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    Pyrido-and pyrimidopyrimidine derivatives as anti-proliferative agents
    1.
    发明授权
    Pyrido-and pyrimidopyrimidine derivatives as anti-proliferative agents 有权
    吡啶并嘧啶并嘧啶衍生物作为抗增殖剂

    公开(公告)号：US08772272B2

    公开(公告)日：2014-07-08

    申请号：US12724203

    申请日：2010-03-15

    申请人： Eddy Jean Edgard Freyne ,  Marc Willems ,  Pierre Henri Storck ,  Virginie Sophie Poncelet ,  Kristof Van Emelen ,  Peter Jacobus Johnnes Antonius Buijnsters ,  Werner Constant Johan Embrechts ,  Timothy Pietro Suren Perera

    发明人： Eddy Jean Edgard Freyne ,  Marc Willems ,  Pierre Henri Storck ,  Virginie Sophie Poncelet ,  Kristof Van Emelen ,  Peter Jacobus Johnnes Antonius Buijnsters ,  Werner Constant Johan Embrechts ,  Timothy Pietro Suren Perera

    IPC分类号： A61K31/33 ,  A61K31/519 ,  C07D487/00 ,  C07D487/18

    CPC分类号： C07D498/16 ,  C07D471/04 ,  C07D487/04 ,  C07D487/16 ,  C07D487/22

    摘要： The present invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein a1-a2=a3-a4 represents a divalent radical selected from N—CH═CH—CH, N—CH═N—CH or CH—CH═N—CH; Z represents NH; Y represents —C3-9alkyl-, —C1-5alkyl-NR13—C1-5alkyl-, —C1-6alkyl-NH—CO— or —CO—NH—C1-6alkyl-; X1 represents —O— or —NR11—; X2 represents —C1-2alkyl-, —O—C1-2alkyl, —O— or —O—CH2—; R1 represents hydrogen or halo; R2 represents hydrogen, cyano, halo, hydroxycarbonyl-, C1-4alkyloxycarbonyl-, Het16-carbonyl- or Ar5; R3 represents hydrogen; R4 represents hydroxy, C1-4alkyloxy-, Ar4—C1-4alkyloxy or R4 represents C1-4alkyloxy substituted with one or where possible two or more substituents selected from C1-4alkyloxy- or Het2-; R11 represents hydrogen; R12 represents hydrogen, C1-4alkyl- or C1-4alkyl-oxy-carbonyl-; R13 represents Het14-C1-4alkyl, in particular morpholinyl-C1-4alkyl; Het2 represents a heterocycle selected from morpholinyl or piperidinyl optionally substituted with C1-4alkyl-, preferably methyl; Het14 represents morpholinyl; Het16 represents a heterocycle selected from morpholinyl or pyrrolidinyl; Ar4 represents phenyl; Ar5 represents phenyl optionally substituted with cyano.

    摘要翻译： 本发明涉及N-氧化物形式的化合物，其药学上可接受的加成盐和立体化学异构体，其中a1-a2 = a3-a4表示选自N-CH = CH-CH，N- CH = N-CH或CH-CH = N-CH; Z表示NH; Y表示-C3-9烷基 - ，-C1-5烷基-NR13-C1-5烷基 - ，C1-6烷基-NH-CO-或-CO-NH-C1-6烷基 - ; X1表示-O-或-NR11-; X2表示-C1-2烷基 - ， - O-C1-2烷基，-O-或-O-CH2-; R1表示氢或卤素; R 2表示氢，氰基，卤素，羟基羰基 - ，C 1-4烷氧基羰基 - ，Het 16 - 羰基 - 或Ar 5; R3表示氢; R 4表示羟基，C 1-4烷氧基 - ，Ar 4 -C 1-4烷氧基或R 4表示被一个或多个可能的两个或多个选自C 1-4烷氧基或Het 2-的取代基取代的C 1-4烷氧基; R11表示氢; R 12表示氢，C 1-4烷基 - 或C 1-4烷基 - 氧基 - 羰基 - ; R13表示Het14-C1-4烷基，特别是吗啉基-C 1-4烷基; Het2表示选自任选被C 1-4烷基，优选甲基取代的吗啉基或哌啶基的杂环; Het14代表吗啉基; Het16表示选自吗啉基或吡咯烷基的杂环; Ar4表示苯基; Ar 5表示任选被氰基取代的苯基。

