embodiment of Formula (V), A1means(A2); A2B1D1and E1denote H; and Y1denotes CN. In another embodiment of Formula (V), A1means(A2); A2B1D1and E1denote H; and Y1means CF3. In another embodiment of Formula (V), A1means(A2); A2B1D1and E1denote H; and Y1denotes Cl. In another embodiment of Formula (V), A1means(A2); A2D1and E1denote H; B1denotes Cl, and Y1the seat is t NO 2. In another embodiment of Formula (V), A1means(A2); Y1, A2B1and E1denote H; and D1means Br. In another embodiment of Formula (V), A1means(A2); Y1, A2D1and E1denote H; and B1means Br. In another embodiment of Formula (V), A1means(A2); Y1, A2D1and E1denote H; and B1indicates NO2. In another embodiment of Formula (V), A1means(A2); Y1, A2D1and E1denote H; and B1IT denotes. In another embodiment of Formula (V), A1means(A2); Y1, A2D1and E1denote H; and B1means F. In another embodiment of Formula (V), E1and Y1together with the atoms to which they are attached, represent heterogen, and A2B1and D1represent H. In another embodiment of Formula (V), Y1and B1together with the atoms to which they are attached, are benzene, and A2D1and E1independently selected from H. In another embodiment of Formula (V), E1and Y1together with the atoms to which they are attached, are benzene and A2B1and D1denote N. In another embodiment of Formula (V), A2and B1together with the atoms to which they are attached, represent the Oh heteroaryl; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2. In another embodiment of Formula (V), A2and B1together with the atoms to which they are attached, represent cycloalkyl; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2. In another embodiment of Formula (V), A2and B1together with the atoms to which they are attached, represent geteroseksualen; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2. In another embodiment of Formula (V), A2and B1together with the atoms to which they are attached, represent geteroseksualen; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2.

Another variant of implementation refers to compounds having the Formula V, which are

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

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-(phenylsulfonyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(3-cyanophenyl)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-{[3-(trifluoromethyl)phenyl]sulfonyl}benzamide;

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

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(3-forfinal)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-(2-naphthylmethyl)benzamide;

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-(isoquinoline-5-ylsulphonyl)benzamide;

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

Another variant implementation of the invention pertains to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs that can be used as inhibitors of anti-apoptotic proteins Bcl-2, and compounds have the Formula (VI)

in which A1B1D1E1, Y1and Z3have the meanings described for Formula (I).

In one embodiment of Formula (VI)

A1denotes N or C(A2);

A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3or NO2;

or

E1and Y1together with the atoms to which they are attached, are benzene, or heteroaryl, and

A2B1and D1independently selected from H;

or

Y1and B1together with the atoms to which o is attached, represent benzene, and

A2D1and E1independently selected from H;

or

A2and B1together with the atoms to which they are attached, represent heteroaryl, cycloalkyl, geteroseksualen or geteroseksualen; and

D1E1and Y1independently selected from H, F, Cl, Br, I or NO2;

Z3means R38or R40;

R38denotes phenyl;

R40means cycloalkenyl;

moreover, the cyclic group represented by E1and Y1together, Y1and B1together, A2and B1together, R30, R30A, R37B, R38and R40no not substituted, is not further substituted, substituted or optionally substituted by one or more substituents independently selected from R57, OR57, NR57C(O)R57or (O);

R57means R58or R61;

R58denotes phenyl,

R61denotes alkyl, which is unsubstituted or substituted by one or two or three substituents, independently selected from N(R62)2or F, Cl, Br or I;

R62means R66;

R66denotes alkyl; and

moreover, the cyclic groups represented by R58not substituted or substituted by one or more substituents, independently selected from F, Cl, Br or I.

In one of the variations is those of the Formula (VI), A1means(A2); and A2denotes N. In another embodiment of Formula (VI), A1denotes n

In another embodiment of Formula (VI), A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3or NO2. In another embodiment of Formula (VI), A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, CN, CF3or NO2. In another embodiment of Formula (VI), A1means(A2); A2denotes H; and B1D1E1and Y1independently selected from H, OH, F, Cl, Br, CN, CF3or NO2. In another embodiment of Formula (VI), A1means(A2); and A2B1D1, Y1and E1denote N. In another embodiment of Formula (VI), A1means(A2); A2B1D1and E1denote H; and Y1indicates NO2. In another embodiment of Formula (VI), A1means(A2); A2B1D1and E1denote H; and Y1means Br. In another embodiment of Formula (VI), A1means(A2); A2B1D1and E1denote H; and Y1means F. In another embodiment of Formula (VI), A1means(A2); A2B1D1and E1denote H; and Y1denotes CN. In another embodiment of Formula (VI), A1means(A2); A2B 1D1and E1denote H; and Y1means CF3. In another embodiment of Formula (VI), A1means(A2); A2B1D1and E1denote H; and Y1denotes Cl. In another embodiment of Formula (VI), A1means(A2); A2D1and E1denote H; B1denotes Cl, and Y1indicates NO2. In another embodiment of Formula (VI), A1means(A2); Y1, A2B1and E1denote H; and D1means Br. In another embodiment of Formula (VI), A1means(A2); Y1, A2D1and E1denote H; and B1means Br. In another embodiment of Formula (VI), A1means(A2); Y1, A2D1and E1denote H; and B1indicates NO2. In another embodiment of Formula (VI), A1means(A2); Y1, A2D1and E1denote H; and B1IT denotes. In another embodiment of Formula (VI), A1means(A2); Y1, A2D1and E1denote H; and B1means F. In another embodiment of Formula (VI), E1and Y1together with the atoms to which they are attached, represent heterogen, and A2B1and D1represent H. In another embodiment of Formula (VI), Y1and B1together with the atoms to which they join the tive, represent benzene, and A2D1and E1independently selected from H. In another embodiment of Formula (VI), E1and Y1together with the atoms to which they are attached, are benzene and A2B1and D1denote N. In another embodiment of Formula (VI), A2and B1together with the atoms to which they are attached, represent heteroaryl; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2. In another embodiment of Formula (VI), A2and B1together with the atoms to which they are attached, represent cycloalkyl; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2. In another embodiment of Formula (VI), A2and B1together with the atoms to which they are attached, represent geteroseksualen; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2. In another embodiment of Formula (VI), A2and B1together with the atoms to which they are attached, represent geteroseksualen; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2.

Another variant implementation of the invention pertains to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs that can be used as inhibitors of antiapoptotic be the Cove Bcl-2, moreover, the compounds have the Formula (VII)

in which A1B1D1E1, Y1and Z3have the meanings described for Formula (I).

In one embodiment of Formula (VII)

A1denotes N or C(A2);

A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3or NO2;

or

E1and Y1together with the atoms to which they are attached, are benzene, or heteroaryl, and

A2B1and D1independently selected from H;

or

Y1and B1together with the atoms to which they are attached, are benzene, and

A2D1and E1independently selected from H;

or

A2and B1together with the atoms to which they are attached, represent heteroaryl, cycloalkyl, geteroseksualen or geteroseksualen; and

D1E1and Y1independently selected from H, F, Cl, Br, I or NO2;

Z3means R38or R40;

R38denotes phenyl;

R40means cycloalkenyl;

moreover, the cyclic group represented by E1and Y1together, Y1and B1together, A2and B1together, R30, R30A, R37B, R38and R40regardless not substituted, is not further substituted, substituted or until omnitele substituted by one or more substituents, independently selected from R57, OR57, NR57C(O)R57or (O);

R57means R58or R61;

R58denotes phenyl,

R61denotes alkyl, which is unsubstituted or substituted by one or two or three substituents, independently selected from N(R62)2or F, Cl, Br or I;

R62means R66;

R66denotes alkyl; and

moreover, the cyclic groups represented by R58not substituted or substituted by one or more substituents, independently selected from F, Cl, Br or I.

In one embodiment of Formula (VII), A1means(A2); and A2denotes N. In another embodiment of Formula (VII), A1denotes n

In another embodiment of Formula (VII), A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3or NO2. In another embodiment of Formula (VII), A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, CN, CF3or NO2. In another embodiment of Formula (VII), A1means(A2); A2denotes H; and B1D1E1and Y1independently selected from H, OH, F, Cl, Br, CN, CF3or NO2. In another embodiment of Formula (VII), A1means(A2); and A2B1D1, Y1and E1denote N. In another embodiment of Formula (VII), A1about the means(A 2); A2B1D1and E1denote H; and Y1indicates NO2. In another embodiment of Formula (VII), A1means(A2); A2B1D1and E1denote H; and Y1means Br. In another embodiment of Formula (VII), A1means(A2); A2B1D1and E1denote H; and Y1means F. In another embodiment of Formula (VII), A1means(A2); A2B1D1and E1denote H; and Y1denotes CN. In another embodiment of Formula (VII), A1means(A2); A2B1D1and E1denote H; and Y1means CF3. In another embodiment of Formula (VII), A1means(A2); A2B1D1and E1denote H; and Y1denotes Cl. In another embodiment of Formula (VII), A1means(A2); A2D1and E1denote H; B1denotes Cl, and Y1indicates NO2. In another embodiment of Formula (VII), A1means(A2); Y1, A2B1and E1denote H; and D1means Br. In another embodiment of Formula (VII), A1means(A2); Y1, A2D1and E1denote H; and B1means Br. In another embodiment of Formula (VII), A1means(A2); Y1, A2D1and E1 denote H; and B1indicates NO2. In another embodiment of Formula (VII), A1means(A2); Y1, A2D1and E1denote H; and B1IT denotes. In another embodiment of Formula (VII), A1means(A2); Y1, A2D1and E1denote H; and B1means F. In another embodiment of Formula (VII), E1and Y1together with the atoms to which they are attached, represent heteroaryl, and A2B1and D1denote N. In another embodiment of Formula (VII), Y1and B1together with the atoms to which they are attached, are benzene, and A2D1and E1independently selected from H. In another embodiment of Formula (VII), E1and Y1together with the atoms to which they are attached, are benzene and A2B1and D1denote N. In another embodiment of Formula (VII), A2and B1together with the atoms to which they are attached, represent heteroaryl; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2. In another embodiment of Formula (VII), A2and B1together with the atoms to which they are attached, represent cycloalkyl; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2. In another embodiment of Formula (VII), A2and B1together with the atoms, to the m they are attached, are geteroseksualen; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2. In another embodiment of Formula (VII), A2and B1together with the atoms to which they are attached, represent geteroseksualen; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2.

Another variant implementation of the invention pertains to compounds or therapeutically acceptable salts, prodrugs, metabolites, or salts of prodrugs that can be used as inhibitors of anti-apoptotic proteins Bcl-2, and compounds have the Formula (VIII)

in which A1B1D1E1, Y1and Z3have the meanings described for Formula (I).

In one embodiment of Formula (VIII),

A1denotes N or C(A2);

A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3or NO2;

or

E1and Y1together with the atoms to which they are attached, are benzene, or heteroaryl, and

A2B1and D1independently selected from H;

or

Y1and B1together with the atoms to which they are attached, are benzene, and

A2D1and E1independently selected from H;

or

A2and B together with the atoms to which they are attached, represent heteroaryl, cycloalkyl, geteroseksualen or geteroseksualen; and

D1E1and Y1independently selected from H, F, Cl, Br, I or NO2;

Z3means R38or R40;

R38denotes phenyl;

R40means cycloalkenyl;

moreover, the cyclic group represented by E1and Y1together, Y1and B1together, A2and B1together, R30, R30A, R37B, R38and R40regardless not substituted, is not further substituted, substituted or optionally substituted by one or more substituents independently selected from R57, OR57, NR57C(O)R57or (O);

R57means R58or R61;

R58denotes phenyl,

R61denotes alkyl, which is unsubstituted or substituted by one or two or three substituents, independently selected from N(R62)2or F, Cl, Br or I;

R62means R66;

R66denotes alkyl; and

moreover, the cyclic groups represented by R58not substituted or substituted by one or more substituents, independently selected from F, Cl, Br or I.

In one embodiment of Formula (VIII), A1means(A2); and A2denotes N. In another embodiment of Formula (VIII), A1the convoy is achet N.

In another embodiment of Formula (VIII), A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, I, CN, CF3or NO2. In another embodiment of Formula (VIII), A2B1D1E1and Y1independently selected from H, OH, F, Cl, Br, CN, CF3or NO2. In another embodiment of Formula (VIII), A1means(A2); A2denotes H; and B1D1E1and Y1independently selected from H, OH, F, Cl, Br, CN, CF3or NO2. In another embodiment of Formula (VIII), A1means(A2); and A2B1D1, Y1and E1denote N. In another embodiment of Formula (VIII), A1means(A2); A2B1D1and E1denote H; and Y1indicates NO2. In another embodiment of Formula (VIII), A1means(A2); A2B1D1and E1denote H; and Y1means Br. In another embodiment of Formula (VIII), A1means(A2); A2B1D1and E1denote H; and Y1means F. In another embodiment of Formula (VIII), A1means(A2); A2B1D1and E1denote H; and Y1denotes CN. In another embodiment of Formula (VIII), A1means(A2); A2B1D1and E1denote H; and Y1means CF3. In another embodiment of Formula (VII), A1means(A2); A2B1D1and E1denote H; and Y1denotes Cl. In another embodiment of Formula (VIII), A1means(A2); A2D1and E1denote H; B1denotes Cl, and Y1indicates NO2. In another embodiment of Formula (VIII), A1means(A2); Y1, A2B1and E1denote H; and D1means Br. In another embodiment of Formula (VIII), A1means(A2); Y1, A2D1and E1denote H; and B1means Br. In another embodiment of Formula (VIII), A1means(A2); Y1, A2D1and E1denote H; and B1indicates NO2. In another embodiment of Formula (VIII), A1means(A2); Y1, A2D1and E1denote H; and B1IT denotes. In another embodiment of Formula (VIII), A1means(A2); Y1, A2D1and E1denote H; and B1means F. In another embodiment of Formula (VIII), E1and Y1together with the atoms to which they are attached, represent heteroaryl, and A2B1and D1denote N. In another embodiment of Formula (VIII), Y1and B1together with the atoms to which they are attached, are benzene, and A2D1and E1independently selected from H. Drugom embodiment of Formula (VIII), E1and Y1together with the atoms to which they are attached, are benzene and A2B1and D1denote N. In another embodiment of Formula (VIII), A2and B1together with the atoms to which they are attached, represent heteroaryl; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2. In another embodiment of Formula (VIII), A2and B1together with the atoms to which they are attached, represent cycloalkyl; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2. In another embodiment of Formula (VIII), A2and B1together with the atoms to which they are attached, represent geteroseksualen; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2. In another embodiment of Formula (VIII), A2and B1together with the atoms to which they are attached, represent geteroseksualen; and D1E1and Y1independently selected from H, F, Cl, Br, I or NO2.

The pharmaceutical composition,combined therapy,treatment and introduction

Another variant implementation includes pharmaceutical compositions comprising a compound having the Formula (I), and excipient.

Another variant implementation includes methods of treating cancer in a mammal, comprising applying to therapeuti the Eski acceptable number of connections, having the Formula (I).

Another variant implementation includes methods of treating autoimmune disease in a mammal, comprising introducing him therapeutically acceptable amount of a compound having the Formula (I).

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

Another variant of implementation relates to methods of treatment of the patient's illness, during which is expressed anti-apoptotic proteins Bcl-2, and these methods include the introduction to the patient a therapeutically effective amount of the compounds having Formula (I).

Another variant of implementation relates to compositions for treating bladder cancer, brain cancer, breast cancer, cancer of the bone marrow, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, gastric cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or b-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, lung cancer, prostate cancer, melcochita the CSOs lung cancer, cancer of the spleen, and these compositions include excipient and a therapeutically effective amount of the compounds having Formula (I).

Another variant of implementation relates to methods of treating bladder cancer, brain cancer, breast cancer, cancer of the bone marrow, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, gastric cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or b-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, lung cancer, prostate cancer, small-cell lung cancer, cancer of the spleen in a patient, and these methods include the introduction to the patient a therapeutically effective amount of the compounds having the Formula (I).

Another variant of implementation relates to compositions for treating diseases during which is expressed anti-apoptotic proteins Bcl-2, and these compositions include excipient and a therapeutically effective amount of the compounds having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

Another variant of implementation from OSISA to methods for treating the patient's disease, during which is expressed anti-apoptotic proteins Bcl-2, and these methods include the introduction to the patient a therapeutically effective amount of the compounds having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

Another variant of implementation relates to compositions for treating bladder cancer, brain cancer, breast cancer, cancer of the bone marrow, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, gastric cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or b-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, lung cancer, prostate cancer, small-cell lung cancer, cancer of the spleen, and these compositions include excipient and a therapeutically effective amount of the compounds having the Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

Another variant of implementation relates to methods of treating bladder cancer, brain cancer, cancer of the mo is full of cancer, of bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, gastric cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or b-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, lung cancer, prostate cancer, small-cell lung cancer, cancer of the spleen in a patient, and these methods include the introduction to the patient a therapeutically effective amount of the compounds having Formula (I), and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

Metabolites of compounds having Formula (I) obtained as a result of metabolic processes in vitro or in vivo, can also be used to treat diseases associated with anti-apoptotic protein Bcl-2.

Some compounds, the precursors that can be metabolized in vitro or in vivo to form compounds having Formula (I) may also be used to treat diseases associated with expression of the antiapoptotic proteins Bcl-2.

Compounds having the Formula (I) can exist in the form of salts accession acid, sole is joining with the base or zwitterionic. Salts of the compounds obtained in the course of the selection or after cleaning compounds. Salt accession acid compounds get in the reaction of compounds with acid. For example, acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, bansilalpet, bisulfate, butyrate, comfort, camphorsulfonate, digluconate, formate, fumarate, glycerol, glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate, maleate, mesitylenesulfonic, methanesulfonate, naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, triptorelin, para-toluensulfonate and undecanoate compounds and their prodrugs are considered as included in the scope of this invention. Salt accession with base connections get in the reaction of compounds with hydroxide, carbonate or bicarbonate such cations such as lithium, sodium, potassium, calcium and magnesium.

Compounds having the Formula (I) may be administered, for example, buccal, ophthalmically, orally, osmotically, parenterally (intramuscularly, intraperitoneally, intrasternally, intravenously, subcutaneously), rectally, tapicerki, percutaneous or vaginal.

Therapeutically effective amounts of compounds having the Formula (I) depend on the recipient, receiving treatment, to be aemula treatment of the violation and its severity, the compositions containing the compound, time of administration, route of administration, duration of treatment, potential connections, the rate of excretion and enter whether together another medication. The number of compounds according to the invention having the Formula (I) used to obtain a composition, which is daily administered to the patient in a single dose or in separate doses is from about 0.03 to about 200 mg/kg of body weight. Compositions in the form of single doses contain these quantities, or a combination of their subsets.

Compounds having the Formula (I) can be entered with excipients or without excipient. Excipients include, for example, the encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, agents for coatings, dyes, diluents, disintegrators, emulsifiers, fillers, flavoring agents, humectants, lubricants, fragrances, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, soljubilizatory, wetting agents and mixtures thereof.