    PYRIDO-AND PYRIMIDOPYRIMIDINE DERIVATIVES AS ANTI-PROLIFERATIVE AGENTS
    2.
    发明申请
    PYRIDO-AND PYRIMIDOPYRIMIDINE DERIVATIVES AS ANTI-PROLIFERATIVE AGENTS 有权
    作为抗增生剂的吡咯并吡啶并吡啶衍生物

    公开(公告)号：US20100173913A1

    公开(公告)日：2010-07-08

    申请号：US12724203

    申请日：2010-03-15

    申请人： Eddy Jean Edgard Freyne ,  Marc Willems ,  Pierre Henri Storck ,  Virginie Sophie Poncelet ,  Kristof Van Emelen ,  Peter Jacobus Johannes Antonius Buijnsters ,  Werner Constant Johan Embrechts ,  Timothy Pietro Suren Perera

    发明人： Eddy Jean Edgard Freyne ,  Marc Willems ,  Pierre Henri Storck ,  Virginie Sophie Poncelet ,  Kristof Van Emelen ,  Peter Jacobus Johannes Antonius Buijnsters ,  Werner Constant Johan Embrechts ,  Timothy Pietro Suren Perera

    IPC分类号： A61K31/529 ,  C07D498/18 ,  A61P35/00 ,  C07D487/18

    CPC分类号： C07D498/16 ,  C07D471/04 ,  C07D487/04 ,  C07D487/16 ,  C07D487/22

    摘要： The present invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein a1-a2=a3-a4 represents a divalent radical selected from N—CH═CH—CH, N—CH═N—CH or CH—CH═N—CH; Z represents NH; Y represents —C3-9alkyl-, —C1-5alkyl-NR13—C1-5alkyl-, —C1-6alkyl-NH—CO— or —CO—NH—C1-6alkyl-; X1 represents —O— or —NR11—; X2 represents —C1-2alkyl-, —O—C1-2alkyl, —O— or —O—CH2—; R1 represents hydrogen or halo; R2 represents hydrogen, cyano, halo, hydroxycarbonyl-, C1-4alkyloxycarbonyl-, Het16-carbonyl- or Ar5; R3 represents hydrogen; R4 represents hydroxy, C1-4alkyloxy-, Ar4—C1-4alkyloxy or R4 represents C1-4alkyloxy substituted with one or where possible two or more substituents selected from C1-4alkyloxy- or Het2-; R11 represents hydrogen; R12 represents hydrogen, C1-4alkyl- or C1-4alkyl-oxy-carbonyl-; R13 represents Het14-C1-4alkyl, in particular morpholinyl-C1-4alkyl; Het2 represents a heterocycle selected from morpholinyl or piperidinyl optionally substituted with C1-4alkyl-, preferably methyl; Het14 represents morpholinyl; Het16 represents a heterocycle selected from morpholinyl or pyrrolidinyl; Ar4 represents phenyl; Ar5 represents phenyl optionally substituted with cyano.

    摘要翻译： 本发明涉及N-氧化物形式的化合物，其药学上可接受的加成盐和立体化学异构体，其中a1-a2 = a3-a4表示选自N-CH = CH-CH，N- CH = N-CH或CH-CH = N-CH; Z表示NH; Y表示-C3-9烷基 - ，-C1-5烷基-NR13-C1-5烷基 - ，C1-6烷基-NH-CO-或-CO-NH-C1-6烷基 - ; X1表示-O-或-NR11-; X2表示-C1-2烷基 - ， - O-C1-2烷基，-O-或-O-CH2-; R1表示氢或卤素; R 2表示氢，氰基，卤素，羟基羰基 - ，C 1-4烷氧基羰基 - ，Het 16 - 羰基 - 或Ar 5; R3表示氢; R 4表示羟基，C 1-4烷氧基 - ，Ar 4 -C 1-4烷氧基或R 4表示被一个或多个可能的两个或多个选自C 1-4烷氧基或Het 2-的取代基取代的C 1-4烷氧基; R11表示氢; R 12表示氢，C 1-4烷基 - 或C 1-4烷基 - 氧基 - 羰基 - ; R13表示Het14-C1-4烷基，特别是吗啉基-C 1-4烷基; Het2表示选自任选被C 1-4烷基，优选甲基取代的吗啉基或哌啶基的杂环; Het14代表吗啉基; Het16表示选自吗啉基或吡咯烷基的杂环; Ar4表示苯基; Ar 5表示任选被氰基取代的苯基。

    3-cyano-quinoline derivatives with antiproliferative activity
    3.
    发明授权
    3-cyano-quinoline derivatives with antiproliferative activity 有权
    具有抗增殖活性的3-氰基 - 喹啉衍生物

    公开(公告)号：US07655642B2

    公开(公告)日：2010-02-02

    申请号：US10596509

    申请日：2004-12-15

    申请人： Eddy Jean Edgard Freyne ,  Peter Jacobus Johannes Buijnsters ,  Kristof Van Emelen ,  Werner Constant Johan Embrechts ,  Timothy Pietro Suren Perera

    发明人： Eddy Jean Edgard Freyne ,  Peter Jacobus Johannes Buijnsters ,  Kristof Van Emelen ,  Werner Constant Johan Embrechts ,  Timothy Pietro Suren Perera

    IPC分类号： A01N43/00 ,  A61K31/33 ,  C07D487/00

    CPC分类号： C07D215/54 ,  A61K31/4748 ,  C07D498/06

    摘要： The present invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein Z represents NH; Y represents —C3-9alkyl-, —C1-5alkyl-NR12—C1-5alkyl-, —C1-6alkyl-NH—CO— or —CO—NH—C1-6alkyl-; X1 represents —O—; X2 represents a direct bond, —NR11—C1-2alkyl-, —NR11—CH2—, —C1-2alkyl-, —O—C1-2alkyl, —O— or —O—CH2—; R1 represents hydrogen or halo; R2 represents hydrogen, cyano, halo, hydroxycarbonyl-, C1-4alkyloxycarbonyl-, Het16-carbonyl- or Ar5; R3 represents hydrogen, hydroxy, C1-4alkyloxy-, Ar4—C1-4alkyloxy or R3 represents C1-4alkyloxy substituted with one or where possible two or more substituents selected from C1-4alkyloxy- or Het2-; R10 represents hydrogen; R11 represents hydrogen, C1-4alkyl- or C1-4alkyl-oxy-carbonyl-; R12 represents Het14-C1-4alkyl, in particular morpholinyl-C1-4alkyl; Het2 represents a heterocycle selected from morpholinyl or piperidinyl optionally substituted with C1-4alkyl-, preferably methyl; Het14 represents morpholinyl; Het16 represents a heterocycle selected from morpholinyl or pyrrolidinyl; Ar4 represents phenyl; Ar5 represents phenyl optionally substituted with cyano.

    摘要翻译： 本发明涉及下式的化合物：N-氧化物形式，其药学上可接受的加成盐和立体化学异构形式，其中Z代表NH; Y表示-C3-9烷基，-C1-5烷基-NR12-​​C1-5烷基，-C 1-6烷基-NH-CO-或-CO-NH-C 1-6烷基; X1表示-O-; X 2表示直接键，-NR 11 -C 1-2烷基 - ， - NR 11 -CH 2 - ， - C 1-2烷基 - ， - O-C 1-2烷基，-O-或-O-CH 2 - 。 R1表示氢或卤素; R 2表示氢，氰基，卤素，羟基羰基 - ，C 1-4烷氧基羰基 - ，Het 16 - 羰基 - 或Ar 5; R 3表示氢，羟基，C 1-4烷氧基 - ，Ar 4 -C 1-4烷氧基或R 3表示被一个或多个可能的两个或多个选自C 1-4烷氧基 - 或Het 2 - 的取代基取代的C 1-4烷氧基; R10表示氢; R11表示氢，C1-4烷基或C1-4烷基 - 氧 - 羰基 - ; R12表示Het14-C1-4烷基，特别是吗啉基-C 1-4烷基; Het2表示选自任选被C 1-4烷基，优选甲基取代的吗啉基或哌啶基的杂环; Het14代表吗啉基; Het16表示选自吗啉基或吡咯烷基的杂环; Ar4表示苯基; Ar 5表示任选被氰基取代的苯基。