Excipients to obtain compositions comprising a compound having the Formula (I) are administered orally in solid dosage form include, for example, agar-agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-b is trangleball, 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, glycerol, peanut oil, hypromellose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, salt, potassium phosphate, potato starch, povidone, propylene glycol, ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, salts of sodium phosphate, sodium lauryl sulfate, sorbitol, sodium, soy oil, stearic acid, stearyl fumarate, sucrose, surfactants, talc, tragakant, tetrahydrofuranyl alcohol, triglycerides, water and their mixtures. Excipients to obtain compositions comprising the compound according to the invention having the Formula (I), which is injected ophthalmically or orally in liquid dosage forms include, for example, 1,3-butyleneglycol, castor oil, corn oil, cottonseed oil, ethanol, esters of fatty acids and sorbitan oil, wheat germ, peanut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water, and the x of the mixture. Excipients to obtain compositions comprising the compound according to the invention having the Formula (I), which is administered osmotically include, for example, chlorofluorocarbons, ethanol, water and mixtures thereof. Excipients to obtain compositions comprising the compound according to the invention having the Formula (I), which is administered parenterally include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, wheat, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, ringer's solution, safflower oil, sesame oil, soybean oil, U. S. P. or isotonic sodium chloride solution, water and their mixtures. Excipients to obtain compositions comprising the compound according to the invention having the Formula (I), which is administered rectal or vaginal, include, for example, cocoa butter, polyethylene glycol, wax and mixtures thereof.

Compounds having the Formula (I) are expected to be useful when used with alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitoticheskoy agents, antiproliferative agents, antiviral agents, inhibitors of Aurora kinases, other inhibitors and promoters of apoptosis (for example, Bcl-xL, Bcl-w and Bfl-1), activators of a deadly path of the receptor, inhibitors of kinases Bcr-Abl, BiTE (Bi-Specific T cell Engager) antibodies, the conjugate is mi medicines with the antibody, the biological response modifiers, inhibitors of cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2, DVD, inhibitors of receptor homologue of the oncogene virus leukemia (ErbB2), inhibitors of growth factor inhibitors, heat shock protein (HSP)-90, inhibitors of histone deacetylase (HDAC), hormonal therapy, immunological agents, inhibitors of inhibitors of apoptosis proteins (IAPs), embedded antibiotics, kinase inhibitors, inhibitors of kinesin, Jak2 inhibitors, inhibitors of the target of rapamycin in mammals, microRNA inhibitors of mitogen-activated extracellular regulated by signals kinase, multivalent binding proteins, nonsteroidal anti-inflammatory drugs (NSAIDs), inhibitors polyadp (adenosine diphosphate)-ribose polymerase (PARP), platinum chemotherapeutics, inhibitors of Polo-like kinase (Plk) inhibitors phosphoinositide-3 kinase (PI3K) inhibitors calpaine, purine analogues, and pyrimidine analogues, inhibitors of receptor tyrosine kinases, alkaloids echinoidea/deltoidea plants, small interfering ribonucleic acids (siPHK), topoisomerase inhibitors, inhibitors of ubiquitin ligase, etc. or in combination with one or more of these tools.

BiTE anti who ate represent a bi-specific antibody, which direct T cells to attack cancer cells, while linking these two cells. T-cells then attack the cancer cell target. Examples of BiTE antibodies include adecatumumab (Micromet MT201), blinatumomab (Micromet MT103), etc., Without limitation, any theory, one of the mechanisms by which T cells induce apoptosis in cancerous target cells represents the exocytosis of cytolytic components granules, which include perforin and Grasim B. In this regard, it was shown that Bcl-2 attenuates the induction of apoptosis caused by perforin and grannymom B. These data suggest that inhibition of Bcl-2 may enhance the cytotoxic effects called T-cells targeting cancer cells (V. R. Sutton, D. L. Vaux and J. A. Trapani,J. of Immunology1997, 158 (12), 5783).

SiPHK represent molecules with endogenous reasons RNA or chemically modified nucleotides. Modifications do not remove cellular activity, but rather give increased stability and/or increased cell capacity. Examples of chemical modifications include phosphorothioate group, 2'-deoxynucleotides, 2'-OCH3-containing ribonucleotides, 2'-F-ribonucleotides, 2'-methoxyethyl the ribonucleotides, combinations thereof, etc. siPHK can have varying length (e.g., 10-200 base pairs) and structure (e.g., studs, single/dual is the first chain, loops, breaks, mismatch) and are processed in cells with active shutdown gene. Dunaeva siPHK (dsPHK) may have the same number of nucleotides on each chain (blunt ends) or asymmetric (sticky) ends. Overhanging 1-2 nucleotides may be present on the sense and/or antisense chain, as well as at the 5' and/or 3'-end of this chain. For example, it was shown that siPHK, targeting Mcl-1, 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) on multiple lines of tumor cells (Tse et. al,Cancer Research2008, 68(9), 3421 and cited there).

Multivalent binding proteins are binding proteins comprising two or more antigenspecific areas. Multivalent binding proteins designs so that they had three or more antigenspecific plots, and usually they are not naturally occurring antibodies. The term “multispecificity binding protein” means a binding protein capable of binding the Vuh or more related or unrelated targets. Binding proteins dual variable domain (DVD) represent a tetravalent or multivalent binding proteins comprising two or more antigenspecific plot. These DVDs can be monospecific (i.e., capable of binding the same antigen) or multispecificity (i.e., capable of binding two or more antigens). DVD binding protein comprising two polypeptide DVD heavy chain and two polypeptide DVD light chain, referred to as DVD-Ig. Each half of the DVD-Ig polypeptide includes a DVD heavy chain polypeptide DVD light chain and two antigenspecific plot. Each binding site includes the variable domain of the heavy chain variable domain and a light chain with, in total, 6 CDR, involved in the binding of antigen to antigennegative plot. Multispecificity DVD include the DVD-binding proteins that bind DLL4 and VEGF, or C-met and EFGR or ErbB3 and EGFR.

Alkylating agents include altretamine, AMD-473, AP-5280, apisaon, bendamustine, brostallicin, busulfan, Carbogen, 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® (bendamustine), treosulfan, ro is ashamed etc.

Inhibitors of angiogenesis include tyrosine kinase inhibitors endothelium-specific receptor (Tie-2) inhibitors of the receptor for epidermal growth factor (EGFR) inhibitors of receptor insulin-like growth factor-2 (IGFR-2) inhibitors of matrix metalloproteinase-2 (MMP-2) inhibitors of matrix metalloproteinase-9 (MMP-9) inhibitors of the receptor for platelet-derived growth factor (DERIVED), the analogues of thrombospondin, inhibitors of tyrosine kinase receptor for vascular endothelial growth factor (VEGFR), etc.

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

Antiviral agents include ritonavir, hydroxychlordene etc.

Inhibitors of Aurora kinases on the receive ABT-348, AZD-1152, MLN-8054, VX-680, inhibitors And specific Aurora kinase inhibitors In specific Aurora kinase and inhibitors of the pan-Aurora kinase, 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-((phenylsulfanyl)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), etc.

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

Inhibitors SOH-2 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, anti-EGFR of immunoliposome, EGF-vaccine, EMD-7200, ERBITUX® (cetuximab), HR3, antibodies IgA, IRESSA® (gefitinib), TARCEVA® (erlotinib or OSI-774), TP38, protein merge EGFR, 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), anti-HER/2neu bespecifically antibody, B7.her2IgG3, AS HER2 trifunctional bespecifically antibodies, mAB AR-209, mAB 2B-1, etc.

Inhibitors of histone deacetylase includes depsipeptide, lunar abyss-824, MS-275, trioxin, suberoylanilide hydroxamic 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, PU24FCl, PU-3, radicial, SNX-2112, STA-9090 VER49009 etc.

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

The conjugates of drugs with the antibody include an 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 deadly path of the receptor include TRAIL, antibodies or other agents that target TRAIL or death receptor (e.g., 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.

In hibitory MEK include ARRY-142886, ARRY-438162 PD-325901, PD-98059, etc.

The mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, ATP-konkurentnye inhibitors TORC1/TORC2, including PI-103, PP242, PP30, Thorin 1, etc.

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

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

Platinum chemotherapeutic agents 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™ (ribozyme that inhibits angiogenesis (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™ (VA is detaib, ZD-6474), GA101, ofatumumab, ABT-806 (mAb-806), ErbB3 antibodies BSG2 antibodies specific DLL4 antibodies and C-met antibodies, etc.

Antibiotics include embedded antibiotics aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin), daunorubicin, CAELYX® or MYOCET® (liposomal doxorubicin), elsamitrucin, epirubicin, 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, Ekaterin, belotecan, BN-80915, CAMPTOSAR®(irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxane), diflomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin, etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan, mitoxantrone, oracin, pirarubicin, 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 and etc.

Hormonal therapeutic agents include ARIMIDEX® (anastrozole) AROMASIN® (exemestane), arzoxifene, CASODEX® (bikalutamid), CETROTIDE® (cetrorelix), degarelix, deslorelin, DESOPAN® (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® (hormone that stimulates luteinizing hormone (LHRH)), VANTAS® (the implantable Histrelin), VETORYL® (trilostane or morestan), ZOLADEX® (forlin, goserelin), etc.

Deltoids and retinoids include seocalcitol (EB1089, CB1093), 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.

Alkaloids of plants include, but are not limited to, vincristine, vinblastine, vindesine, vinorelbine, etc.,

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

Examples of immunological tools include interferons and other immunobiologii funds. Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, inter is iron gamma-1a, ACTIMMUNE®(interferon gamma-1b) or interferon gamma-n1, combinations thereof, etc., Other tools include ALFAFERONE®, (IFN-α), YOU-002 (oxidized glutathione), BEROMUN® (tasonermin), BEXXAR® (tositumomab), CAMPATH® (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), dacarbazin, denileukin, epratuzumab, GRANOCYTE® (lenograstim), lentinan, leukocyte alpha-interferon, imiqimod, MDX-010 (anti-CTLA-4), melanoma vaccine, mitooma, molgramostim, MYLOTARG™ (gemtuzumab ozogamicin), NEUPOGEN® (filgrastim), OncoVAC-CL, OVAREX® (oregovomab), pemtumomab (Y-muHMFG1), PROVENGE® (sipuleucel-T), sargramostim, sizofiran, azelastin, THERACYS® (Bacillus Calmette-Guerin), ubenimex, VIRULIZIN® (immunotherapy, Lorus Pharmaceuticals), Z-100 (Specific Substance of Maruyama (SSM)), WF-10 (tetrachlorodecaoxide (TCDO)), PROLEUKIN® (aldesleukin), ZADAXIN® (thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-ibritumomab tiuxetan), etc.

The biological response modifiers are tools that modify defense mechanisms of living organisms or biological responses, such as survival, growth or differentiation of tissue cells, so that they had antitumor activity, and include the christening, lentinan, sizofiran, 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 inside the body), flexure is in, GEMZAR® (gemcitabine), TOMUDEX® (raytraced), TROXATYL™ (triacetyluridine troxacitabine), etc.

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

Antimitoticescoe agents 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 ubiquitin ligase includes MDM2 inhibitors, such as tested nutlins, inhibitors NEDD8, such as MLN4924, etc.

Compounds according to the invention can also be used as radio sensibilizators that enhance the effectiveness of radiation therapy. Examples of radiation therapy include radiation therapy with external beam teletherapy, brachytherapy and radiotherapy with sealed, unsealed source, etc.

Additionally, compounds having Formula (I), can be combined with other chemotherapeutics, such as ABRAXANE™ (ABI-007), ABT-100 (inhibitor farnesyltransferase), ADVEXIN® (vaccine Ad5CMV-p53), ALTOCOR® or MEVACOR® (lovastatin), AMPLIGEN® (poly I:poly C12U, a synthetic RNA), APTOSYN® (asialink), AREDIA® (pamidronate acid), Arglabin, L-asparaginase, atamestane (1-methyl-3,17-dione-androsta-1,4-diene), AVAGE® (tazarotene), AVE-8062 (derived combretastatin) BEC2 (mitooma), Kakha the tin or cachectin (tumor necrosis factor), canvaxin (vaccine), CEAVAC® (cancer vaccine), CELEUK® (celmoleukin), CEPLENE® (histamine dihydrochloride), CERVARIX® vaccine human papillomavirus (HPV), CHOP® (C: CYTOXAN® (cyclophosphamide); N: 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 human epidermal growth factor) or TransMID-107R™ (diphtheria toxins), dacarbazine, dactinomycin, 5,6-dimethylxanthene-4-acetic acid (DMXAA), eniluracil, EVIZON™ (squalamine lactate), DIMERICINE® lotion T4N5 liposomes), discodermolide, DX-8951f (eksteen mesilate), enzastaurin, EPO906 (epitalon B), GARDASIL® (recombinant tetravalent vaccine human papillomavirus (Types 6, 11, 16, 18)), GASTRIMMUNE®, GENASENSE®, GMK (ganglioside-conjugate vaccine), GVAX® vaccine for prostate cancer), halofuginone, histrelin, hydroxycarbamide, ibandronic acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox), exotoxin IL-13 is found, interferon-α, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide), lonafarnib, 5,10-methylenetetrahydrofolate, miltefosine (hexadecylphosphocholine), NEOVASTAT® (AE-941), NEUTREXIN® (trimetrexate the glucuronate), NIPENT® (pentostatin),ONCONASE® (enzyme ribonuclease), ONCOPHAGE® (tool-based melanoma vaccine), ONCOVAX® (Vaccine IL-2), ORATHECIN™ (rubitecan), OSIDEM® (cellular Les is arctonoe means on the basis of antibodies) OVAREX® MAb (mouse monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponin from ginseng, including 20(S)protopanaxadiol (aPPD) and 20(S)protopanaxatriol arrt)), panitumumab, PANVAC®-VF (research cancer vaccine), pegaspargase, PEG-Interferon A, phenoxodiol, procarbazine, ropemaster, REMOVAB® (catumaxomab), REVLIMID® (lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide), SORIATANE® (acitretin), staurosporine (Streptomyces staurospores), talabostat (PT100), TARGRETIN® (bexarotene), TAXOPREXIN® (DNA-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)hinzelin the dihydrochloride), TNFERADE™ (adenovector: native DNA, containing the gene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan), tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide), VIRULIZIN®, Ukrain (derivative of alkaloids in plants celandine), vitaxin (anti-v3 antibody),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 having Formula (I) compounds that bind and inhibit anti-apoptotic proteins Bcl-2, was performed using the Test of energy transfer resonance-free is tion with a temporal resolution (TR-FRET). Antibody Tb-anti-GST was acquired by Invitrogen (catalog Number PV4216).

Synthesis of probe

All reagents used in the form in which they were received from the seller, unless otherwise noted. Reagents for the synthesis of peptides, including diisopropylethylamine (DIEA), dichloromethane (DCM), N-organic (NMP), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate (HBTU), N-hydroxybenzotriazole (HOBt) and piperidine were obtained from Applied Biosystems, Inc. (ABI), Foster City, CA or American Bioanalytical, Natick, MA. Preloaded 9-fluorenylmethoxycarbonyl amino acid cartridges (Fmoc) (Fmoc-Ala-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Phe-OH, Fmoc-Gly-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, Fmoc-Arg(Pbf)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH) were obtained from ABI or Anaspec, San Jose, CA. Resin synthesis of peptide resin Fmoc-Rink amide MBHA) and Fmoc-Lys(Mtt)-OH was obtained from Novabiochem, San Diego, CA. The only isomer 6-carboxyfluorescein Succinimidyl ether (6-FAM-NHS) was obtained from Anaspec. Triperoxonane acid (TFA) was obtained from Oakwood Products, West Columbia, SC. Thioanisole, phenol, triisopropylsilane (TIS), 3,6-dioxa-1,8-octanedithiol (DODT) and isopropanol were obtained from Aldrich Chemical Co., Milwaukee, WI. Matrix-assisted mass spectra of laser desorption ionization (MALDI-MS) were recorded on an Applied Biosystems Voyager DE-PRO MS. Mass spectra with elektrorazpredelenie (ESI-MS) would and registered on a Finnigan SSQ7000 (Finnigan Corp., San Jose, California), both in positive and in negative ion mode.

The General procedures for solid-phase peptide synthesis (PPPS)

Peptides were synthesized with, at most, 250 µmol preloaded Wang resin/vessel on peptide synthesizer ABI 433A, using cycles of combination Fastmoc™ scale 250 µmol. Pre-loaded cartridges, containing 1 mmol standard Fmoc-amino acids, except for provisions added fluorophore, where 1 mmol Fmoc-Lys(Mtt)-OH was placed in a cartridge, used with monitoring feedback conductivity. Acetylation of N-Terminus was carried out using 1 mmol of acetic acid in the cartridge in a standard combination.

Remove 4-methyltricyclo (Mtt) From lysine

The resin from the synthesizer was washed three times with dichloromethane and kept moist. 150 ml of a mixture of 95:4:1 dichloromethane:triisopropylsilane:triperoxonane acid was passed through the resin for 30 minutes. The mixture acquired a deep yellow color, then bleached to a bright yellow color. 100 ml of N,N-dimethylformamide was passed through the layer for 15 minutes. The resin is then washed three times with N,N-dimethylformamide and filtered. Ninhydrin tests showed a strong signal for the primary amine.

Tagging resin 6-carboxyfluorescein-NHS (6-FAM-NHS)

The resin was treated with 2 equivalents of 6-FAM-NHS in MESI 1% DIEA/N,N-dimethylformamide and stirred or which at ambient temperature over night. Upon completion, the resin was trenirovki, washed three times with N,N-dimethylformamide, three times (1×DCM and 1×with methanol and dried, obtaining orange resin, which was negative in ninhydrin test.

General procedure for cleavage and removal of the protective group to bind with the resin peptide

The peptides were tsalala from resin, shaking for 3 hours at ambient temperature in splitting the cocktail, consisting of 80% TFA, 5% water, 5% thioanisole, 5% phenol and 2.5% TIS and 2.5% EDT (1 ml/0.1 g resin). The resin was removed by filtration and washed twice TFA. TFA is evaporated from the filtrate, and the product was besieged by a simple ether (10 ml/0.1 g resin) was recuperable by centrifugation, washed twice with simple ether (10 ml/0.1 g resin), and dried, obtaining the crude peptide.

General procedure for the purification of peptides

Crude peptides were purified on a preparative HPLC system Gilson running analytical software Unipoint® (Gilson Inc., Middleton, WI) on radial compression column containing two segments 25×100 mm, filled with particles of a Delta-Pak™ C18 15 μm with a pore size of 100 Å, and suirable one of the methods below gradient. One to two milliliters of the crude peptide solution (10 mg/ml in a mixture of 90% DMSO/water) was purified for one injection. The peaks containing the product(s) from each of the acceleration, United and liofilizirovanny. All preparative acceleration implementation of the conduct at 20 ml/min with suenami as buffer A is 0.1% TFA-water and buffer B: acetonitrile.