    3-CYANO-QUINOLINE DERIVATIVES WITH ANTIPROLIFERATIVE ACTIVITY
    5.
    发明申请
    3-CYANO-QUINOLINE DERIVATIVES WITH ANTIPROLIFERATIVE ACTIVITY 有权
    具有抗增殖活性的3-氰基喹啉衍生物

    公开(公告)号：US20100069424A1

    公开(公告)日：2010-03-18

    申请号：US12624708

    申请日：2009-11-24

    申请人： Eddy Jean Edgard FREYNE ,  Peter Jacobus Johannes Antonius Buijnsters ,  Kristof Van Emelen ,  Werner Constant Johan Embrechts ,  Timothy Pietro Suren Perera

    发明人： Eddy Jean Edgard FREYNE ,  Peter Jacobus Johannes Antonius Buijnsters ,  Kristof Van Emelen ,  Werner Constant Johan Embrechts ,  Timothy Pietro Suren Perera

    IPC分类号： C07D498/08 ,  A61K31/439

    CPC分类号： C07D215/54 ,  A61K31/4748 ,  C07D498/06

    摘要： The present invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein Z represents NH; Y represents —C3-9alkyl-, —C1-5alkyl-NR12—C1-5alkyl-, —C1-6alkyl-NH—CO— or —CO—NH—C1-6alkyl-; X1 represents —O—; X2 represents a direct bond, —NR11—C1-2alkyl-, —NR11—CH2—, —C1-2alkyl-, —O—C1-2alkyl, —O— or —O—CH2—; R1 represents hydrogen or halo; R2 represents hydrogen, cyano, halo, hydroxycarbonyl-, C1-4alkyloxycarbonyl-, Het16-carbonyl- or Ar5; R3 represents hydrogen, hydroxy, C1-4alkyloxy-, Ar4—C1-4alkyloxy or R3 represents C1-4alkyloxy substituted with one or where possible two or more substituents selected from C1-4alkyloxy- or Het2-; R10 represents hydrogen; R11 represents hydrogen, C1-4alkyl- or C1-4alkyl-oxy-carbonyl-; R12 represents Het14-C1-4alkyl, in particular morpholinyl-C1-4alkyl; Het2 represents a heterocycle selected from morpholinyl or piperidinyl optionally substituted with C1-4alkyl-, preferably methyl; Het14 represents morpholinyl; Het16 represents a heterocycle selected from morpholinyl or pyrrolidinyl; Ar4 represents phenyl; Ar5 represents phenyl optionally substituted with cyano.

    摘要翻译： 本发明涉及下式的化合物：N-氧化物形式，其药学上可接受的加成盐和立体化学异构形式，其中Z代表NH; Y表示-C3-9烷基，-C1-5烷基-NR12-​​C1-5烷基，-C 1-6烷基-NH-CO-或-CO-NH-C 1-6烷基; X1表示-O-; X 2表示直接键，-NR 11 -C 1-2烷基 - ， - NR 11 -CH 2 - ， - C 1-2烷基 - ， - O-C 1-2烷基，-O-或-O-CH 2 - 。 R1表示氢或卤素; R 2表示氢，氰基，卤素，羟基羰基 - ，C 1-4烷氧基羰基 - ，Het 16 - 羰基 - 或Ar 5; R 3表示氢，羟基，C 1-4烷氧基 - ，Ar 4 -C 1-4烷氧基或R 3表示被一个或多个可能的两个或多个选自C 1-4烷氧基 - 或Het 2 - 的取代基取代的C 1-4烷氧基; R10表示氢; R11表示氢，C1-4烷基或C1-4烷基 - 氧 - 羰基 - ; R12表示Het14-C1-4烷基，特别是吗啉基-C 1-4烷基; Het2表示选自任选被C 1-4烷基，优选甲基取代的吗啉基或哌啶基的杂环; Het14代表吗啉基; Het16表示选自吗啉基或吡咯烷基的杂环; Ar4表示苯基; Ar 5表示任选被氰基取代的苯基。

    2,4 (4,6) PYRIMIDINE DERIVATIVES
    7.
    发明申请
    2,4 (4,6) PYRIMIDINE DERIVATIVES 有权

    公开(公告)号：US20100160310A1

    公开(公告)日：2010-06-24

    申请号：US11720681

    申请日：2005-12-08

    申请人： Eddy Jean Edgard Freyne ,  Marc Willems ,  Werner Constant Johan Embrechts ,  Kristof Van Emelen ,  Sven Franciscus Anna Van Brandt ,  Frederik Jan Rita Rombouts

    发明人： Eddy Jean Edgard Freyne ,  Marc Willems ,  Werner Constant Johan Embrechts ,  Kristof Van Emelen ,  Sven Franciscus Anna Van Brandt ,  Frederik Jan Rita Rombouts

    IPC分类号： A61K31/5377 ,  C07D471/22 ,  C07D498/22 ,  C07D413/14 ,  A61K31/4985 ,  A61K31/519 ,  A61K31/33 ,  A61P3/10

    CPC分类号： C07D487/18 ,  C07D487/08 ,  C07D487/22 ,  C07D498/08 ,  C07D498/18

    摘要： The present invention concerns the compounds of formula (I), the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein Z1 and Z2 represent NH; Y represents —C3-9alkyl-, —C3-9alkenyl-, —C1-5alkyl-NR6—C1-5alkyl-, —C1-5alkyl-NR7—CO—C1-5alkyl-, —C1-6alkyl-CO—NH—, —C1-6alkyl-NH—CO—, —C1-2alkyl-CO-Het10-CO—, —C1-3alkyl-NH—CO-Het3-, -Het4-C1-3alkyl-CO—NH—C1-3alkyl-, —C1-2alkyl-NH—CO-L1-NH—, —NH—CO-L2-NH—, —C1-2alkyl-CO—NH-L3-CO—, —C1-2alkyl-NH—CO-L1-NH—CO—C1-3alkyl-, —C1-2alkyl-CO—NH-L3-CO—NH—C1-3alkyl-, —C1-2alkyl-NR11—CH2—CO—NH—C1-3alkyl-, Het5-CO—C1-2alkyl-, (C1-5alkyl-CO—NH—C1-3alkyl-CO—NH, —C1-5alkyl-NR13—CO—C1-3alkyl-NH—, —C1-3alkyl-NH—CO-Het27-CO—, or —C1-3alkyl-CO-Het28-CO—NH—; X1 represents a direct bond, O, —O—C1-2alkyl-, —CO—C1-2alkyl-, —NR16—C1-2alkyl-, —CO—NR17—, Het23-C1-2alkyl- or C1-2alkyl; X2 represents a direct bond, O, —O—C1-2alkyl-, —CO—C1-2alkyl-, —NR18—C1-2alkyl-, —CO—NR19—, Het24—C1-2alkyl- or C1-2alkyl; R1 and R5 each independently represent hydrogen, halo, C1-6alkyloxy- or C1-6alkyloxy- substituted with Het1 or C1-4alkyloxy-; R2 and R4 each independently represent hydrogen or halo; R3 represents hydrogen or cyano; R6, R7, R13, R17 and R19 represent hydrogen; R11 represents hydrogen or C1-4alkyl; R16 and R18 represent hydrogen, C1-4alkyl or Het17-C1-4alkyl-; L1, L2 and L3 each independently represents C1-8alkyl optionally substituted with one or where possible two or more substituents selected from phenyl, methylsulfide, cyano, polyhaloC1-4alkyl-phenyl-, C1-4alkyloxy, pyridinyl, mono- or di(C1-4alkyl)-amino- or C3-6cycloalkyl; Het1, Het2, Het17 each independently represent morpholinyl, oxazolyl, isoxazolyl, or piperazinyl; Het3, Het4, Het5 each independently represent morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl; Het10 represents piperazinyl, piperidinyl, pyrrolidinyl or azetidinyl; Het22 represents morpholinyl, oxazolyl, isoxazolyl or piperazinyl wherein said Het22 is optionally substituted with C1-4alkyl; Het23 and Het24 each independently represent a heterocycle selected from pyrrolidinyl, piperazinyl or piperidinyl wherein said Het23 or Het24 are optionally substituted with Het22-carbonyl; Het27 and Het28 each independently represent a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl.