General procedure analytical HPLC

Analytical HPLC was carried out on the system Hewlett-Packard 1200 series with mnogodetnym detector and the sensor fluorescence Hewlett-Packard 1046A under the control of software 3D HPLC ChemStation version A,03,04 (Hewlett-Packard company. Palo Alto, CA) on a column of YMC is 4.6×250 mm, filled with particles of ODS-AQ 5 μm with a pore size of 120 Å, and suirable one way gradient, referred to below, after pre-equilibration to initial conditions within 7 minutes. Eluent consisted of buffer A is 0.1% TFA-water and buffer B: acetonitrile. Volumetric flow rate for all gradient was 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 expanded using the General procedure for the synthesis of peptides, getting protected is associated with the resin peptide (1,020 g). The Mtt group was removed, marked 6-FAM-NHS and tsalala and removing the protective group, as described above, receiving the crude product in the form of a solid orange color (0,37 g). This product was purified HPLC reverse phase. Fractions of the main peak was checked by analytical HPLC with a reverse phase, and pure fractions were isolated and liofilizirovanny, with the main peak provided the target compound (0,0802 g) in the form of a solid yellow; MALDI-MS m/z = 2137,1 [(M+H)+].

Alternative synthesispeptide probe F-Bak: Aceti is-(SEQ ID NO: 1)GQVGRQLAIIGDK(6-FAM)-(SEQ ID NO:2)INR-NH 2

The protected peptide was assembled on 0.25 mmol of resin Fmoc-Rink amide MBHA (Novabiochem) on an automated peptide synthesizer Applied Biosystems 433A running cycles of combination FastmocTMusing pre-loaded with 1 mmol of amino acid cartrigde, except for the fluorescein(6-FAM)- labeled lysine, where he weighed 1 mmol Fmoc-Lys(4-methyltetra) on the cartridge. N-terminal acetyl group consisted of putting in the cartridge 1 mmol of acetic acid and in combination, as described above. Selective removal of 4-methyltricyclo groups was carried out using a solution of 95:4:1 DCM:TIS:TFA (about./about./vol.), pumped through the resin for 15 minutes, followed by quenching the flow of dimethylformamide. The only isomer 6-carboxyfluorescein-NHS was introduced in the reaction with the side chain of lysine in 1% DIEA in N,N-dimethylformamide, and the completion of the reaction was confirmed using ninhydrin test. The peptide was tsalala from the resin and removing the protective groups of the side chains, processing mixture 80:5:5:5:2,5:2,5 TFA/water/phenol/thioanisole/triisopropylsilane: 3,6-dioxa-1,8-octanedithiol (about./about./about./about./about./vol.), and the crude peptide was recuperable deposition simple diethyl ether. The crude peptide was purified by high-performance liquid chromatography reverse phase, and its purity and identity were confirmed by analytical high-performance liquid chromatography with on atoi phase and matrix-assisted mass spectrometry laser desorption (m/z = 2137,1 ((M+H) +)).

Test energy transfer fluorescence resonance with a temporal resolution (TR-FRET)

Representative compounds serially diluted in dimethyl sulfoxide (DMSO), starting with a concentration of 50 mm (2 starting concentration; 10% DMSO) and 10 μl was transferred to a plate with 384 wells. Then 10 μl of a mixture of protein/probe/antibody was added to each well at final concentrations listed in TABLE 1. The samples were then mixed on a shaker for 1 minute and incubated for an additional 3 hours at ambient temperature. For each test mixture probe/antibody and protein/probe/antibody were included in each test tablet as negative and positive control, respectively. Fluorescence was measured on an Envision (Perkin Elmer) using excitation filter 340/35 nm and emission filters 520/525 (peptide F-Bak) and 495/510 nm (Tb-labeled antihistimine antibody). The inhibition constants (Ki) are shown 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 to test the TR-FRET
ProteinProbe Protein (nm)Probe (nm)AntibodyAntibody (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 of Bcl-2 Ki (μm)
Example No.TR-FRET binding: Bcl-2 Ki (μm)
50,184564
60,211918
80,975006
90,026482
110,208284
130,072896
140,748598
150,047989
160,273003
180,745889
190,402855
200,279946
210,087297
220,017280
230,027303
240,010344
260,626725
270,004156
280,000125
290,002272
300,00020883
310,021618
320,0059419
330,0040901
340,0051381
350,0088374
360,031748
370,010612
380,0001741
nd
41nd
42nd
43nd
44nd
45nd
nd = not determined

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

The data in TABLE 2 shows the inhibition constants against inhibiting peptide probe Bak BH3 proteins Bcl-2 and show that the compounds according to the invention have a high binding affinity to the anti-apoptotic protein Bcl-2. Therefore, it is expected that the compounds can be used in treating diseases during which is expressed anti-apoptotic protein Bcl-2.

It is expected that, as compounds having the Formula I, are associated with Bcl-2, they can also be used as compounds the Oia, bind to the antiapoptotic proteins, which has close structural homology with Bcl-2, such as, for example, anti-apoptotic proteinsBcl-XL, Bcl-w, Mcl-1 and Bfl-1/A1.

Involvement of protein Bcl-2 in bladder cancer, brain cancer, breast cancer, cancer of the bone marrow, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, gastric cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of the processes of T-cell or b-cell origin, melanoma, myelogenous leukemia, myeloma, cancer of the oral cavity, cancer of the ovary, non-small cell lung cancer, prostate cancer, small cell lung cancer, cancer of the spleen, etc. described in the joint application PCT US 2004/36770, published as WO2005/049593, and PCT US 2004/37911, published as WO2005/024636.

Involvement of protein Bcl-2 in immune and autoimmune diseases are described in theCurrent Allergy and Asthma Reports2003, 3, 378-384;British Journal of Haematology2000, 110(3), 584-90;Blood2000,95(4), 1283-92; andNew England Journal of Medicine2004, 351(14), 1409-1418.

Involvement of protein Bcl-2 in arthritis disclosed in the joint provisional application for U.S. patent 60/988479.

Involvement of protein Bcl-2 in the rejection of bone marrow transplant bone revealed in a joint application for U.S. patent 11/941196.

Overexpression of proteins Bcl-2 correlates with resistance to chemotherapy and clinical outcome the development of the disease, General forecast or their combinations at various cancers and immune system disorders. Cancer includes, but is not limited to, hematologic and solid tumors such as acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer (including positive for estrogen receptor breast cancer), bronchogenic cancer, Burkitt's lymphoma, cervical cancer, chondrosarcoma, chordoma, horiokartsinoma, chronic leukemia, chronic lymphocytic leukemia, chronic miliitary (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, deproliferation changes (dysplasia and metaplasia), embryonal cancer, endometrial cancer, ehotelier.com, ependymoma, epithelial cancer, erythroleukemia, stomach cancer, positive for estrogen receptor breast cancer, essential thrombocythemia, Ewing's sarcoma, fibrosarcoma, gastric cancer, a tumor of germ cells of the testes, trophoblast disease of pregnancy, glioblastoma, head and neck cancer, b the disease heavy chains, hemangioblastoma, hepatoma, hepatocellular cancer, harmoniously 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 both diffuse b-cell lymphoma, follicular lymphoma, Hodgkins lymphoma and non-Hodgkins the Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or b-cell origin, leukemia, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, cancer of the papilla, peripheral T-cell lymphoma, pinealoma, polycythemia Vera, prostate cancer (including hormone-insensitive (refractory) prostate cancer), colorectal cancer, renal cell cancer, retinoblastoma, rhabdomyosarcoma, sarcoma, cancer of the sebaceous glands, seminoma, skin cancer, small cell is AK lung, solid tumors (carcinoma and sarcoma), stomach cancer, squamous cell carcinoma, sinovioma, cancer of the sweat glands, testicular cancers (including cancer of the reproductive cells of the testicles), thyroid cancer, macroglobulinemia Waldenström, tumors of the testis, cancer of the uterus, tumor Wilms ' tumor, etc.

It is also expected that compounds having Formula (I) can inhibit the growth of cells expressing Bcl-2, derived from a pediatric cancer or tumor, including the embryonic rhabdomyosarcoma, pediatric acute lymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic an ependymoma, pediatric anaplastic both lymphoma, pediatric anaplastic a medulloblastoma, pediatric atypical teratoid/Rathenow tumor of the Central nervous system, pediatric biphenotypic acute leukemia, pediatric Burkitt's lymphoma, pediatric cancer family of Ewing tumors such as primitive neuroectodermal tumors, pediatric diffuse anaplastic tumor Wilma, pediatric tumor Wilma with favorable histology, pediatric glioblastoma, pediatric medulloblastoma, pediatric neuroblastoma, pediatric originating from the neuroblastoma myelocytomatosis, pediatric pre-B-cell cancers(such as leukemia), pediatric pleasecome, pediatric Rathenow tumor of the kidney, pediatric rhabdomyosarcoma, and pediatric T-cell cancers such as lymphoma and skin cancer, etc.,

Autoimmune disorders include the syndrome of acquired immunodeficita (AIDS), autoimmune lymphoproliferative syndrome, hemolytic anemia, inflammatory diseases, and thrombocytopenia, acute or chronic immunopathological disease associated with organ transplantation, Addisonova disease, allergic disease, alopecia, alopecia areata, atheromatous disease/arteriosclerosis, atherosclerosis, arthritis (including osteoarthritis, juvenile chronic arthritis, septic arthritis, Lyme arthritis, psoriatic arthritis and reactive arthritis), autoimmune bullous disease, abetalipoproteinemia associated with acquired immune deficiency diseases, acute immunopathological disease associated with organ transplantation, acquired acrocyanosis, acute and chronic parasitic or infectious processes, acute pancreatitis, acute renal failure, acute rheumatic fever, acute transverse myelitis, adenocarcinoma, atriale ectopic, (acute) respiratory distress syndrome adult, complex, AIDS-dementia, alcoholic cirrhosis, alcohol-induced liver damage caused by alcohol the m hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allergies, asthma, allograft rejection, deficiency of alpha-1-antitrypsin deficiency, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, angina associated with ankylosing spondylitis disease lung degeneration of anterior horn cells, mediated by antibody cytotoxicity, antiphospholipid syndrome, reactions antireceptor hypersensitivity, aortic and peripheral aneurysms, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, arthropathy, fatigue, asthma, ataxia, atopic allergies, atrial fibrillation (permanent or paroxysmal) atrial fibrillation, atrioventricular blockade, atrophic autoimmune hypothyroidism, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune hepatitis type 1 (classical autoimmune or lapoinya 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, blockade bundle branch, burns, cachexia, cardiac arrhythmia syndrome stun attack, tumors of the heart is a, cardiomyopathy, inflammatory response to cardiopulmonary bypass, graft rejection of cartilage degeneration of the cerebellar cortex, cerebellar disorders, chaotic or multifocal tachycardia fibrillation, comorbidities chemotherapy, chlamydia, homeostatic, chronic alcoholism, chronic active hepatitis, chronic fatigue syndrome, chronic immunopathological disease associated with organ transplantation, chronic eosinophilic pneumonia, chronic inflammatory pathologies, chronic mucocutaneous candidiasis, chronic obstructive pulmonary disease (COPD), chronic salitsilovogo intoxication, colorectal General varying human immunodeficiency (common variable gipogammaglobulinemia), conjunctivitis, collagenosis-associated intermediate lung disease, contact dermatitis, Coombs-positive hemolytic anemia, pulmonary heart disease Creutzfeld-Jakob disease, cryptogenic autoimmune hepatitis, cryptogenic fibrosing alveolitis, culture negative sepsis, cystic fibrosis, comorbidities during cytokine therapy, Crohn's disease, dementia boxers, demyelinating diseases, Dengue haemorrhagic fever, dermatitis, scleroderma, with dermatitis, dermatological conditions, dermatomyositis/polymyositis-related is this disease of the lung, diabetes, diabetic arteriosclerotic disease, diabetes, disease type diffuse Taurus Levi, extended cardiomyopathy, advanced congestive cardiomyopathy, discoid lupus erythematosus, disorders of the basal ganglia, disseminated intravascular coagulation, down's syndrome in middle age, drug-induced means intermediate lung disease, drug-induced hepatitis, drug movement disorders induced by drugs which block CNS dopamine receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy, enteropathic synovitis, epiglottitis, virus infection Epstein-Barr, erythromelalgia, extrapyramidal and cerebellar disorders, family hematopoietically lymphohistiocytic, graft rejection embryonic thymus, Friedrich's ataxia, functional peripheral arterial disorders, female infertility, fibrosis, fibrotic disease of the lung, fungal sepsis, gas gangrene, gastric ulcer, giant cell arteritis diagnostics, glomerular nephritis, glomerulonephritis syndrome?, goitrous autoimmune hypothyroidism (goiter Hashimoto), gouty arthritis, graft rejection of any organ or tissue, graft-versus-host, gram-negative sepsis, gr is polojitelnii sepsis, granulomas due to intracellular organisms, infection streptococcal group B (GBS), diffuse toxic goiter, hemosiderosis-associated lung disease, hairy cell leukemia, hairy cell leukemia, a disease Hallervorden-Spitze, Hashimoto thyroiditis, hay fever, rejection of a heart transplant, hemachromatosis, hematopoietic malignancies (leukemia and lymphoma), hemolytic anemia, hemolytic uremic syndrome/thrombolytic thrombocytopenic purple, bleeding, purple Henka-Seleina, hepatitis A, hepatitis B, hepatitis C, HIV infection/HIV neuropathy, Hodgkin's disease, hypoparathyroidism, horey's disease, hyperkinetic movement disorders, allergic reactions, hypersensitivity pneumonitis, hyperthyroidism, hypokinetic movement disorders, changes in the hypothalamic-pituitary-adrenal axis, idiopathic Addisonova disease, idiopathic leukopenia, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia, idiosyncratic liver disease, infantile spinal muscular atrophy, infectious diseases, inflammation of the aorta, inflammatory bowel disease, insulin-dependent diabetes mellitus, intermediate pneumonitis, iridocyclitis/uveitis/optic neuritis, damage caused by ischemia-reperfusion, ischemic stroke, see the ilen malignant anemia, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma, Kawasaki disease, kidney transplant rejection, legionellosis, leishmanias, leprosy, lesions of corticospinal system, disease, linear IgA, lipedema, transplant rejection liver, Lyme disease, lymphedema, lymphocytic infiltrative lung disease, malaria, male idiopathic infertility or NOS, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, microscopic vasculitis of the kidneys, headache migraine headache, mitochondrial multi-system violation, mixed collagenosis associated with mixed collagenosis disease of the lung, the monoclonal gammopathy, multiple myeloma, Multisystem degeneration (Mencel Dejerine-Thomas Shi-Drager and Machado-Joseph), myalgic encephalitis/Royal disease Free, myasthenia gravis, microscopic vasculitis of the kidneys, Mycobacterium avium intracellulare, Mycobacterium tuberculosis, myelodysplastic syndrome, myocardial infarction, myocardial ischemic disorders, nasopharyngeal cancer, chronic lung disease of the newborn, nephritis, nephrosis, nephrotic syndrome, neurodegenerative diseases, neurogenic I muscular atrophy, neutropenias fever, non-alcoholic steatohepatitis, occlusion of the abdominal aorta and its branches, obtenerse blood is arsenia, rejection of an organ transplant, orchitis/epididymitis, for the treatment of orchitis/vasectomy, organomegaly, osteoarthritis, osteoporosis, ovulation disorders, graft rejection in the pancreas, parasitic diseases, transplant rejection parathyroid cancer, Parkinson's disease, an inflammatory disease of the pelvis, utricularia vulgaris, leaf bladderwort, pemphigoid, perennial rhinitis, pericardial disease, peripheral atherosclerotic disease, peripheral vascular disorders, peritonitis, malignant anemia, phacogenic uveitis, pneumocystis carinii pneumonia, pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy syndrome and skin changes), postperfusion syndrome syndrome PPS (post pump syndrome) syndrome cardiotomy post-MI, post-infectious intermediate lung disease, premature ovulation, primary biliary cirrhosis, primary sclerosing hepatitis, primary myxoedema, primary pulmonary hypertension, primary sclerosing cholangitis, primary vasculitis, progressive supranuclear palsy, psoriasis, psoriasis type 1, psoriasis type 2, the psoriatic arthropathy, pulmonary arterial hypertension, secondary to collagen disorders, pulmonary manifestation of polyarteritis of polyarteritis, postnasal the positive intermediate lung disease, radiation fibrosis, radiation therapy, phenomenon and Raynaud's disease, a disease Rayno, disease Refsum, tachycardia with a regular close-QRS, disease, Reiter, renal disease NOS, renovascular hypertension, reperfusion injury, restrictive cardiomyopathy, associated with rheumatoid arthritis intermediate lung disease, rheumatoid spondylitis, sarcoidosis syndrome Schmidt, scleroderma, senile horey, senile Dementia type Taurus Levi, sepsis syndrome, septic shock, the seronegative arthropathy, shock, sickle cell anemia, is associated with disease Sjogren lung disease, syndrome Sjogren, rejection of allograft skin syndrome skin changes, graft rejection of the small intestine, autoimmunity sperm, multiple sclerosis (all subtypes), spinal ataxia, spenomegaly degeneration, spondyloarthropathy, the sporadic spondyloarthropathy, sporadic polyglandular failure type I, polyglandular deficiency type II, of still's disease, streptococcal myositis, stroke, structural lesions of the cerebellum, subacute sclerosing panencephalitis, sympathetic ophthalmia, syncope, syphilis of the cardiovascular system, systemic anaphylaxis, systemic inflammatory syndrome response system start juvenile rheumatoid arthritis, systems is th lupus erythematosus, associated with systemic lupus erythematosus lung disease, systemic sclerosis associated with systemic sclerosis intermediate lung disease, T-cell or FAB ALL, disease/Takayasu's arteritis, telangiectasia, mediated by Th2 Type and Th1 Type of the disease, thromboangiitis obliterans, thrombocytopenia, thyroiditis, toxicity, toxic shock syndrome, transplants, trauma/hemorrhage, autoimmune hepatitis type 2 (anti-LKM or antibody-based test hepatitis), type B insulin resistance with a black acanthosis, hypersensitive reaction type III, hypersensitivity type IV, arthropathy in ulcerative colitis, ulcerative colitis, unstable angina, uremia, urosepsis, urticaria, uveitis, diseases of the heart valves, varicose changes veins, vasculitis, vasculitis diffuse lung disease, venous diseases, venous thrombosis, ventricular fibrillation, vitiligo acute liver disease, viral and fungal infections, vital encephalitis/aseptic meningitis, vital-associated hemophagocytosis syndrome, Wegener's granulomatosis syndrome Wernicke-Korsakov, gepatolentikuliarnaya degeneration, xenograft rejection of any organ or tissue, associated with yersiniosis and salmonellosis arthropathies, etc.

Schemes and experimental data

The following abbreviations have the decree is by value. 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 hydrogenizing 1,4-phthalazinedione ether; DBU means 1,8-diazabicyclo[5,4,0]undec-7-ene; DIBAL means diisobutylaluminium hydride; DIEA means diisopropylethylamine; DMAP means N,N-dimethylaminopyridine; 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 is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Fmoc means fluorenylmethoxycarbonyl; HATU means O-(7-asobancaria-1-yl)-N,N ' N 'N'-tetramethyluronium hexapterus; HMPA means of hexamethylphosphoramide; IPA means isopropyl alcohol; MP-BH3means the macroporous triphenylamine metropolitical cyanoborohydride; Thea means triethylamine; TFA means triperoxonane acid; THF means tetrahydrofuran; NCS means N-chlorosuccinimide; NMM means N-methylmorpholine; NMP means N-methylpyrrolidine; PPh3means triphenylphosphine.

The following schema presents as probably the most is handy and easy-to-understand descriptions of procedures and conceptual aspects of this invention. Compounds according to the invention can be obtained by means of chemical synthesis, examples of which are shown here. It is clear that the order of steps in the methods may vary, exactly what these reagents, solvents and reaction conditions can be replaced by others, and that vulnerable groups can be protected and the protective group may be removed, as necessary.

SCHEME 1

The compounds of Formula (4) can be obtained as shown in SCHEME 1, and can be used as described in SCHEME 8 to obtain the compounds of Formula I, which are representative of compounds according to the present invention. The compounds of Formula (1) in which R denotes alkyl, can be converted into compounds of the Formula (2) using the Z3L1MgX1where X1denotes a halide, in a solvent such as but not limited to, 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 R57X2in which X2denotes a halide, and R57matter described herein. The compounds of Formula (3), when processing an aqueous solution of NaOH or LiOH, lead to compounds of the Formula (4).

SCHEME 2

As shown in SCHEME 2, compound f is rmula (5) can be introduced into the reaction with compounds of the Formula (6) and a reducing agent to obtain compounds of the Formula (7). Examples of reducing agents include sodium borohydride, cyanoborohydride sodium, triacetoxyborohydride sodium, cyanoborohydride on a polymer substrate, etc., the Reaction is usually carried out in a solvent such as but not limited to, methanol, tetrahydrofuran and dichloromethane, or a mixture thereof. The compounds of Formula (8) can be obtained from compounds of Formula (7) as described in SCHEME 1, and can be used as described in SCHEME 8 to obtain the compounds of Formula I.

SCHEME 3

The compounds of Formula (9), when introduced into reaction with the compound of the Formula (10), in which X denotes a halide or triflate, and the ground lead to the compound of Formula (11). The Foundation, which can be used in this reaction include triethylamine, diisopropylethylamine, etc. of Compounds of Formula (13), in which Y has the values described herein for substituents on Z3can be obtained from compounds of Formula (11) and compounds of Formula (12) using a combination of Suzuki, a renowned specialist and readily available in the literature. The compounds of Formula (14) can be obtained from compounds of Formula (13) as described in SCHEME 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 bytevalue from compounds of Formula (15) and compounds of Formula (16), in which R denotes alkyl, and R38matter described here, using a combination of Suzuki, a renowned specialist and readily available in the literature. The compounds of Formula (17) can be reduced to compounds of the Formula (18) using a reducing agent such asLiAlH4in a solvent such as, but not limited to, simple diethyl ether or THF. The compounds of Formula (19) can be obtained from compounds of Formula (18) using periodinane dessa-Martin or Swern oxidation conditions known to the specialist and readily available in the literature. The compounds of Formula (19) can be introduced into the reaction 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, cyanoborohydride on a polymer substrate, etc., the Reaction is usually carried out in a solvent such as, but not limited to, 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 described in SCHEME 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), in which R denotes alkyl, can be the ü converted into the compounds of Formula (23), by reaction of compounds of formula (22), in which X1denotes Cl, Br, I or CF3SO3-with compounds of Formula R41HE and a catalyst, with or without the first base. Examples of catalysts include complex triftorbyenzola copper (I) and toluenePdCl2Pd(OAc)2andPd2(dba)3. The first examples of the bases 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 reaction of compounds of formula (22) when X1denotes Cl, F or NO2and compounds of the Formula R41HE first base. The first examples of the bases include triethylamine, N,N-diisopropylethylamine,Cs2CO3, Na2CO3, K3PO4and mixtures thereof.

SCHEME 6

The compounds of Formula (18) can be introduced into the reaction methylsulphonyl chloride and a base such as but not limited to, triethylamine, followed by addition of N-tert-butoxycarbonylamino, to obtain the compounds of Formula (24). The compounds of Formula (25) can be obtained by reaction of compounds of Formula (24) with triphenylsilanol and triperoxonane acid. The compounds of Formula (25) can be introduced into the reaction with SOEDINENIYa (26) and HK 2PO4obtaining compounds of Formula (27) in a solvent such as, but not limited to, dimethyl sulfoxide. The compounds of Formula (28) can be obtained from compounds of Formula (27) as described in SCHEME 1, and can be used as described in SCHEME 8 to obtain compounds of Formula I.

SCHEME 7

As shown in SCHEME 7, compounds of Formula (1) can be introduced into reaction with a suitable triphenylphosphonium bromide of Formula (29) and a base such as, but not limited to, sodium hydride or n-utility, to obtain the compounds of Formula (30). The reaction is usually carried out in a solvent such as THF or DMSO. The compounds of Formula (31) can be obtained from compounds of Formula (30) as described in SCHEME 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 described herein may be converted into compounds of Formula (33) by reaction of compounds of formula (32) with ammonia. The compounds of Formula (33) can be converted into compounds of Formula (I) by reaction of compounds of formula (33) and compounds of Formula(4), (8), (14), (21), (28), (31) or (37) and a binder, with or without the first base. Examples of the binder include 1-ethyl-3-[3-(dimethylamino)propyl]-Carbo is aimed hydrochloride, 1,1'-carbonyldiimidazole and benzotriazol-1-yl-oxytriphenylamine hexaphosphate. 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 reaction of compounds of formula (33) and compounds of Formula (34) and first base. The first examples of bases include, but are not limited to, sodium hydride, triethylamine, N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, and mixtures thereof.

SCHEME 10

As shown in SCHEME 10, compounds of Formula (35) in which L represents a bond, alkyl, O, S, S(O), S(O)2, NH, etc. can be introduced into the reaction with compounds of Formula (36) to obtain the compounds of Formula (37). The reaction is usually carried out at elevated temperatures in a solvent such as, but not limited to, dimethylsulfoxide, and it may require the use of a base, such as, but not limited to, potassium phosphate, potassium carbonate, etc., the compounds of Formula (38) can be obtained from compounds of Formula (37), as described in SCHEME 1, and can be used as described in SCHEME 8 to obtain the compounds of Formula I.

SCHEME 11

Compounds Of Formulas Is (39), in which Y has the values described herein for substituents on Z3can be obtained from compounds of Formula (39A), in which X denotes a halide or triflate, and Y represents-B(OH)2using the combination of Suzuki, a renowned specialist and readily available in the literature. The compounds of Formula (39) can be introduced into reaction with piperazine-1-tert-BUTYLCARBAMATE and a reducing agent, such as triacetoxyborohydride sodium, to obtain the compounds of Formula (40). The reaction is usually carried out in a solvent such as, but not limited to, methylene chloride. The compounds of Formula (41) can be obtained from compounds of Formula (40) by reaction of compounds of formula (40) with R57X, where X denotes a halide, and NaH in a solvent such as N,N-dimethylformamide, and then the resulting material can be treated with triphenylsilanol and triperoxonane acid in dichloromethane. The compounds of Formula (41) can be used as described in Scheme 10, and L1-Z3is as shown in Formula (41).

SCHEME 12

As shown in SCHEME 12, a substituted piperazine-2-ones, in which R57denotes alkyl, can be introduced into the reaction with compounds of the Formula (6) and a reducing agent, such as triacetoxyborohydride sodium in dichloromethane to obtain compounds of Formula (42). Connected to the I Formula (42) can be reduced to compounds of Formula (43) using a reducing agent, such as but not limited to, lithium-aluminiumhydride, in a solvent such as but not limited to, tetrahydrofuran. The compounds of Formula (43) can be used as described in Scheme 10, and L1-Z3is as shown in Formula (43).

The following examples are provided as probably the most useful and readily understood description of procedures and conceptual aspects of this invention. Illustrated compounds were named using ACD/ChemSketch Version of 5.06 (05 June, 2001, Advanced Chemistry Development Inc., Toronto, Ontario), or ChemDraw® Ver. 9,0,5 (CambridgeSoft, Cambridge, MA). Intermediate compounds were named using ChemDraw® Ver. 9,0,5 (CambridgeSoft, Cambridge, MA).

EXAMPLE 1

4-[4-(3,3-diphenylprop-2-enyl)piperazine-1-yl]-N-[(3-nitrophenyl)sulfonyl]benzamide

EXAMPLE 1A

4-(4-(etoxycarbonyl)phenyl)piperazine-1-tert-butylcarbamoyl

A suspension of ethyl-4-perbenzoate (16,8 g of 0.1 mol), piperazine-1-tert-BUTYLCARBAMATE (18,6 g of 0.1 mol) and potassium carbonate (20.7 g, and 0.15 mol) in dimethyl sulfoxide (100 ml) was stirred under N2at 120°C for 10 hours. The reaction mixture was cooled to ambient temperature and poured into water (1 liter). The solid product was filtered, washed with water and dried in a vacuum oven overnight at 40°C.

EXAMPLE 1B

4-(piperazine-1-yl)ethylbenzoic

EXAMPLE 1A (13.3 g, 39.8 mmol) was dissolved in DIH armetale (50 ml), and was added HCl (40 ml, 4M solution in dioxane). The mixture was stirred until all starting material was not subjected to removal of the protective group, as shown by TLC. The mixture was partially concentrated and diluted simple ether. Solid HCl salt was filtered and washed with ether. The dry solid was dissolved in water and neutralized with a saturated solution of potassium carbonate to pH 10-11. The solid product was filtered, washed with water and dried in a vacuum drying Cabinet.

EXAMPLE 1C

4-(4-(3,3-biphenylyl)piperazine-1-yl)ethylbenzoic

To a solution of EXAMPLE 1B (6,27 g, 26.8 mmol) and 3,3-diphenylacetaldehyde (7,26 g, 34.8 mmol) in a mixture of dichloromethane/methanol (30 ml/30 ml) was added acetic acid (0.6 ml) followed by adding the ambient temperature of triacetoxyborohydride sodium (charged 8.52 g, with 40.2 mmol). The reaction mixture was stirred over night at ambient temperature. Organic solvents were concentratedin a vacuum, and the residue was separated between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and the solvent evaporatedin a vacuum. The remaining residue was led from acetonitrile.

EXAMPLE 1D

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

To a solution of EXAMPLE 1C (10,00 g, 23,4 mm is l) in a mixture of tetrahydrofuran/methanol (100/50 ml) was added a solution of the monohydrate of lithium hydroxide (2,59 g, 70 mmol) in water (30 ml). The reaction mixture was stirred at 60°C for 16 hours, then was cooled to ambient temperature, and the organic solvents were concentrated. The white solid residue was dissolved in hot water, and then the product was neutralized with HCl (3 equivalent). After cooling to ambient temperature, the precipitate was filtered, washed with water and dried in a vacuum oven overnight at 40°C.

EXAMPLE 1E

4-[4-(3,3-diphenylprop-2-enyl)piperazine-1-yl]-N-[(3-nitrophenyl)sulfonyl]benzamide

A suspension of EXAMPLE 1D (39,8 mg, 0.05 mmol), 3-nitrobenzenesulfonamide (20.2 mg, 0.05 mmol), 4-dimethylaminopyridine (24,4 mg, 0.1 mmol) and 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (38,4 mg, 0.1 mmol) in dichloromethane (3 ml) was stirred for 16 hours at ambient temperature. The reaction mixture was concentrated and purified HPLC reverse phase (Bond SB-C8, gradient from 30% to 100% CH3CN/water/0.1% of TFA).1H NMR (500 MHz, dimethylsulfoxide-d6) δ 10,49 (Shir.s, 1H), 8,68 (s, 1H), 8,43-charged 8.52 (m, 1H), at 8.36 (d, 1H), of 7.90 (t, 1H), 7,79 (d, 2H), 7,47 (t, 2H), 7,43 (t, 1H), 7,32-7,40 (m, 3H), 7,27 (d, 2H), 7,18 (d, 2H), 6,99 (d, 2H), of 6.26 (t, 1H), 3,84 (d, 2H), 3,38-3,54 (Shir.s, 4H), 3,32 (Shir.s, 4H).

EXAMPLE 2

N-[(2-bromophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)cyclohex-1-EN-1-yl]methyl}piperazine-1-yl)benzamid

EXAMPLE 2A

4-(4-((2-branikloks-1-enyl)methyl)piperazine-1-yl)ethylbenzoic

In a round bottom flask of 100 ml was loaded 2-branikloks-1-interbanded, (obtained as described Arnold, A. et. al.Collect. Czech. Chem. Commun.,1961,26, 3059-3073), (42 mmol), ethyl ester of 4-piperazine-1-yl-benzoic acid (42 mmol) and ethanol (50 ml). The mixture was stirred and added cyanoborohydride sodium (42 mmol). Acetic acid is used to set a pH of 5-6. The reaction mixture was stirred under N2when the ambient temperature during the night. The reaction mixture was filtered and washed with ethanol. The filtered solid was discarded, and the combined organic layers were concentrated under vacuum. The mixture was purified by chromatography on silica gel with elution with 5-10% ethyl acetate in hexano, receiving the target connection.

EXAMPLE 2B

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

This compound was obtained by replacing EXAMPLE 5A EXAMPLE 2A in EXAMPLE 5B.

EXAMPLE 2C

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

This compound was obtained, substituting EXAMPLE 5B EXAMPLE 2B in EXAMPLE 5C.

EXAMPLE 2D

N-[(2-bromophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)cyclohex-1-EN-1-yl]methyl}piperazine-1-yl)benzamid

This compound was obtained by replacing EXAMPLE 2C and 2-bromobenzaldehyde EXAMPLE 1D and 3-nitrobenzenesulfonamide, respectively, in EXAMPLE 1E.1H NMR (500 MHz, dimiti the sulfoxide-d 6) δ 12,54 (Shir.s, 1H) 9,29 (Shir.s, 1H) 8,18 (DD, 1H) to 7.84 (m, 3H) 7,66 (m, 1H) to 7.59 (m, 1H) 7,42 (m, 2H) 7,16 (m, 2H) of 6.96 (m, 2H) 3,95 (m, 2H) 3,62 (m, 2H) 3,17 (m, 2H) and 2.83 (m, 2H) 2,24 (m, 4H) 1,72 (m, 4H).

EXAMPLE 3

N-[(3-bromophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)cyclohex-1-EN-1-yl]methyl}piperazine-1-yl)benzamid

This compound was obtained by replacing EXAMPLE 2C and 3-bromobenzaldehyde EXAMPLE 1D and 3-nitrobenzenesulfonamide, respectively, in EXAMPLE 1E.1H NMR (500 MHz, dimethylsulfoxide-d6) δ 12,29 (Shir.s, 1H) 9,26 (s, 1H) 8,08 (m, 1H) 7,94 (m, 2H) 7,78 (d, 2H) 7,60 (t, 1H) 7,42 (d, 2H) 7.15m (d, 2H) of 6.96 (d, 2H) 3,91 (m, 2H) 3,61 (m, 2H), and 3.16 (m, 2H) 2,80 (m, 2H) 2,24 (m, 4H) 1,71 (m, 4H).

EXAMPLE 4

N-[(4-bromophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)cyclohex-1-EN-1-yl]methyl}piperazine-1-yl)benzamid

This compound was obtained by replacing EXAMPLE 2C and 4-bromobenzaldehyde EXAMPLE 1D and 3-nitrobenzenesulfonamide, respectively, in EXAMPLE 1E.1H NMR (400 MHz, dimethylsulfoxide-d6) δ 12,24 (Shir.s, 1H) was 9.33 (Shir.s, 1H) 7,87 (m, 4H) to 7.77 (m, 2H) 7,40 (m, 2H) 7.15m (m, 2H) 6,95 (m, 2H) 3,91 (m, 2H) 3,61 (m, 2H), and 3.16 (m, 2H) 2,82 (m, 2H) 2,24 (m, 4H) 1,72 (m, 4H).

EXAMPLE 5

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

EXAMPLE 5A

4-(4-(2-bromobenzyl)piperazine-1-yl)ethylbenzoic

A solution of EXAMPLE 1B ((LK 23: 43 g, 100.0 mmol), 2-bromobenzyl bromide (26,24 g, 105,0 mmol) and diisopropylethylamine (20,94 ml, 120,0 mmol) in acetonitrile (200 ml) was stirred at ambient temperature for two is aces. The precipitate was collected by filtration, obtaining the target compound, which was used without further purification.

EXAMPLE 5B

4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazine-1-yl)ethylbenzoic

A suspension of EXAMPLE 5A (13,83 g, to 34.3 mmol), 4-Chlorfenvinphos acid (? 7.04 baby mortality g, 45,0 mmol), bis(triphenylphosphine)palladium (II) dichloride (0,481 g, China 0,686 mmol, 2 mol.%) and aqueous 2M Na2CO3(22.5 ml, 45,0 mmol) in a mixture of 1,2-dimethoxyethane/H2O/ethanol (7:3:2, 200 ml) was heated at 90°C for 4.5 hours and was diluted with ethyl acetate (200 ml). The layers were separated and the organic phase was dried(MgSO4), filtered and concentrated. The residue was purified by chromatography on silica gel with elution with a gradient from 5% to 40% ethyl acetate/hexane, receiving the target connection.

EXAMPLE 5C

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

A suspension of EXAMPLE 5B (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) was heated at 95°C for 16 hours, concentrated to dryness, treated with water (600 ml), was heated up to 80°C and filtered. The filtrate was treated with 1M HCl (90 ml) and the precipitate was collected by filtration and dried, obtaining the target compound.

EXAMPLE 5D

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

The target compound was obtained by replacing EXAMPLE 1D EXAMPL the 5C in EXAMPLE 1E. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 8,66 (t, 1H), charged 8.52 (m, 1H), of 8.37 (d, 1H), to 7.93 (t, 1H), 7,74 (d, 3H), 7,52 (m, 4H), 7,39 (m, 2H), 7,32 (m, 1H), 6,92 (d, 2H), 4,37 (Shir.s, 2H), 3,90 (m, 2H), 3,11 (m, 4H), 2,87 (m, 2H).

EXAMPLE 6

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

The target compound was obtained, substituting EXAMPLE 5C and benzosulfimide EXAMPLE 1D and 3-nitrobenzenesulfonamide, respectively, in EXAMPLE 1E.1H NMR (300 MHz, dimethylsulfoxide-d6) δ 12,16 (Shir.s, 1H), 7,98 (m, 1H), 7,95 (m, 1H), to 7.75 (m, 3H), of 7.70 (m, 1H), 7.62mm (m, 2H), 7,71 (d, 2H), 7,54 (m, 4H), 7,38 (d, 2H), 7,34 (d, 1H), 6,93 (d, 2H), 4,37 (Shir.s, 2H), 3,91 (m, 2H), 3,26 (m, 2H), to 3.09 (m, 2H), 2,86 (m, 2H).

EXAMPLE 7

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

EXAMPLE 7A

4-((4'-chlorobiphenyl-2-yl)methyl)piperazine-1-tert-butylcarbamoyl

4'-Chlorobiphenyl-2-carboxaldehyde (4.1 g), piperazine-1-tert-butylcarbamoyl (to 4.23 g) and triacetoxyborohydride sodium (5,61 g) in CH2Cl2(60 ml) was stirred for 24 hours. The reaction mixture was extinguished with methanol and poured into a simple ether. The solution was washed with water and brine, concentrated and chromatographically on silica gel with 2-25% ethyl acetate/hexane.

EXAMPLE 7B

1-((4'-chlorobiphenyl-2-yl)methyl)piperazine

EXAMPLE 7A (3.0 g) and triethylsilane (1 ml) was stirred in CH2Cl2(30 ml) and triperoxonane acid (30 ml) for 2 hours, and Rea is operating and the mixture was concentrated, then took in the simple ether and again concentrated. The product was used without further purification.

EXAMPLE 7C

2-(benzyloxy)-4-formatives

4-fluoro-2-hydroxymethylbenzene (2.00 g), benzyl bromide (1,54 ml) and cesium carbonate (4,60 g) in N,N-dimethylformamide (50 ml) was stirred for 24 hours. The reaction mixture was taken away by a simple ether and washed 3x 1M NaOH solution and brine, then concentrated, obtaining the target compound.

EXAMPLE 7D

2-(benzyloxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazine-1-yl)methylbenzoate

EXAMPLE 7C (570 mg), EXAMPLE 7B (754 mg) and K2CO3(605 mg) was stirred in dimethyl sulfoxide at 125°C for 5 hours. The reaction mixture was cooled and was chromatographically on silica gel with 10% ethyl acetate/hexane.

EXAMPLE 7E

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

The target compound was obtained, substituting EXAMPLE 5B EXAMPLE 7D in EXAMPLE 5C.

EXAMPLE 7F

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

The target compound was obtained by replacing EXAMPLE 1D EXAMPLE 7E in EXAMPLE 1E. The crude material was chromatographically on silica gel with 20-50% ethyl acetate/hexane.1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11,95 (Shir.s, 1H), 8,66 (d, 1H), 8,59 (d, 1H), of 8.47 (m, 2H), 8,25 (m, 2H), 7,89 (m, 2H), 7,71 (d, 2H), 7,37-rate of 7.54 (m, 7H), 7,26 (m, 1H), 6,60 (d, 1H), is 6.54 (d, 1H), total of 5.21 (who, 2H), 3,42 (s, 2H), 3,26 (m, 4H), of 2.38 (m, 4H).

EXAMPLE 8

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3-nitrophenyl)sulfonyl]-2-(2-phenylethane)benzamid

EXAMPLE 8A

4-fluoro-2-pentoxiylline

4-fluoro-2-hydroxymethylbenzene (1,00 g) and finitely alcohol (of 0.64 ml) was added to triphenylphosphine (1.54 g) and diisopropylcarbodiimide (1,04 ml) in tetrahydrofuran (20 ml) at 0°C, and the mixture was stirred at ambient temperature for 24 hours. The reaction mixture was chromatographically on silica gel with 5% ethyl acetate/hexane.

EXAMPLE 8B

4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazine-1-yl)-2-pentoxiylline

The target compound was obtained by replacing the EXAMPLE 7C EXAMPLE 8A in EXAMPLE 7D.

EXAMPLE 8C

4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazine-1-yl)-2-pentoxyverine acid

The target compound was obtained, substituting EXAMPLE 5B EXAMPLE 8B in EXAMPLE 5C.

EXAMPLE 8D

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3-nitrophenyl)sulfonyl]-2-(2-phenylethane)benzamid

The target compound was obtained by replacing EXAMPLE 1D EXAMPLE 8C in EXAMPLE 1E. The reaction mixture was chromatographically on silica gel with 20-50% ethyl acetate/hexane.1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11,05 (Shir.s, 1H), 8,71 (d, 1H), 8,53 (d, 1H), of 8.37 (d, 1H), to 7.93 (DD, 2H), 7,30-to 7.50 (m, 11H), 7,25 (m, 2H), of 6.49 (m, 2H), 4,33 (t, 2H), 3,42 (s, 2H), 3,26 (m, 4H), 3,14 (t, 2H), is 2.37 (m, 4H).

EXAMPLE 9

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl] piperazin-1-yl}-N-[(3-nitrophenyl)sulfonyl]-2-phenoxybenzamide

EXAMPLE 9A

4-fluoro-2-proximitysensor

2-bromo-4-formatives (1 g), phenol (0.565 g), cesium carbonate (1,96 g), triflate complex of copper (I) and toluene (0,087 g) and ethyl acetate (0,034 ml) in toluene (12 ml) was stirred at 110°C for 24 hours. The reaction mixture was cooled and was chromatographically on silica gel with 5% ethyl acetate/hexane.

EXAMPLE 9B

4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazine-1-yl)-2-proximitysensor

The target compound was obtained by replacing the EXAMPLE 7C EXAMPLE 9A in EXAMPLE 7D.

EXAMPLE 9C

4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazine-1-yl)-2-phenoxybenzoic acid

The target compound was obtained, substituting EXAMPLE 5B EXAMPLE 9B in EXAMPLE 5C.

EXAMPLE 9D

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

The target compound was obtained by replacing EXAMPLE 1D EXAMPLE 9C in EXAMPLE 1E. The reaction mixture was chromatographically on silica gel with 20-50% ethyl acetate/hexane.1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11,50 (Shir.s, 1H), charged 8.52 (s, 1H), 8,42 (d, 1H), 8,16 (d, 1H), 7,78 (t, 1H), 7,33-EUR 7.57 (m, 8H), 7,22 (m, 3H), of 6.96 (DD, 1H), 6,77 (m, 3H), to 6.39 (d, 1H), 3,49 (s, 2H), 3,18 (m, 4H), 2,43 (m, 4H).

EXAMPLE 10

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-2-phenoxy-N-(phenylsulfonyl)benzamide

The target compound was obtained by replacing EXAMPLE 1D EXAMPLE 9C and 3-nitrobenzenesulfonamide benzosulfimide in EXAMPLE 1E. The reaction mixture of chromatography is ovali on silica gel with 20-50% ethyl acetate/hexane. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11,55 (Shir.s, 1H), 7,82 (m, 3H), 7,42-to 7.64 (m, 7H), 7,34 (m, 5H), 7,25 (d, 1H), 7,10 (DD, 1H), 6.90 to (d, 2H), 6.75 in (d, 1H), 6.35mm (d, 1H), 3,37 (s, 2H), 3,14 (m, 4H), of 2.34 (m, 4H).

EXAMPLE 11

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

The target compound was obtained by replacing EXAMPLE 1D EXAMPLE 5C and 3-nitrobenzenesulfonamide 4-bromobenzaldehyde in EXAMPLE 1E, except that the purification was performed by flash chromatography on silica gel with elution with a gradient of 30% ethyl acetate/hexane to 50% ethyl acetate/hexane.1H NMR (400 MHz, dimethylsulfoxide-d6) δ 7,89 for 7.78 (m, 4H), 7,73 (d, 2H), 7,55-the 7.43 (m, 5H), 7,39 (m, 2H), 7,27-7,24 (m, 1H), 6.90 to (d, 2H), 3,48 (Shir.s, 2H), 3,26 (Shir.s, 4H), 2,45 (Shir.s, 4H).

EXAMPLE 12

4-[4-(1,1'-biphenyl-4-ylmethyl)-3-isopropylpiperazine-1-yl]-N-(phenylsulfonyl)benzamide

EXAMPLE 12A

3-isopropylpiperazine-2-he

2-bromo-3-methylethylamine (2.2 g, 10,52 mmol) in ethanol (15 ml) was added dropwise over 2.5 hours to stir at reflux a solution of ethane-1,2-diamine (13,2 ml, 197 mmol) in ethanol (60 ml). The mixture was heated for a further 2.5 hours and was added sodium ethylate in ethanol (21% weight) (4,0 ml, 10,80 mmol) and the mixture was heated for a further 90 minutes. The reaction mixture was then cooled and concentrated. After trituration with simple ether, the target compound was used in the next stage without d is linesa cleanup.

EXAMPLE 12B

4-((4'-chlorobiphenyl-2-yl)methyl)-3-isopropylpiperazine-2-he

EXAMPLE 12A (590 mg, 4,15 mmol) and 4'-chlorobiphenyl-2-carboxaldehyde (970 mg, 4,48 mmol) was dissolved in CH2Cl2(16 ml) was added triacetoxyborohydride sodium (1050 mg of 4.95 mmol). The reaction mixture was stirred at ambient temperature for two days under a drying tube. The reaction mixture was divided between saturated aqueous NaHCO3and ethyl acetate. The organic layer was washed with saline, dried over Na2SO4and purified flash chromatography using 7/3 hexane/ethyl acetate.

EXAMPLE 12C

1-(biphenyl-2-ylmethyl)-2-isopropylpiperazine

a 1.0 M solution of lithium-aluminiumhydride in tetrahydrofuran (4.8 ml, 4.8 mmol) was cooled to 0 ° C, then was added dropwise a solution of EXAMPLE 12B (0.45 g, 1,31 mmol) in tetrahydrofuran (9 ml). The reaction mixture was stirred at ambient temperature overnight. The next day was added an additional amount of solution lithium-aluminiumhydride (4.8 ml, 4.8 mmol) and the reaction mixture was stirred at ambient temperature for another two days. The reaction mixture then was cooled to 0 ° C and carefully added water (0.75 ml), then4h. NaOH (0.75 ml) and additional water (2.2 ml). Added Na2SO4and a simple ether (25 ml) and after stirring in the course is the development of 45 minutes, the mixture was filtered through Celite® (diatomaceous clay). Concentration of the filtrate gave the target compound.

EXAMPLE 12D

4-(4-(biphenyl-2-ylmethyl)-3-isopropylpiperazine-1-yl) -2-proximitysensor

The target compound was obtained by replacing piperazine-1-tert-butylcarbamoyl EXAMPLE 12C and ethyl-4-perbenzoate EXAMPLE 9A in EXAMPLE 1A.

EXAMPLE 12E

4-(4-(biphenyl-2-ylmethyl)-3-isopropylpiperazine-1-yl)-2-phenoxybenzoic acid

The target compound was obtained, substituting EXAMPLE 5B EXAMPLE 12D in EXAMPLE 5C.

EXAMPLE 12F

4-[4-(1,1'-biphenyl-4-ylmethyl)-3-isopropylpiperazine-1-yl]-N-(phenylsulfonyl)benzamide

The target compound was obtained by replacing EXAMPLE 1D EXAMPLE 12E and 3-nitrobenzenesulfonamide benzosulfimide in EXAMPLE 1E, except that the purification was performed by preparative HPLC using a C18 column, 250×50 mm, 10 μm and elwira with a gradient of 20-100% CH3CN vs. 0.1% TFA in water, getting the product in the form of triptoreline salt.1H NMR (300 MHz, dimethylsulfoxide-d6) δ 12,15 (Shir.s, 1H), 8,90 (Shir.s, 1H), to 7.99 (d, 2H), to 7.75 (m, 4H), of 7.65 (m, 3H), 7,40 (m, 8H), 6.90 to (m, 2H), 4,82 (very wide.s, 1H), 4,50 (very wide.s, 1H), 4,20 (very wide.s, 1H), of 3.77, 3,20, 2,90 (all very wide.since, in General, 6H), 2,10 (very wide.s, 1H), of 0.95 (d, 3H), of 0.80 (d, 3H).

EXAMPLE 13

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

EXAMPLE 13A

4-fluoro-2-(phenylthio)methylbenzoate

5-fluoro-2-(methoxycarbonyl)phenylboronic acid (1,00 g), 2-(Fe is ylthio)isoindoline-1,3-dione (0,86 g) and (2-hydroxy-3,5-diisopropylbenzene)copper (0,29 g) was stirred in dioxane (15 ml) at 50°C for 24 hours. The reaction mixture was chromatographically on silica gel with 5% ethyl acetate/hexane.

EXAMPLE 13B

4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazine-1-yl)-2-(phenylthio)methylbenzoate

The target compound was obtained by replacing the EXAMPLE 7C EXAMPLE 13A in EXAMPLE 7D.

EXAMPLE 13C

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

The target compound was obtained, substituting EXAMPLE 5B EXAMPLE 13B in EXAMPLE 5C.

EXAMPLE 13D

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

The target compound was obtained by replacing EXAMPLE 1D EXAMPLE 13C in EXAMPLE 1E. The reaction mixture was chromatographically on silica gel with 20-50% ethyl acetate/hexane.1H NMR (300 MHz, dimethylsulfoxide-d6) δ 8,63 (d, 1H), 8,42 (d, 1H), 8,32 (d, 1H), to 7.84 (DD, 1H), 7,74 (d, 1H), 7,30-7,56 (m, 10H), 7,25 (m, 2H), 7,17 (m, 1H), of 6.71 (DD, 1H), 6,11 (d, 1H), 3,68 (s, 2H), and 3.31 (m, 4H), of 2.97 (m, 4H).

EXAMPLE 14

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

EXAMPLE 14A

2-(benzylamino)-4-formatives

2-amino-4-formatives (0,90 g), benzaldehyde (0.54 ml), triacetoxyborohydride sodium (1,58 g) and acetic acid (0.3 ml) in CH2Cl2(20 ml) was stirred for 3 hours. The reaction mixture was extinguished with methanol, concentrated and chromatographically on silica gel with 5% ethyl acetate/hexane.

EXAMPLE 14B

2-(benzylamino)-4-(4-(4'-chlorobiphenyl-2-yl)methyl)piperazine-1-yl)methylbenzoate

The target compound was obtained by replacing the EXAMPLE 7C EXAMPLE 14A in EXAMPLE 7D.

EXAMPLE 14C

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

The target compound was obtained, substituting EXAMPLE 5B EXAMPLE 14B in EXAMPLE 5C.

EXAMPLE 14D

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

The target compound was obtained by replacing EXAMPLE 1D EXAMPLE 14C in EXAMPLE 1E. The reaction mixture was chromatographically on silica gel with 20-50% ethyl acetate/hexane.1H NMR (300 MHz, dimethylsulfoxide-d6) δ 9,75 (Shir.s, 1H), to 8.62 (d, 1H), 8,42 (d, 1H), 8,29 (d, 1H), a 7.85 (DD, 1H), 7,66 (d, 1H), 7,42-7,58 (m, 7H), 7,14-7,31 (m, 6H), 6,14 (DD, 1H), 5,88 (s, 1H), 4,32 (d, 2H), 3,60 (s, 2H), and 3.16 (m, 4H), to 2.55 (m, 4H).

EXAMPLE 15

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

EXAMPLE 15A

2-benzyl-4-formatives

5-fluoro-2-(methoxycarbonyl)phenylboronic acid (1,00 g), benzyl bromide (0,50 ml), K2CO3(1.75 g) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)(0.17 g) was stirred in tetrahydrofuran (20 ml) at 60°C for 24 hours. The reaction mixture was chromatographically on silica gel with 2% ethyl acetate/hexane.

EXAMPLE 15B

2-benzyl-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazine-1-yl)methylbenzoate

The target compound was obtained by replacing the EXAMPLE 7C EXAMPLE 15A in EXAMPLE 7D.

EXAMPLE 15C

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

The target compound was obtained, substituting EXAMPLE 5B EXAMPLE 15B in EXAMPLE 5C.

EXAMPLE 15D

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

The target compound was obtained by replacing EXAMPLE 1D EXAMPLE 15C in EXAMPLE 1E. The reaction mixture was chromatographically on silica gel with 20-50% ethyl acetate/hexane.1H NMR (300 MHz, DMSO-d6) δ 11,95 (Shir.s, 1H), 8,56 (d, 1H), of 8.37 (d, 1H), they were 8.22 (d, 1H), 7,79 (DD, 1H), was 7.36-7,56 (m, 8H), 7,25 (d, 1H), 6,98 (m, 3H), 6,92 (m, 2H), 6,72 (s, 1H), 6,69 (d, 1H), 4,15 (s, 2H), 3.46 in (lat.s, 4H), 3.15 in (Shir.s, 4H), 2,44 (Shir.s, 4H).

EXAMPLE 16

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

The target compound was obtained, substituting EXAMPLE 5C and 4-nitrobenzenesulfonamide EXAMPLE 1D and 3-nitrobenzenesulfonamide, respectively, in EXAMPLE 1E.1H NMR (300 MHz, dimethylsulfoxide-d6) δ to 8.41 (d, 2H), to 8.20 (d, 2H), of 7.75 (d, 2H), 7,71 (Shir.s, 1H), 7,52 (m, 4H), 7,40 (d, 2H), 7,33 (m, 1H), 6,92 (d, 2H), 4,18 (Shir.s, 2H), 3,42 (m, 4H), 2,89 (m, 4H).

EXAMPLE 17

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

The target compound was obtained, substituting EXAMPLE 5C and 4-hydroxybenzenesulfonate EXAMPLE 1D and 3-nitrobenzenesulfonamide, respectively, in EXAMPLE 1E.1H NMR (300 MHz, dimethylsulfoxide-d6) δ of 7.95 (d, 2H), of 7.90 (d, 2H), 7,54 (m, 5H), 7,42 (m, 6H),? 7.04 baby mortality(d, 2H), 4,30 (Shir.s, 2H), 3,19 (m, 4H), 2,89 (m, 4H).

EXAMPLE 18

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

EXAMPLE 18A

4-fluoro-2-penicillinbinding

2-bromo-4-formatives (1,00 g), (E)-styrylboronic acid (0,89 g), tetrakis(triphenylphosphine)palladium (0) (0.50 g) and K3PO4(2.28 g) was stirred in dioxane (17 ml) at 90°C for 24 hours. The reaction mixture was chromatographically on silica gel with 1-5% ethyl acetate/hexane. The product in methanol (10 ml) was added to 20 wt.% fresh dry 5% Pd-C and stirred for 4 days with H2in a thick-walled bottle for reactions under pressure. The mixture was filtered through a nylon membrane and concentrated.

EXAMPLE 18B

4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazine-1-yl)-2-penicillinbinding

The target compound was obtained by replacing the EXAMPLE 7C EXAMPLE 18A in EXAMPLE 7D.

EXAMPLE 18C

4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazine-1-yl)-2-phenetylamine acid

The target compound was obtained, substituting EXAMPLE 5B EXAMPLE 18B in EXAMPLE 5C.

EXAMPLE 18D

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

The target compound was obtained by replacing EXAMPLE 1D EXAMPLE 18C in EXAMPLE 1E. The reaction mixture was chromatographically on silica gel with 20-50% ethyl acetate/hexane.1H NMR (300 MHz, DMSO-d6) δ 12,20 (Shir.s, 1H), to 8.70 (d, 1H), 8.3 (l, 1H), 8,24 (d, 1H), 7,82 (DD, 1H), 7,35-7,56 (m, 8H), 7,26 (d, 1H), 7,17 (m, 3H), to 6.95 (m, 2H), 6,69 (m, 2H), 3.46 in (lat.s, 4H), 3.15 in (Shir.s, 4H), 2,85 (t, 2H), 2,62 (t, 2H), 2,44 (Shir.s, 4H).

EXAMPLE 19

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

The target compound was obtained, substituting EXAMPLE 5C and 4-fermentalization EXAMPLE 1D and 3-nitrobenzenesulfonamide, respectively, in EXAMPLE 1E.1H NMR (300 MHz, dimethylsulfoxide-d6) δ 8,03 (m, 2H), to 7.75 (m, 3H), 7,52 (m, 3H), 7,47 (m, 3H), 7,40 (m, 2H), 7,34 (Shir.s, 1H), 6,92 (d, 2H), to 4.38 (Shir.s, 2H), 3,88 (m, 2H), 3,12 (m, 4H), 2,87 (m, 2H).

EXAMPLE 20

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

The target compound was obtained, substituting EXAMPLE 5C and 3-fermentalization EXAMPLE 1D and 3-nitrobenzenesulfonamide, respectively, in EXAMPLE 1E.1H NMR (300 MHz, dimethylsulfoxide-d6) δ of 7.82 (m, 1H), to 7.77-to 7.68 (m, 5H), to 7.59 (m, 1H), 7,52 (m, 4H), 7,40 (m, 2H), 7,34 (m, 1H), 6,93 (d, 2H), 4,23 (Shir.s, 2H), 3,53 (m, 4H), to 2.94 (m, 4H).

EXAMPLE 21

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3-nitrophenyl)sulfonyl]-2-(phenylsulfinyl)benzamid

EXAMPLE 21A

4-fluoro-2-(phenylsulfinyl)methylbenzoate

OXONE® (peroxosulfates potassium) (ceiling of 5.60 g) was added in portions over 1 hour to EXAMPLE 13A (1,00 g) in a mixture of acetic acid (30 ml), water (30 ml) and CH2Cl2(20 ml) and the reaction mixture was stirred for another 1 hour. The reaction mixture was collected ethyl acetate, n is washed with a solution of Na 2S2O3, water and brine, concentrated and chromatographically on silica gel with 5-25% ethyl acetate/hexane.

EXAMPLE 21B

4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazine-1-yl)-2-(phenylsulfinyl)methylbenzoate

The target compound was obtained by replacing the EXAMPLE 7C EXAMPLE 21A in EXAMPLE 7D.

EXAMPLE 21C

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

The target compound was obtained, substituting EXAMPLE 5B EXAMPLE 21B in EXAMPLE 5C.

EXAMPLE 21D

4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3-nitrophenyl)sulfonyl]-2-(phenylsulfinyl)benzamid

The target compound was obtained by replacing EXAMPLE 1D EXAMPLE 21C in EXAMPLE 1E. The reaction mixture was chromatographically on silica gel with 20-50% ethyl acetate/hexane.1H NMR (300 MHz, dimethylsulfoxide-d6) δ 8,53 (d, 1H), 8,28 (d, 1H), 8,14 (d, 1H), 7,875 (d, 1H), 7,69 (DD, 1H), 7.62mm (s, 1H), 7,37-7,51 (m, 7H), 7.23 percent (m, 2H), to 7.15 (m, 3H), 6,95 (d, 2H), 3,42 (s, 2H), 3,26 (m, 4H), 2,48 (m, 4H).

EXAMPLE 22

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

The target compound was obtained by replacing EXAMPLE 9C and 4-nitrobenzenesulfonamide EXAMPLE 1D and 3-nitrobenzenesulfonamide, respectively, in EXAMPLE 1E.1H NMR (300 MHz, dimethylsulfoxide-d6) δ 12,14 (Shir.s, 1H), 8,31 (d, 2H), 8,02 (d, 2H), 7,70 (Shir.s, 1H), 7,51 (m, 5H), 7,38 (d, 2H), 7,32 (d, 1H), 7,26 (t, 2H), 7,02 (t, 1H), 6,78 (m, 3H), 6,46 (s, 1H), or 4.31 (Shir.s, 2H), 3,74 (who, 2H), 3,05 (m, 4H), 2,80 (m, 2H).

EXAMPLE 23

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

The target compound was obtained by replacing EXAMPLE 9C and 3-fermentalization EXAMPLE 1D and 3-nitrobenzenesulfonamide, respectively, in EXAMPLE 1E.1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11,89 (Shir.s, 1H), 7,70 (Shir.s, 1H), 7,65 (m, 1H), to 7.59 (m, 3H), 7,52 (m, 5H), 7,38 (d, 2H), 7,32 (m, 3H), 7,07 (t, 1H), 6,85 (d, 2H), 6,77 (DD, 1H), 6,44 (s, 1H), 4,35 (Shir.s, 2H), of 3.77 (m, 2H), 3,24 (m, 2H), 3,03 (m, 2H), 2,86 (m, 2H).

EXAMPLE 24

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

The target compound was obtained by replacing EXAMPLE 9C and 4-fermentalization EXAMPLE 1D and 3-nitrobenzenesulfonamide, respectively, in EXAMPLE 1E.1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11,80 (Shir.s, 1H), a 7.85 (m, 2H), 7,70 (Shir.s, 1H), 7,51 (m, 5H), 7,39-7,29 (m, 7H), was 7.08 (t, 1H), 6,85 (d, 2H), 6,77 (DD, 1H), 6,44 (s, 1H), 4,34 (Shir.s, 2H), 3,74 (m, 2H), 3,03 (m, 4H), 2,82 (m, 2H).

EXAMPLE 25

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

EXAMPLE 25A

4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazine-1-yl)-2-methoxymethylethoxy

4-bromo-2-methoxymethylethoxy (700 mg), EXAMPLE 7B (983 mg), K3PO4(909 mg), Tris(dibenzylideneacetone)dipalladium (0) (78 mg) and 2-(di-tert-butylphosphino)diphenyl (102 mg) was stirred in 1,2-dimethoxyethane (10 ml) at 80°C for 24 hours. The reactions is nnow mixture was chromatographically on silica gel with 20-50% ethyl acetate/hexane.

EXAMPLE 25B

4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazine-1-yl)-2-methoxybenzoic acid

The target compound was obtained, substituting EXAMPLE 5B EXAMPLE 25A in EXAMPLE 5C.

EXAMPLE 25C

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

The target compound was obtained by replacing EXAMPLE 1D EXAMPLE 25B in EXAMPLE 1E. The reaction mixture was chromatographically on silica gel with 20-50% ethyl acetate/hexane.1H NMR (300 MHz, dimethylsulfoxide-d6) δ of 11.15 (Shir.s, 1H), 8,73 (d, 1H), 8,53 (d, 1H), 8,39 (d, 1H), to $ 7.91 (DD, 2H), 7,34-of 7.55 (m, 7H), 7,27 (m, 1H), 6,50 (m, 2H), 3,88 (s, 3H), 3.43 points (s, 2H), or 3.28 (m, 4H), 2.40 a (m, 4H).

EXAMPLE 26

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

EXAMPLE 26A

4-fluoro-2-(phenylsulfonyl)methylbenzoate

EXAMPLE 13A (0,30 g) and KMnO4(1.80 g) was stirred in acetic acid (40 ml) at 60°C for 24 hours. The reaction mixture was filtered through a layer of silica gel, concentrated and chromatographically on silica gel with 50% ethyl acetate/hexane.

EXAMPLE 26B

4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazine-1-yl)-2-(phenylsulfonyl)methylbenzoate

The target compound was obtained by replacing the EXAMPLE 7C EXAMPLE 26A in EXAMPLE 7D.

EXAMPLE -26 C

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

The target compound was obtained, substituting EXAMPLE 5B EXAMPLE 26B in the USE of THE E 5C.

EXAMPLE 26D

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

The target compound was obtained by replacing EXAMPLE 1D EXAMPLE -26 C in EXAMPLE 1E. The reaction mixture was chromatographically on silica gel with 20-50% ethyl acetate/hexane.1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11,90 (Shir.s, 1H), 8,66 (d, 1H), 8.30 to (d, 1H), 8,24 (d, 1H), 7,73 (DD, 2H), 7,74 (d, 1H), 7,32-7,56 (m, 13H), 7,25 (m, 1H), 7,12 (d, 1H), 3,41 (s, 2H), 3,06 (m, 4H), 2,44 (m, 4H).

EXAMPLE 27

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

The target compound was obtained by replacing EXAMPLE 1D EXAMPLE 9C and 3-nitrobenzenesulfonamide 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1E, except that the purification was performed by flash chromatography on silica gel with 50% ethyl acetate (in hexano).1H NMR (400 MHz, dimethylsulfoxide-d6) δ 8,33 (Shir.s, 1H), of 7.96 (d, 1H), a 7.85 (d, 1H), 7,56 (d, 2H), 7,50-7,39 (m, 6H), 7,28-7,25 (m, 1H), 7,21 (t, 2H), 6,95 (t, 1H), 6.75 in (d, 3H), 6.42 per (d, 1H), 3,30 (Shir.s, 4H), 3,20 (Shir.s, 2H), of 2.51 (Shir.s, 4H).

EXAMPLE 28

4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)piperazine-1-yl]-2-(1H-indol-4-yloxy)-N-[(3-nitrophenyl)sulfonyl]benzamide

EXAMPLE 28A

4'-chloro-3-hydroxybiphenyl-2-carbaldehyde

The target compound was obtained by replacing EXAMPLE 5A 2-bromo-6-hydroxybenzaldehyde in EXAMPLE 5B.

EXAMPLE 28B

4-((4'-chloro-3-hydroxybiphenyl-2-yl)methyl)piperazine-1-Tr is t-butylcarbamoyl

The target compound was obtained by replacing 4'-chlorobiphenyl-2-carboxaldehyde EXAMPLE 28A in EXAMPLE 7A.

EXAMPLE 28C

4-((4'-chloro-3-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazine-1-tert-butylcarbamoyl

EXAMPLE 28B (500 mg, of 1.24 mmol) was dissolved in anhydrous N,N-dimethylformamide (8 ml) was added NaH (60% suspension in mineral oil, 150 mg, 3.72 mmol). The reaction mixture was stirred at ambient temperature for 15 minutes under N2with the subsequent addition of 2-chloro-N,N-dimethylethanamine hydrochloride (360 mg, 2.48 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was extinguished saturated aqueous NH4Cl was extracted with ethyl acetate, and the organic layer was washed with water and brine and dried over Na2SO4. After filtration, the filtrate was concentrated, obtaining an oil residue, which was used in the next stage without further purification.

EXAMPLE 28D

2-(4'-chloro-2-(piperazine-1-ylmethyl)biphenyl-3-yloxy)-N,N-dimethylethanamine

The target compound was obtained by replacing EXAMPLE 7A EXAMPLE 28C in EXAMPLE 7B.

EXAMPLE 28E

2-(1H-indol-4-yloxy)-4-formatives

2,4-deformationof (2 g, 11.6 mmol)), K3PO4(2.4 g, 11.3 mmol) and 4-hydroxyindole (1.40 g, 10.5 mmol) was stirred at 115°C in diglyme (20 ml) for 24 hours. The reactions is nnow the mixture was cooled and poured in a simple ether. The solution was washed three times with 1M NaOH solution, then brine, then dried over Na2SO4and filtered. The filtrate was then concentrated, and the crude product was chromatographically on silica gel with 20% ethyl acetate/hexane.

EXAMPLE 28F

2-(1H-indol-4-yloxy)-4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazine-1-yl)methylbenzoate

A solution of EXAMPLE 28D (100 mg, 0,269 mmol) and EXAMPLE 28E (161 mg, 0,538 mmol) in dimethyl sulfoxide (15 ml) was treated dwuhosnovny potassium phosphate (94 mg, 0,538 mmol) at 135ºC during the night. The reaction mixture was cooled to ambient temperature and was diluted with dichloromethane. The organic layer was washed with water and brine and concentrated. The residue was purified on 0%-10% 7h. ammonia in methanol/dichloromethane.

EXAMPLE 28G

2-(1H-indol-4-yloxy)-4-(4-((4'-chloro-3-(2-(dimethylamino) ethoxy) biphenyl-2-yl)methyl)piperazine-1-yl)benzoic acid

The target compound was obtained, substituting EXAMPLE 5B EXAMPLE 28F in EXAMPLE 5C.

EXAMPLE 28N

4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)piperazine-1-yl]-2-(1H-indol-4-yloxy)-N-[(3-nitrophenyl)sulfonyl]benzamide

The target compound was obtained by replacing EXAMPLE 1D EXAMPLE 28G in EXAMPLE 1E.1H NMR (400 MHz, dimethylsulfoxide-d6) δ 11,08 (Shir.s, 1H), 8,43 (t, 1H), 8,19 (DD, 1H), 7,98 (d, 1H), 7,63 (d, 1H), 7,50-the 7.43 (m, 5H), 7,35 (m, 1H), 7,19 (t, 1H), 7,10-7,01 (m, 2H), 6,86 (m, 2H), 6,62 (DD, 1H), 6,1 (m, 3H), 4,28 (m, 2H), 2,92(m, 4H), was 2.76(s, 6H), 2,46 (m, 2H), 2,30 (m, 6H).

EXAMPLE 29

4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)piperazine-1-yl]-2-(1H-indol-4-yloxy)-N-(phenylsulfonyl)benzamide

This example was obtained by replacing EXAMPLE 28G and benzosulfimide EXAMPLE 1D and 3-nitrobenzenesulfonamide, respectively, in EXAMPLE 1E.1H NMR (400 MHz, DMSO-d6) δ to 11.31 (s, 1H), 7,73 (m, 2H), EUR 7.57 (d, 1H), 7,51 (m, 3H), 7,37-7,44 (m, 4H), 7,28 (m, 2H), 7,16 (d, 1H), 7,05 (d, 1H), 6,97 (m, 1H), at 6.84(d, 1H), to 6.67 (DD, 1H), 6,38 (d, 1H), 6,28 (m, 1H), and 6.25 (d, 1H), 4,15 (m, 2H), 3,29(m, 2H), 2,96(m, 6H), 2,46 (s, 6H), 2,28 (m, 4H).

EXAMPLE 30

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

EXAMPLE 30A

2-(1H-indol-5-yloxy)-4-peratives

2,4-deflorationsouth (1,14 g), K3PO4(1.30 grams) and 5-hydroxyindole (0,90 g) was stirred at 110°C in diglyme (12 ml) for 24 hours. The reaction mixture was cooled and poured in a simple ether. The solution was washed three times with 1M aqueous NaOH solution and brine, and dried over Na2SO4. The solution is then filtered, concentrated, and the crude product was chromatographically on silica gel with 20% ethyl acetate/hexane.

EXAMPLE 30B

4,4-dimethyl-2-(tripterocalyx)cyclohex-1-emailcomponent

To the suspension is washed with hexane NaH (17 g) in dichloromethane (700 ml) was added dropwise at 0°C 5,5-dimethyl-2-methoxycarbonyl yclohexanol (38,5 g). After stirring for 30 minutes, the mixture was cooled to -78°C and added triftormetilfullerenov anhydride (40 ml). The reaction mixture was heated to ambient temperature and was stirred for 24 hours. The organic layer was washed with saline, dried over Na2SO4was filtered and concentrated, obtaining the product.

EXAMPLE 30C

2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-emailcomponent

EXAMPLE 30B (62,15 g), 4-Chlorfenvinphos acid (32,24 g), CsF (64 g) and tetrakis(triphenylphosphine)palladium (0) (2g) in a mixture of 2:1 1,2-dimethoxyethane/methanol (600 ml) was heated to 70°C for 24 hours. The mixture was concentrated. Added a simple ether (4x 200 ml) and the mixture was filtered. The combined ethereal solution was concentrated, receiving the product.

EXAMPLE 30D

(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol

To the mixtureLiBH4(13 g), EXAMPLE 30C (53,8 g) and simple ether (400 ml) slowly by syringe was added methanol (25 ml). The mixture was stirred at ambient temperature for 24 hours. The reaction mixture was suppressed 1H. aqueous solution of HCl with ice cooling. The mixture was diluted with water and was extracted with simple ether (3x 100 ml). The extracts were dried over Na2SO4, filtered and concentrated. The crude product was chromatographically on silica gel, 0-30% ethyl acetate/hexane.

EXAMPLE 30E

2-(4-chlorophenyl)-4,4-dimethyl logex-1-uncarbonized

To a mixture of EXAMPLE 30D (1.25 g) in dichloromethane (20 ml) was slowly added periodinane dessa-Martin (2,78 g). The reaction mixture was stirred at ambient temperature for 3 hours and diluted simple ether. The resulting mixture was washed with an aqueous solution of NaOH and water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified flash chromatography, elwira 0-100% dichloromethane in hexane, obtaining the target compound.

EXAMPLE 30F

4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-tert-butylcarbamoyl

This example was obtained by replacing 4'-chlorobiphenyl-2-carboxaldehyde EXAMPLE 30E in EXAMPLE 7A.

EXAMPLE 30G

1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine

This example was obtained by replacing EXAMPLE 7A EXAMPLE 30F in EXAMPLE 7B.

EXAMPLE N

2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-yl)ethylbenzoic

EXAMPLE 30A (330 mg), EXAMPLE 30G (335 mg) and HK2PO4(191 mg) was stirred in dimethyl sulfoxide (5 ml) at 140°C for 24 hours. The reaction mixture was diluted with ethyl acetate, washed three times with water, washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was chromatographically on silica gel with 30% ethyl acetate/hexane.

EXAMPLE 30I

2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorine is phenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-yl)benzoic acid

This sample was obtained, substituting EXAMPLE 5B EXAMPLE N in EXAMPLE 5C.

EXAMPLE 30J

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

This example was obtained by replacing EXAMPLE 1D EXAMPLE 30I in EXAMPLE 1E.

EXAMPLE 31

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-(phenylsulfonyl)benzamide

This example was obtained by replacing 3-nitrobenzenesulfonamide benzosulfimide and EXAMPLE 1D EXAMPLE 30I in EXAMPLE 1E.1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11,19 (s, 1H), 7,88 (d, 2H), 7,65 (t, 1H), of 7.48 (m, 5H), 7,33 (d, 2H), 7,20 (m, 1H), 7,03 (d, 2H), to 6.88 (DD, 1H), only 6.64 (DD, 1H), 6.42 per (m, 1H), 6,13 (d, 1H), 3,03 (m, 4H), of 2.72 (m, 2H), 2,18 (m, 6H), of 1.94 (m, 2H), 1.39 in (t, 2H), 0,92 (s, 6H).

EXAMPLE 32

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

This example was obtained by replacing 3-cyanobenzenesulfonyl 3-nitrobenzenesulfonamide and EXAMPLE 30I EXAMPLE 1D in EXAMPLE 1E.1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11,14 (s, 1H), 8,28 (Shir.s, 1H), 8,12 (d, 1H), of 8.06 (d, 1H), 7,66 (t, 1H), 7,51 (d, 1H), 7,37 (m, 4H), 7,13 (d, 1H),? 7.04 baby mortality (d, 2H), 6,83 (DD, 1H), only 6.64 (DD, 1H), 6,38 (m, 1H), 6,16 (d, 1H), 3,06 (m, 4H), and 2.83 (m, 2H), and 2.27 (m, 4H), of 2.15 (m, 2H), 1,96 (s, 2H), 1.39 in (t, 2H), 0,92 (s, 6H).

EXAMPLE 33

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-(trifluoromethyl)phenyl]Sul is the IMT}benzamide

This example was obtained by replacing 3-(trifluoromethyl)benzosulfimide 3-nitrobenzenesulfonamide and EXAMPLE 30I EXAMPLE 1D in EXAMPLE 1E.1H NMR (300 MHz, dimethylsulfoxide-d6) δ of 11.15 (s, 1H), 8,20 (Shir.s, 1H), 8,12 (d, 1H), 8,02 (d, 1H), 7,73 (t, 1H), 7,50 (d, 1H), 7,39 (m, 2H), 7,33 (d, 2H), 7,16 (d, 1H), 7,03 (d, 2H), at 6.84 (DD, 1H), 6,63 (DD, 1H), to 6.39 (t, 1H), 6,14 (d, 1H), 3.04 from (m, 4H), and 2.79 (m, 2H), 2,24 (m, 4H), of 2.15 (m, 2H), 1,95 (m, 2H), 1.39 in (t, 2H), 0,92 (s, 6H).

EXAMPLE 34

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

This example was obtained by replacing 3-chlorobenzenesulfonamide 3-nitrobenzenesulfonamide and EXAMPLE 30I EXAMPLE 1D in EXAMPLE 1E.1H NMR (300 MHz, dimethylsulfoxide-d6) δ of 11.15 (s, 1H), of 7.90 (m, 1H), 7,80 (d, 1H), of 7.70 (d, 1H), 7,52 (m, 2H), 7,40 (m, 2H), 7,33 (d, 2H), 7,17 (d, 1H), 7,03 (d, 2H), 6,85 (DD, 1H), 6,63 (DD, 1H), 6,40 (t, 1H), x 6.15 (d, 1H), 3,03 (m, 4H), to 2.74 (m, 2H), 2,19 (m, 6H), of 1.95 (m, 2H), 1,38 (t, 2H), 0,92 (s, 6H).

EXAMPLE 35

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

This example was obtained by replacing 3-fermentalization 3-nitrobenzenesulfonamide and EXAMPLE 30I EXAMPLE 1D in EXAMPLE 1E.1H NMR (300 MHz, dimethylsulfoxide-d6) δ br11.01 (s, 1H), to 8.20 (m, 3H), 7,54 (m, 2H), 7,34 (d, 2H), 7,29 (m, 2H),? 7.04 baby mortality (d, 2H), 6,92 (m, 2H), 6,70 (DD, 1H), 6,56 (DD, 1H), 6.30-in (t, 1H), x 6.15 (d, 1H), 2,97 (m, 4H), to 2.74 (m, 2H), 2,17 (m, 6H), of 1.95 (m, 2H), 1,38 (t, 2H), 0,92 (s, 6H).

EXAMPLE 36

4-(4-{[2-(4-chlorophenyl)-4,4-dimethy cyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-(2-naphthylmethyl)benzamid

This example was obtained by replacing EXAMPLE 30I EXAMPLE 1D and naphthalene-2-sulfonamide 3-nitrobenzenesulfonamide in EXAMPLE 1E.1H NMR (500 MHz, dimethylsulfoxide-d6) δ 11,27 (s, 1H), 11,20 (s, 1H), 8,58 (s, 1H), 8,12 (d, 1H), 8,02 (DD, 2H), 7,87 (DD, 1H), 7,72 (t, 1H), 7,66 (t, 1H), of 7.48 (d, 1H), 7,40 was 7.45 (m, 2H), 7,33 (d, 2H), 7,22 (d, 1H), 7,03 (d, 2H), 6.89 in (DD, 1H), 6,63 (DD, 1H), 6.42 per (s, 1H), 6,14 (d, 1H), to 3.02 (s, 4H), 2,71 (s, 2H), 2,09-of 2.21 (m, 6H), was 1.94 (s, 2H), 1,37 (t, 2H), of 0.91 (s, 6H).

EXAMPLE 37

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-(isoquinoline-5-ylsulphonyl)benzamid

EXAMPLE 37A

isoquinoline-5-sulfonamide

Isoquinoline-5-sulfonyl chloride (528 mg) was dissolved in tetrahydrofuran (8 ml), cooled to 0°C, then concentrated, added NH4OH (0.7 ml) and the reaction mixture was allowed to warm to ambient temperature overnight. The product was filtered, washed with water and dried under vacuum.

EXAMPLE 37B

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-(isoquinoline-5-ylsulphonyl)benzamid

This example was obtained by replacing EXAMPLE 37A 3-nitrobenzenesulfonamide and EXAMPLE 30I EXAMPLE 1D in EXAMPLE 1E.1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11,17 (s, 1H), 9,43 (s, 1H), and 8.50 (d, 1H), 8,42 (d, 1H), 8,39 (s, 2H), 7,82 (t, 1H), 7,40 (m, 3H), 7,34 (d, 2H), 7,15 (s, 1H),? 7.04 baby mortality (d, 2H), 6,78 (DD, 1H), 6,60 (DD, 1H), 6,40 (s, 1H), 6,12 (d, 1H), 3,01 (Shir.s, 4H), 2,80 (very wide.s, 2H), 2,25 (very wide.s, 4H), 2.13 in (width is, 2H), 1,95 (s, 2H), 1,38 (t, 2H), 0,92 (s, 6H).

EXAMPLE 38

N-[(4-chloro-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indazol-4-yloxy)benzamide

EXAMPLE 38A

Tert-butyl ester 4-hydroxy-indazol-1-carboxylic acid tert-butyl ester 4-hydroxy-indazol-2-carboxylic acid

4-hydroxyindole (3.94 g) was added to tetrahydrofuran (250 ml) and cooled to 0°C using an ice bath. Was added sodium hydride (60% dispersion in mineral oil, 1.23 g) and the mixture was stirred at 0°C for five minutes. The solution was allowed to warm to ambient temperature and was stirred for additional 20 minutes. The solution was again cooled to 0°C using an ice bath, was added tert-butyldimethylchlorosilane (4,65 g). The solution was allowed to warm to ambient temperature and was stirred for 16 hours. The volume of solvent was reduced under vacuum, the residue was filtered through a layer of silica gel and washed with ethyl acetate, and the solvent was removed under vacuum. To the residue was added acetonitrile (200 ml), di-tert-butyl dicarbonate (7,06 g) and 4-(dimethylamino)pyridine (0,359 g). The solution was stirred at ambient temperature for three hours, and the solvent was removed under vacuum. To the residue was added tetrahydrofuran (200 ml) and tetrabutylammonium fluoride (1M in tetrahydrofuran, 82 ml). Dissolve is stirred at ambient temperature for four days, the solvent was removed under vacuum, and the residue was taken in ethyl acetate. The solution was extracted with saturated aqueous ammonium chloride, was extracted with brine and dried on anhydrous sodium sulfate. The solution was filtered under vacuum on silica gel, and the solvent was removed under vacuum.

EXAMPLE 38B

Methyl ester of 4-fluoro-2-(1H-indazol-4-yloxy)-benzoic acid

EXAMPLE 38A (5,56 g) was added to diglyme (200 ml), was added tert-butyl potassium (1M in tetrahydrofuran, 30,8 ml). The solution was mixed at ambient temperature for 15 minutes, was added 2,4-deformationof, and the solution was heated at 115°C for 16 hours. The solution was cooled, the solvent was removed under vacuum, the residue was taken in dichloromethane (100 ml), and added triperoxonane acid (22,6 ml). The solution was stirred at ambient temperature for 16 hours, the solvent was removed under vacuum, the residue was taken in ethyl acetate and washed with saturated aqueous sodium bicarbonate, and the organic layer was dried with anhydrous sodium sulfate. The material was purified flash chromatography on silica gel using 30% ethyl acetate (hexane), increasing to 40% ethyl acetate (hexane).

EXAMPLE 38C

Methyl ester of 2-(1H-Indazol-4-yloxy)-4-piperazine-1-yl-benzoic acid

EXAMPLE 38B (2.00 g) and piperazine (2,71 g) was added to dimethylsulfone the CID (60 ml), and the mixture was heated to 100°C for one hour. The solution was cooled, added to dichloromethane, washed with water twice, washed with saturated aqueous sodium bicarbonate, and dried on anhydrous sodium sulfate. The solvent was removed under vacuum.

EXAMPLE 38D

Methyl ester 4-{4-[2-(4-chlorophenyl)-4,4-dimethyl-cyclohex-1-animetal]-piperazine-1-yl}-2-(1H-indazol-4-yloxy)-benzoic acid

This example was obtained by replacing EXAMPLE 30E 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 38C piperazine-1-tert-butylcarbamoyl in EXAMPLE 7A.

EXAMPLE 38E

4-{4-[2-(4-chlorophenyl)-4,4-dimethyl-cyclohex-1-animetal]-piperazine-1-yl}-2-(1H-indazol-4-yloxy)-benzoic acid

This example was obtained by replacing EXAMPLE 38D EXAMPLE 5B in EXAMPLE 5C.

EXAMPLE 38F

N-[(4-chloro-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indazol-4-yloxy)benzamide

This example was obtained by replacing EXAMPLE 38E EXAMPLE 1D and 4-chloro-3-nitrobenzenesulfonamide 3-nitrobenzenesulfonamide in EXAMPLE 1E.1H NMR (300 MHz, dimethylsulfoxide-d6) δ 13,04 (s, 1H), 8,17 (Shir.s, 1H), of 7.75 (s, 1H), 7,73 (d, 1H), 7,66-to 7.61 (m, 2H), 7,38 (d, 2H), 7,11-7,01 (m, 4H), 6,79 (DD, 1H), is 6.54 (d, 1H), 6,10 (DD, 1H), 3,38 was 3.05 (m, 8H), 2,73 (Shir.s, 2H), 2,19 (m, 2H), 2.00 (evens Shire.s, 2H), 1,44 (t, 2H), 0,95 (s, 6H).

EXAMPLE 39

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(2-chloropyridin-3-yl)sulfonyl]benzamide

This connection what was olocale, substituting EXAMPLE 5C and 2-chloropyridin-3-sulfonamide EXAMPLE 1D and 3-nitrobenzenesulfonamide, respectively, in EXAMPLE 1E.1H NMR (300 MHz, DMSO-d6) δ 9,70 (m, 1H), 8,67 (m, 1H), 8,54 (m, 1H), to 7.77 (m, 4H), 7,53 (m, 4H), of 7.36 (m, 3H), 6,93 (m, 2H), 4,36 (m, 2H), 3,93 (m, 2H), 3.27 to (m, 2H), 3,11 (m, 2H), 2,89 (m, 2H).

EXAMPLE 40

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(7-nitro-1H-benzimidazole-5-yl)sulfonyl]benzamide

The target compound was obtained, substituting EXAMPLE 5C and 7-nitro-1H-benzo[d]imidazole-5-sulfonamide EXAMPLE 1D and 3-nitrobenzenesulfonamide, respectively, in EXAMPLE 1E.1H NMR (300 MHz, dimethylsulfoxide-d6) δ to 8.70 (s, 1H), 8,65 (DD, 2H), to 7.75 (m, 3H), 7,54 (m, 4H), 7,37 (m, 3H), 6,92 (d, 2H), 4,70 (s, 2H), 4,32 (Shir.s, 2H), of 3.77 (Shir.s, 2H), 3,27, 3,18, 2,91 (all Shire.since, in General, 6H).

EXAMPLE 41

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)sulfonyl]benzamide

The target compound was obtained, substituting EXAMPLE 5C EXAMPLE 1D and 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-sulfonamide 3-nitrobenzenesulfonamide in EXAMPLE 1E, except that the purification was performed by preparative HPLC using a C18 column, 250×50 mm, 10 µm, and elwira with a gradient of 20-100% CH3CN vs. 0.1% TFA in water, getting the product in the form of triptoreline salt.1H NMR (300 MHz, dimethylsulfoxide-d6) δ 12,08 (very wide.s, 1H), 11,02 (s, 1H), to 7.77 (d, 3H), 7,55 (m, 6H), 7,40 (m, 3H), 7,14 (d, 1H), 6,92 (d, 2H), 4,70 (s, 2H), to 4.38 (Shir.s, 1H), of 3.77 (Shir.s, 1H), of 3.45 (m, 2H), 3,25, 3,10,2,94 (all Shire.with, in General, 6H).

EXAMPLE 42

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(6-chloro-1,1-dioxide-2H-1,2,4-benzothiadiazin-7-yl)sulfonyl]benzamide

This Sample was obtained, substituting EXAMPLE 5C EXAMPLE 1D and chlorthiazide 3-nitrobenzenesulfonamide in EXAMPLE 1E.1H NMR (400 MHz, dimethylsulfoxide-d6) δ at 8.36 (s, 1H), 8,10 (s, 1H), 7,78 (d, 2H), to 7.64 (s, 1H), 7,50 (m, 7H), 7,28 (m, 1H), to 6.88 (d, 2H), 3,32 (m, 10H).

EXAMPLE 43

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-({5-[ethyl(TRIFLUOROACETYL)amino]-1-naphthyl}sulfonyl)benzamide

EXAMPLE 43A

N-ethyl-2,2,2-Cryptor-N-(5-sulfamoylanthranilic-1-yl)ndimethylacetamide

5-(N-ethyl-2,2,2-triptoreline)naphthalene-1-sulfonyl chloride (100 mg) was dissolved in tetrahydrofuran (1.0 ml), cooled to 0°C, then added concentrated ammonia (0,11 ml). The reaction mixture was stirred at 0°C for 3 hours, then concentrated and divided between water and ethyl acetate. The organic layer was dried over Na2SO4was filtered and concentrated, obtaining the target compound.

EXAMPLE 43B

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-({5-[ethyl(TRIFLUOROACETYL)amino]-1-naphthyl}sulfonyl)benzamide

The target compound was obtained, substituting EXAMPLE 5C EXAMPLE 1D and EXAMPLE 43A 3-nitrobenzenesulfonamide in EXAMPLE 1E, except that the purification was performed by preparative HPLC using a C18 column, 250×50 mm, 10 μm, and elwira with a gradient of 20-100% CH3CN PR is against of 0.1% TFA in water, getting the product in the form of triptoreline salt.1H NMR (300 MHz, dimethylsulfoxide-d6) δ 12,50 (very wide.s, 1H), 9,58 (very wide.s, 1H), 8,83 (d, 1H), 8,45 (d, 1H), 8.30 to (d, 1H), a 7.85 (m, 1H) 7,78 (m, 5H), 7,55 (d, 4H), 7,39 (m, 3H), 6.90 to (d, 2H), to 4.38 (Shir.s, 1H), 4,25 (m, 1H), 3,83 (Shir.s, 1H), of 3.45 (m, 2H), 3,30 (m, 1H) 3,25, 3,10, 2,85 (all Shire.since, in General, 6H), of 1.12 (t, 3H).

EXAMPLE 44

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfonyl]benzamide

The target compound was obtained, substituting EXAMPLE 5C and 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-sulfonamide EXAMPLE 1D and 3-nitrobenzenesulfonamide, respectively, in EXAMPLE 1E.1H NMR (300 MHz, dimethylsulfoxide-d6) δ 12,00 (Shir.s, 1H), 7,89 (d, 1H), 7,73 (d, 2H), 7,69 (DD, 1H), 7,55 (d, 2H), 7,47 (m, 4H), 7,37 (m, 2H), 7,24 (m, 1H), 6.90 to (d, 2H), 3,40 (s, 2H), 3,24 (Shir.m, 4H), 2,39 (Shir.m, 4H), 1,66 (Shir.s, 4H), 1,25 (s, 12H).

EXAMPLE 45

4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(2-oxo-2H-chromen-6-yl)sulfonyl]benzamide

The target compound was obtained, substituting EXAMPLE 5C and 2-oxo-2H-chromen-6-sulfonamide EXAMPLE 1D and 3-nitrobenzenesulfonamide, respectively, in EXAMPLE 1E.1H NMR (300 MHz, dimethylsulfoxide-d6) δ 12,08 (very wide.s, 1H), to 8.41 (d, 1H), 8,27 (d, 1H), 8,11 (DD, 1H), to 7.75 (m, 3H), to 7.61 (d, 1H), 7,54 (m, 4H), 7,40 (d, 2H), 7,34 (DD, 1H), 6,93 (d, 2H), only 6.64 (d, 1H), to 4.38 (Shir.s, 2H), 3,88 (Shir.s, 1H), 3,25, 3,10, 2,94 (all Shire.since, in General, 6H).

1. The compound or its therapeutically acceptable salt, and the connection is selected and the following connections:
4-[4-(3,3-diphenylprop-2-enyl)piperazine-1-yl]-N-[(3-nitrophenyl)sulfonyl]benzamide;
N-[(2-bromophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)cyclohex-1-EN-1-yl]methyl}piperazine-1-yl)benzamide;
N-[(3-bromophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)cyclohex-1-EN-1-yl]methyl}piperazine-1-yl)benzamide;
N-[(4-bromophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)cyclohex-1-EN-1-yl]methyl}piperazine-1-yl)benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3-nitrophenyl)sulfonyl]benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-(phenylsulfonyl)benzamide;
2-(benzyloxy)-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3-nitrophenyl)sulfonyl]benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3-nitrophenyl)sulfonyl]-2-(2-phenylethane)benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3-nitrophenyl)sulfonyl]-2-phenoxybenzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-2-phenoxy-N-(phenylsulfonyl)benzamide;
N-[(4-bromophenyl)sulfonyl]-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}benzamide;
4-[4-(1,1'-biphenyl-4-ylmethyl)-3-isopropylpiperazine-1-yl]-N-(phenylsulfonyl)benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3-nitrophenyl)sulfonyl]-2-(phenylthio)benzamide;
2-(benzylamino)-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3-nitrophenyl)sulfonyl]benzamide;
2-benzyl-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]Pipa is Azin-1-yl}-N-[(3-nitrophenyl)sulfonyl]benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-nitrophenyl)sulfonyl]benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-hydroxyphenyl)sulfonyl]benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3-nitrophenyl)sulfonyl]-2-(2-phenylethyl)benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-forfinal)sulfonyl]benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3-forfinal)sulfonyl]benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3-nitrophenyl)sulfonyl]-2-(phenylsulfinyl)benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-nitrophenyl)sulfonyl]-2-phenoxybenzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3-forfinal)sulfonyl]-2-phenoxybenzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-forfinal)sulfonyl]-2-phenoxybenzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-2-methoxy-N-[(3-nitrophenyl)sulfonyl]benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3-nitrophenyl)sulfonyl]-2-(phenylsulfonyl)benzamide;
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazine-1-yl}-N-[(4-chloro-3-nitrophenyl)sulfonyl]-2-phenoxybenzamide;
4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)piperazine-1-yl]-2-(1H-indol-4-yloxy)-N-[(3-nitrophenyl)sulfonyl]benzamide;
4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-yl}methyl)piperazine-1-yl]-2-(1H-indol-4-yloxy)-N-(phenylsulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-(phenylsulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(3-cyanophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(3-chlorophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-N-[(3-forfinal)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-(2-naphthylmethyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-EN-1-yl]methyl}piperazine-1-yl)-2-(1H-indol-5-yloxy)-N-(isoquinoline-5-ylsulphonyl)benzamide;
4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(2-chloropyridin-3-yl)sulfonyl]benzamide;
4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)sulfonyl]benzamide;
4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(6-chloro-1,1-dioxide-2H-1,2,4-benzothiadiazin-7-yl)sulfonyl]benzamide;
4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-({5-[ethyl(TRIFLUOROACETYL)amino]-1-naphthyl}sulfonyl)benzamide;
4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(5,5,8,8-Tetra is Teal-5,6,7,8-tetrahydronaphthalen-2-yl)sulfonyl]benzamide;
4-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazine-1-yl}-N-[(2-oxo-2H-chromen-6-yl)sulfonyl]benzamide.

2. Pharmaceutical composition for treating bladder cancer, brain cancer, breast cancer, cancer of the bone marrow, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, gastric cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of the process of T-cell or b-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, lung cancer, prostate cancer, small-cell lung cancer, cancer of the spleen, moreover, this composition includes excipient and a therapeutically effective amount of the compounds or therapeutically acceptable salts under item 1.

3. A method of treating bladder cancer, brain cancer, breast cancer, cancer of the bone marrow, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, gastric cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of the process of T-cell or b-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, lung cancer, prostate cancer, small-cell lung cancer, cancer of salute the key of the patient, moreover, this method includes the introduction to the patient a therapeutically effective amount of the compounds or therapeutically acceptable salts under item 1.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I

or its pharmaceutically acceptable salts wherein R1-3, R5-7, a, X, Y, Y', Y" and Z have the values specified in cl. 1 of the patent claim which are muscarinic receptor antagonists. The invention also refers to pharmaceutical compounds, methods for preparing and methods for using such compounds.

EFFECT: preparing the compounds applicable as muscarinic receptor antagonists.

25 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to versions of a method of producing a phenylpropionic acid derivative of general formula: or salt thereof, where R2a is a methoxy group or ethoxy group; R3b is a cyclopentyl group and R5 is a methyl group which can be substituted with one or more phenyl groups, or an oxygen-containing heterocyclic group used as an intermediate compound during synthesis of 3-{5-[4-(cyclpentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid (T-5224), having anti-arthritic action and osteoclast inhibitory action. One of the versions of the method involves reaction of a benzophenol derivative of general formula: 3 , where R2a and R3b are as described above, or salts thereof with a 6-(halogenmethyl)-1,2-benzisoxazol-3(2H)-one derivative of general formula: , where R5 is as described above, and X is a halogen atom. The disclosed method can be used as a method for simple and safe synthesis of T-5224 with high output. The invention also relates to methods of producing intermediate compounds and novel intermediate compounds.

EFFECT: high efficiency of the composition.

28 cl, 23 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a new improved method for preparing derivatives of 3,3-diarylpropylamines of the general formula (I) and sterically highly pure stable intermediate substances and their using for preparing pharmaceutical compositions. Method for preparing 3,3-diarylpropylamines of the general formula (I) wherein R means hydrogen atom, linear or branched (C1-C6)-alkyl but preferably methyl or isopropyl; R' and R'' can be similar or different and mean linear or branched (C1-C6)-alkyl but preferably methyl or isopropyl. Method involves condensation of cinnamic acid with compound of the general formula (1) to form compound of the general formula (2a) and the following reaction of the latter with chiral tertiary amine - cinchonidine to yield the corresponding salt of compound of the general formula (2b): and then from this compound the crystalline form of compound of the formula (3): is isolated followed by its either direct reduction with equivalent excess of hydride to yield lactol of the formula (5a) or via intermediate step by formation of corresponding acid chloroanhydride to form ester with alcohols of type R-OH wherein R is given above and the following conversion to compound of the formula (4): and the latter is hydrogenated with diisobutylaluminum-hydride or tri-tert.-butoxyaluminum-hydride to yield lactol of the formula (5) . Prepared lactols of the formula (5a) or (5) after reductive amination with secondary amine form compounds of the formula (I).

EFFECT: improved preparing method.

10 cl, 1 sch, 1 tbl, 13 ex

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

FIELD: chemistry.

SUBSTANCE: method consists in an interaction of α-aminonitrile with amines with heating. As α-aminonitrile, 2-amino-2-cyanoadamantane is used, and as amines - cyclohexylamine, 3-aminopropanol and morpholine. The process is carried out in the presence of potassium carbonate at 80-100°C.

EFFECT: method makes it possible to increase the output of 2-amino-2-cyanoadamantane derivatives.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel method of obtaining 2-amino-2-cyanoadamantane derivatives of the given general formula , which can be applied as semi-products in a synthesis of biologically active amino acids, diamines and heterocyclic compounds. The claimed method consists in a reaction of adamantanone-2 with amines and a cyanogroup carrier in heating in the presence of potassium carbonate. As amines used are cyclohexylamine, 2-aminoethanol, aniline, piperidine, morpholine or piperazine, and as the cyanogroup carrier used is acetone cyanohydrin or 2-amino isobutyronitrile. The process is carried out in one stage for 1.5-2 h at 80-100°C. In the given general formula R=H, , -CH2CH2OH, C6H5, R-R1=-(CH2)5-, -CH2CH2OCH2CH2-, -CH2CH2NHCH2CH2-.

EFFECT: method makes it possible to obtain derivatives of 2-amino-2-cyanoadamantane of the said general formula with the high output.

8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel method of obtaining 2-amino-2-cyanoadamantane derivatives of the given general formula , which can be applied as semi-products in a synthesis of biologically active amino acids, diamines and heterocyclic compounds. The method consists in a reaction of adamantanone-2 with derivatives of amines in the presence of potassium carbonate with heating. As amine derivatives used are aminonitriles from the group 2-N-cyclohexylamino-2-cyanopropane, 2-N-piperidino-2-cyanopropane, 2-N-benzylamino-2-cyanopropane with a molar ratio adamantanone-2:aminonitrile, equal to 1:1.2-1.5, and a temperature of 80-100°C. The process takes place in one stage for 60-70 min.

EFFECT: method makes it possible to obtain derivatives of 2-amino-2-cyanoadamantane of the given general formula with the high output.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) and pharmaceutically acceptable salts thereof, having the capacity to bind amyloid peptides and/or amyloids. In formula (I), EDG is an electron donor group, πCE is a pi-coupling element and WSG is a water-soluble group. EDG is -NR4R5, where R4 and R5 independently denote hydrogen, R12-substituted or unsubstituted C1-C10alkyl, where R4 and R5 are optionally linked to form a R12-substituted or unsubstituted 6-member heterocycloalkyl, where said 6-member heterocycloalkyl optionally contains a heteroatom selected from O or N, R12 is an unsubstituted C1-C10alkyl or unsubstituted 6-member heterocycloalkyl, where said 6-member heterocycloalkyl contains a heteroatom selected from O or N. The pi-coupling element has the formula -L1-(A1)q-L2-(A2)r-L3-, in which q and r are independently equal to 0 or 1 and at least one of q and r is equal to 1, A1 and A2 denote an unsubstituted group , L1, L2 and L3 independently denote a bond or a binding group of formula , where x is an integer from 1 to 50. The water-soluble group is a R25-substituted C1-C5alkyl or group, where R25 is -OR26 or a R29-substituted 5-member heterocycloalkyl containing two O atoms, R26 is hydrogen, R29 is an unsubstituted C1-C10alkyl and y is an integer from 1 to 50.

EFFECT: invention relates to specific compounds of formula (I), pharmaceutical compositions and a method of detecting an amyloid peptide.

14 cl, 11 dwg, 5 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperasin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzolsulfonamide or its pharmaceutically acceptable salt, which includes: (a) interaction of 4,4-dimethylcyclohexanone, alkylformiate, selected from group, including methylformiate, ethylformiate, n-propylformiate, tertbutylformiate and their any combination, and first base, selected from group, including sodium hydrate, sodium tert-butoxide, potassium tert-butoxide and their any combination, with obtaining (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone, with separation or without separation of (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone; (b) interaction of (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone, second base, selected from group, including triethylamine, 2,6-lutidine, pyridine, imidazole, diisopropylethylamine, N-methylmorpholine, dimethylaniline and their any combination, and first reagent silyl ether protecting group, selected from group, including trimethylchlorosilane, tert-butylchlorodimethylsilane, triisopropylchlorosilane, tert-butylchlorodiphenylsilane and their any combination, with obtaining first protected (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone, with separation or without separation of first protected (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone; (c) interaction of first protected (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and 4-chlorophenylmagnesium bromide with obtaining first protected (2E)-1-(4-chlorophenyl)-2-(hydroxymethylene)-4,4-dimethylcyclohexanol; with separation or without separation of first protected (2E)-1-(4-chlorophenyl)-2-(hydroxymethylene)-4,4-dimethylcyclohexanol; (d) interaction of first protected (2E)-1-(4-chlorophenyl)-2-(hydroxymethylene)-4,4-dimethylcyclohexanol and first acid, selected from group, including tetra-n-butylammoniumfluoride, trifluoroacetic acid, hydrochloric acid, sulfuric acid and any their combination, with obtaining 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde, with separation or without separation of 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde; (e) interaction of 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde, ethyl 4-piperazin-1-ylbenzoate and first reducing agent, selected from group, including sodium triacetoxyborohydrode, sodium cyanoborohydride and their combinations, with separation or without separation of ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-yl)methyl)piperazin-1-yl)benzoate; (f) ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-yl)methyl)piperazin-1-yl)benzoate interaction of and aqueous solution of third base, selected from group, including sodium hydroxide, potassium hydroxide and their combinations, with separation or without separation of 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-yl)methyl)piperazin-1-yl)benzoic acid; and (g) interaction of 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-yl)methyl)piperazin-1-yl)benzoic acid, 4-(((1R)-3-morpholin-4yl-1-((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzolsulfonamide and first binding reagent, selected from group, including 1-ethyl-3(3-(dimethylamino)propyl)-carbodiimidhydrochloride, dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1,1'-carbonyldiimidasole and their any combination, with or without fourth base, selected from group, including 1,8-diazabicyclo(5.4.0)undec-7-ene, potassium tret-butoxide and their combinations, and with or without first auxiliary binding reagent, selected from group, including 4-dimethylaminopyridine, hydroxybenzotriazole, 1-hydroxy-7-aza-benzotriazole and any their combination, with separation or without separation of N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperasin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzolsulfonamide.

EFFECT: new method of obtaining N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperasin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzolsulfonamide, which can be applied in medicine as stimulator of apoptosis.

10 cl, 17 ex

FIELD: chemistry.

SUBSTANCE: invention relates to tranquilising compounds, contributing to reduction of anxiety, increase of cognitive and motor activity, namely to 4-(1-hydroxy-1-methyl-2-morpholinoethyl)benzoic acid (1) and 4-(1-hydroxy-2-morpholinocyclohexyl)benzoic acid (2), their pharmaceutically acceptable salts and esters. In addition, object of invention is also presented by method of obtaining and compounds.

EFFECT: compounds, possessing anxiolytic activity, which do not manifest considerable sedative action, hypotension and excitatory action on central nervous system.

2 cl, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (XVIII): which can be used for monitoring and studying the metabolism in clinical and preclinical examinations. The invention also concerns a method for preparing the specified compound.

EFFECT: development of the effective method for preparing the compound.

2 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a tosylate salt of trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)-phenyl]-cyclobutane carboxamide of formula The invention also relates to a pharmaceutical composition, as well as a treatment method.

EFFECT: obtaining a novel biologically active salt of a compound, having activity on histamine receptor type 3.

11 cl, 1 ex, 1 tbl, 3 dwg

FIELD: medicine.

SUBSTANCE: there are described compound of formula, its pharmaceutically acceptable salt or their mixture, enentiomerically pure 4-{(R)-(3-aminophenyl)[4-(4-fluorobenzyl)pyperazin-1-yl]-N,N-diethylbenzamide or its pharmaceutically acceptable salt. Also described are method of anxiety therapy, method of pain therapy and method of depression therapy in animal.

EFFECT: compounds are of use in therapy, in particular for elimination of pain, depression and anxiety.

5 cl, 1 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound presented by formula

,

wherein A1 means benzene or heterocycle specified in a group consisting of pyridine, pyrazine, imidazole, thiazole, pyrimidine, thiophen, pyridazine, benzoxazine and oxobenzoxazine; A2 means benzene, if needed substituted by fluorine, or thiophen; B1 means hydrogen, lower alkyl, if needed substituted by piperazinyl or morpholino, halogen-substituted lower alkyl, lower alkoxy substituted by carbamoyl, acylamino, carbamoyl or lower alkylcarbonyloxy (provided A1 means thiazole, B1 does not mean acylamino); B2 means hydrogen or a functional group containing at least one nitrogen atom specified in a group consisting of acylamino, pyrrolidinyl, morpholino, piperidinyl, if needed substituted by acyl, piperazinyl, if needed substituted by lower alkyl or acyl, pyrazolyl, diazabicyclo[2.2.1]heptyl, if needed substituted by acyl, and di-(lower alkyl)amino, if needed substituted by amino or acylamino (provided A1 means thiazole, B2 does not mean acylamino); Y means a group presented by formula

,

wherein J means ethylene or lower alkynylene; L means a bond; M means a bond; X means -(CH2)m-, -(CH2)m-O- or -(CH2)m-NR2- (wherein m is an integer of 0 to 3, and R2 means hydrogen); D means -NR3-, wherein R3 means hydrogen; and E means amino, or its pharmaceutically acceptable salt. The compounds of formula (I) are used for preparing a pharmaceutical agent or a pharmaceutical composition for treating or preventing the VAP-1 related diseases.

EFFECT: benzene or thiophen derivative as a VAP-1 inhibitor.

13 cl, 25 tbl, 125 ex

FIELD: chemistry.

SUBSTANCE: invention relates organic chemistry and specifically to novel pyridine amide derivatives of general formula I where n equals 1; R1 and R2 together denote a residue selected from a group consisting of -CH=N-NH- and -CH=CH-N=CH-, which is bonded in any desirable direction to the parent structure or R2 and R3 together denote a residue selected from a group consisting of -CH=N-NH-; -CR28=N-NH-; -S-C(=S)-NH-; -S-CR29=N-; -N=CR30-O-; -N=CH-NH-; -N=N-NH-; -O-CH2-O-; -CH2-CH2-CH2-NH, -O-CH2-CH2-O-; -N=CH-CH=N-; -CH=CH-CH=N-, which is bonded in any desirable direction to the parent structure, or R3 and R4 together denote a -CH=N-NH- residue, which is bonded in any desirable direction to the parent structure, or R4 and R5 together denote a -CH=N-NH- residue, which is bonded in any desirable direction to the parent structure, and the rest of the residues R1, R2, R3, R4 and R5, mutually independently, in each case denote H; where R28 denotes F; Cl; Br or I; R29 and R30, mutually independently, in each case denote -NH-C(=O)-R31; -NH2; -NH-S(=O)2-R32; -NH-C(=O)-O-R33; -S-R34; where R31, R32, R33 and R34, mutually independently, in each case denote a straight or branched, saturated, unsubstituted aliphatic C1-10 residue; R6 denotes H or denotes a straight or branched, saturated, unsubstituted aliphatic C1-10 residue; R7 denotes hydrogen or -OH; R denotes -CF3; or denotes an unsubstituted tert-butyl residue; T denotes C-R35 and U denotes C-R36, V denotes N and W denotes C-R38; where R35 and R36 denote H; where R38 denotes -NR40R41; -OR42 or -SR43; where R40, R41, R42 and R43, mutually independently, in each case denote a straight or branched, saturated, unsubstituted aliphatic C1-10 residue; or denote a saturated, unsubstituted 3-, 4-, 5-, 6-, 7-, 8- or 9-member cycloaliphatic residue, or where R40 and R41 in each case together with a nitrogen atom as a ring member which binds them together, form a saturated 6-member heterocycloaliphatic residue, optionally substituted with one R57 residue, where R57 denotes a straight or branched, saturated, unsubstituted aliphatic C1-10 residue; in each case in form of corresponding physiologically acceptable salts. The invention also relates to a method of producing a compound of formula I, a medicinal agent based on the compound of formula I and use of the compound of formula I.

EFFECT: obtaining novel amide derivatives of pyridine, useful in treating vanilloid receptor 1 mediated diseases.

25 cl, 1 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a non-halogen curable composition which contains a benzoxazine monomer (a) of formula

,

where each R is independently an allyl, an unsubstituted or substituted phenyl, unsubstituted or substituted C1-C8-alkyl, or unsubstituted or substituted C3-C8-cycloalkyl; (b) at least one epoxy resin; (c) a catalyst which contains a phenol compound; (d) an additive which increases impact strength of formula

,

where m equals 1 or 2; n equals 2-6; R0 is an n-valent radical of an elastomeric prepolymer after removal of the end isocyanate, amino or hydroxyl group, where the elastomeric prepolymer is soluble or dispersible in epoxy resin; X and Y are independently -O- or -NR3-, where at least one X or Y is -NR3-; R2 is a (m+1)-valent polyphenol or aminophenol radical after removing the phenol hydroxyl group and optionally an amino group; and R3 is a hydrogen atom, C1-C6-alkyl or phenol; and (e) a solvent. The invention also includes production method.

EFFECT: non-halogen curable composition is especially suitable for use in motor car and aerospace engineering since after curing, the composition forms a composite having high glass transition temperature.

12 cl, 2 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I) , where Ar denotes each of R2, R3, R4, R5, R4' and R5' denote hydrogen; A denotes C(O); D denotes oxygen or NR8; E denotes CR63R64CR65R66; R63 and R64 denote hydrogen; R65 and R66 independently denote hydrogen or C1-4alkyl; k equals 0; m equals 1; R6 denotes a group -(X)p-Y-(Z)q-R10, or R6 denotes α- or β-branched C3-6alkyl (optionally substituted with C6cycloalkyl); X and Z independently denotes a C1-4alkylene group; p and q are independently equal to 0 or 1; Y denotes a bond; R8 denotes hydrogen; R10 denotes hydrogen or a saturated 5-7-member ring system; R7 denotes a 6-member aromatic ring, optionally substituted with a halogen, carboxyl, C1-6alkyl, C1-2alkoxy or a 5-member heteroaromatic ring (which is optionally substituted with C1-6alkyl); or a pharmaceutically acceptable salt thereof. Compounds of formula (I) or a pharmaceutically acceptable salt thereof are used to produce a medicinal agent for treating respiratory distress syndrome (ARDS), pulmonary emphysema, bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), asthma or rhinitis.

EFFECT: high efficiency of using said compounds.

7 cl, 1 tbl, 102 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I-a), pharmaceutically acceptable salts, N-oxides, solvates and prodrugs, and a pharmaceutical composition based on said compounds. The compounds have DP receptor antagonist properties and can be used to treat diseases mediated by activity thereof, such as allergic rhinitis, atopic dermatitis, bronchial asthma and food allergy. In general formula (I-a) R1 is a hydrogen atom or a C1-4 alkyl group, each R4, R5 and R6 independently denotes methyl or ethyl, indicates that the substitute protrudes from the plane of the page, m is O, n is an integer from 1 to 2 and i is O, under the condition that when n equals 2, R5 can be identical or different.

EFFECT: improved method.

6 cl, 3 dwg, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing beta-mimetics of formula , where values of n, R1, R2, R3 are given in the claim, which can be used in medicine. The method is realised by reacting a compound of formula 1a with a compound of formula 1b in toluene for 3-9 hours to obtain a compound of formula 1c. The compound of formula 1 is then obtained by splitting the protective group from the compound of formula 1c.

EFFECT: improved method of producing beta-mimetics.

6 cl, 1 dwg

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