    2,4 (4,6) PYRIMIDINE DERIVATIVES
    9.
    发明申请
    2,4 (4,6) PYRIMIDINE DERIVATIVES 有权

    公开(公告)号：US20120065395A1

    公开(公告)日：2012-03-15

    申请号：US13277651

    申请日：2011-10-20

    申请人： Eddy Jean Edgard Freyne ,  Marc Willems ,  Werner Constant Johan Embrechts ,  Kristof Van Emelen ,  Sven Franciscus Anna Van Brandt ,  Frederik Jan Rita Rombouts

    发明人： Eddy Jean Edgard Freyne ,  Marc Willems ,  Werner Constant Johan Embrechts ,  Kristof Van Emelen ,  Sven Franciscus Anna Van Brandt ,  Frederik Jan Rita Rombouts

    IPC分类号： C07D239/48 ,  C07D405/12 ,  C07D403/12

    CPC分类号： C07D487/18 ,  C07D487/08 ,  C07D487/22 ,  C07D498/08 ,  C07D498/18

    摘要： The present invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein Z1 and Z2 represent NH; Y represents —C3-9alkyl-, —C3-9 alkenyl-, —C1-5alkyl-NR6—C1-5alkyl-, —C1-5alkyl-NR7—CO—C1-5alkyl-, —C1-6alkyl-CO—NH—, —C1-6alkyl-NH—CO—, —C1-2alkyl-CO-Het10-CO—, —C1-3alkyl-NH—CO-Het3-, -Het4-C1-3alkyl-CO—NH—C1-3alkyl-, —C1-2alkyl-NH—CO-L1-NH—, —NH—CO-L2-NH—, —C1-2alkyl-CO—NH-L3-CO—, —C1-2alkyl-NH—CO-L1-NH—CO—C1-3 alkyl-, —C1-2alkyl-CO—NH-L3-CO—NH—C1-3alkyl-, —C1-2alkyl-NR11—CH2—CO—NH—C1-3alkyl-, Het5-CO—C1-2alkyl-, —C1-5alkyl-CO—NH—C1-3alkyl-CO—NH—, —C1-5alkyl-NR13—CO—C1-3alkyl-NH—, —C1-3alkyl-NH—CO-Het27-CO—, or —C1-3alkyl-CO-Het28-CO—NH—; X1 represents a direct bond, O, —O—C1-2alkyl-, —CO—C1-2alkyl-, —NR16—C1-2alkyl-, —CO—NR17—, Het23-C1-2alkyl- or C1-2alkyl; X2 represents a direct bond, O, —O—C1-2alkyl-, —CO—C1-2alkyl-, —NR18—C1-2alkyl-, —CO—NR19—, Het24-C1-2alkyl- or C1-2alkyl; R1 and R5 each independently represent hydrogen, halo, C1-6alkyloxy- or C1-6alkyloxy- substituted with Het1 or C1-4alkyloxy-; R2 and R4 each independently represent hydrogen or halo; R3 represents hydrogen or cyano; R6, R7, R13, R17 and R19 represent hydrogen; R11 represents hydrogen or C1-4alkyl; R16 and R18 represent hydrogen, C1-4alkyl or Het17-C1-4alkyl-; L1, L2 and L3 each independently represents C1-8alkyl optionally substituted with one or where possible two or more substituents selected from phenyl, methylsulfide, cyano, polyhaloC1-4alkyl-phenyl-, C1-4alkyloxy, pyridinyl, mono- or di(C1-4alkyl)-amino- or C3-6cycloalkyl; Het1, Het2, Het17 each independently represent morpholinyl, oxazolyl, isoxazolyl, or piperazinyl; Het3, Het4, Het5 each independently represent morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl; Het10 represents piperazinyl, piperidinyl, pyrrolidinyl or azetidinyl; Het22 represents morpholinyl, oxazolyl, isoxazolyl or piperazinyl wherein said Het22 is optionally substituted with C1-4alkyl; Het23 and Het24 each independently represent a heterocycle selected from pyrrolidinyl, piperazinyl or piperidinyl wherein said Het23 or Het24 are optionally substituted with Het22-carbonyl; Het27 and Het28 each independently represent a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl.