DK2185562T3 - Pyrrolopyrimidiner, som er egnede til behandling af proliferative sygdomme - Google Patents

Pyrrolopyrimidiner, som er egnede til behandling af proliferative sygdomme Download PDF

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DK2185562T3
DK2185562T3 DK08775359.6T DK08775359T DK2185562T3 DK 2185562 T3 DK2185562 T3 DK 2185562T3 DK 08775359 T DK08775359 T DK 08775359T DK 2185562 T3 DK2185562 T3 DK 2185562T3
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alkyl
oxa
hexaazacyclooctadec
mol
metheno
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Gaston Stanislas Marcella Diels
Holte Peter Ten
Eddy Jean Edgard Freyne
Thierry Andre Regis Grand-Perret
Emelen Kristof Van
Werner Constant Johan Embrechts
Pascal Ghislain André Bonnet
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

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Claims (13)

1. Forbindelse med formlen:
N- oxidformerne, de farmaceutisk acceptable additionssalte, de kvaternære aminer og de stereokemisk isomere former deraf, hvor Y betegner -Ci-6alkyl-NR3-CO-Ci-6alkyl-; -Ci-galkyl-CO-Het1-Ci_6alkyl-; -Ci_6alkyl-Het2-CO-NR4-Ci_6alkyl- eller -Ci_6alkyl-NR3-CO-Ci-6alkyl-NR4-CO-Ci_6alkyl-; hvor hvert -Ci_6alkyl- i en hvilken som helst af -Ci_6alkyl-NR3-CO-Ci_6alkyl-; -Ci_6alkyl-C0-Het1-Ci_6alkyl-; -Ci-6alkyl-Het2-CO-NR4-Ci-6alkyl- eller -Ci_ 6alkyl-NR3-CO-Ci_6alkyl-NR4-CO-Ci_6alkyl- eventuelt og uafhængigt er substitueret med en substituent valgt blandt hydroxy, phenyl og Het3; X1 betegner en direkte binding, -0-; -NR5- eller -Ci_4alkyl-NR6- , hvor -Ci_4alkyl-delen er direkte bundet til phenylringen; X2 betegner en direkte binding eller -Ci-4alkyl-NR7-, hvor -Ci-4alkyl-delen er direkte bundet til pyrrolopyrimidinringsysternet; Q betegner hydrogen, halogen, Ci_6alkyl, C3_6cycloalkyl, Het5, -NR9R10, Ci-4alkyl-0-, C3_6cycloalkyl-0-, Het6-0-, Ar4-0, Ci-4alkyl-S (0) i-2-, C3-6Cycloalkyl-S (0) 1-2-, Het7-S (0) i_2-, Ar2-S(0)i_2, Ci_ 4alkyl-S- eller C3_6cycloalkyl-S-; R1 og R2 hver uafhængigt betegner hydrogen; halogen; hydroxy; Ci-galkyl; C3-6cycloalkyl; Ci_4alkyl-0-; C3-6cycloalkyl-0-; Het4; cyano; Ci_6alkyl, som er substitueret med en eller, hvor det er muligt, to, tre eller flere substituenter valgt blandt halogen, hydroxy og Ci_4alkyl-0-; Ci_4alkyl-0-, som er substitueret med en eller, hvor det er muligt, to, tre eller flere substituenter valgt blandt halogen, hydroxy, Ci_4alkyl-0-, C1-4alkyl-0-C1-4alkyl-0-, phenyl, C3_6cycloalkyl, C3-6cycloalkyl-0-, C3-6cycloalkyl-NH-CO-, Het8-0-, Het9-CO-, Ar3-
0-, Ar6-S-, HetAr1-S-, thiazolyl-NR11-, pyridinyl-NR12-, pyrazinyl-NH-, Ci-4alkyl-0-Ci-4alkyl-NR13-, Ar7-NH-, HetAr2-NH-; C3-6cycloalkyl-0-, som er substitueret med en eller, hvor det er muligt, to, tre eller flere substituenter valgt blandt halogen, hydroxy og Ci-4alkyl-0-; pyranyl-0-; tetrahydrofuran-0-; Ar8-NH-C0-NH-; Ci_6alkyl-NH-CO-NH-; C3-6cycloalkyl-NH-CO-NH-; C3-6Cycloalkyl-Ci-4alkyl-NH-CO-NR14-; Ci_4alkyl-0-NR15-; Ar5-NH-; R3 og R4 hver uafhængigt betegner hydrogen, Ci-4alkyl, Ci-4alkyl, som er substitueret med Ci-4alkyl-0-, morpholinyl eller piperazinyl; eller C3_6cycloalkyl; R5, R6 og R7 hver uafhængigt betegner hydrogen, Ci_4alkyl, C3-6cycloalkyl eller Ci_4alkyl, som er substitueret med Ci_4alkyl-0-, C3-6cycloalkyl, phenyl eller pyridyl; R8 betegner hydrogen, Ci_6alkyl eller C3_6cycloalkyl; R9, R10, R11, R12 og R13 hver uafhængigt betegner hydrogen, Ci_ 6alkyl, C3_6cycloalkyl; 14 IS R og R hver uafhængrgt betegner hydrogen, Ci_4alkyl, C3-6cycloalkyl eller benzyl; Ar , Ar , Ar , Ar , Ar , Ar og Ar hver uafhængigt betegner phenyl, som eventuelt er substitueret med en eller, hvor det er muligt, to eller flere substituenter valgt blandt halogen, cyano, amino, Ci-4alkyl, Ci-4alkyl-0-, halogen-Ci_4alkyl, polyhalogen-Ci_4alkyl, C3_6cycloalkyl, hydroxy-Ci_4alkyl, Ci-4alkyloxyCi-4alkyl og polyhydroxy-Ci_4alkyl; Het1 og Het2 hver uafhængigt betegner piperidinyl, piperazinyl, pyrrolidinyl eller azetidinyl; Het3, Het4, Het5, Het6, Het7, Het8 og Het9 hver uafhængigt betegner morpholinyl, pyrrolidinyl, piperazinyl eller piperidinyl, hvor nævnte Het , Het , Het , Het , Het , Het og Het9 uafhængigt og eventuelt er substitueret med en eller, hvor det er muligt, to eller flere substituenter valgt blandt halogen, cyano, amino, Ci-4alkyl, halogen-Ci_4alkyl, polyhalogen-Ci-4alkyl, C3_6cycloalkyl, phenyl, hydroxy-Ci-4alkyl, Ci_4alkyloxyCi_4alkyl og polyhydroxy-Ci_4alkyl; HetAr1 og HetAr2 hver uafhængigt betegner et aryl- eller heteroarylringsystem valgt fra gruppen bestående af phenyl, naphthyl, quinolinyl, benzoxazolyl, pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrrolyl, pyrazolyl, indolyl, pyridazinyl, benzimidazolyl, benzothienyl og benzothiazolyl.
2. Forbindelse ifølge krav 1, hvor: Y betegner -Ci-6alkyl-NR3-CO-Ci_6alkyl-; -Ci-ealkyl-CO-Het1-Ci-6alkyl-; -Ci-6alkyl-Het2-CO-NR4-Ci-6alkyl- eller -Ci_6alkyl-NR3-CO-Ci-6alkyl-NR4-CO-Ci_6alkyl-; hvor hvert -Ci-6alkyl- i en hvilken som helst af -Ci-6alkyl-NR3-CO-Ci-6alkyl-; -Ci-6alkyl-C0-Het4-Ci-6alkyl-; -Ci-6alkyl-Het2-CO-NR4-Ci_6alkyl- eller -Ci-6alkyl-NR3-CO-Ci-6alkyl-NR4-CO-Ci-6alkyl- eventuelt og uafhængigt er substitueret med en substituent valgt blandt hydroxy, phenyl og Het3; X1 betegner en direkte binding, -0-; -NR5- eller -Ci_4alkyl-NR6- , hvor -Ci_4alkyl-delen er direkte bundet til phenylringen; X2 betegner en direkte binding eller -Ci_4alkyl-NR7-, hvor -Ci_ 4alkyl-delen er direkte bundet til pyrrolopyrimidinringsysternet; Q betegner hydrogen, halogen, Ci_6alkyl, C3-6cycloalkyl, Het5, -NR9R10, Ci_4alkyl-0-, C3-6cycloalkyl-0-, Het6-0-, Ar4-0, Ci_4alkyl-S(0)i-2-, C3-6cycloalkyl-S (0) 1-2-, Het7-S (0) i_2-, Ar2-S(0)i_2, Ci_ 4alkyl-S- eller C3_6cycloalkyl-S-; R1 og R2 hver uafhængigt betegner hydrogen; halogen; Ci-6alkyl; C3_6cycloalkyl; Ci-4alkyl-0-; C3_6cycloalkyl-0-; Het4; cyano; Ci_ 6alkyl, som er substitueret med en eller, hvor det er muligt, to, tre eller flere substituenter valgt blandt halogen, hydroxy og Ci-4alkyl-0-; Ci-4alkyl-0-, som er substitueret med en eller, hvor det er muligt, to, tre eller flere substituenter valgt blandt halogen, hydroxy, Ci-4alkyl-0-, phenyl og C3_6cycloalkyl; C3_6cycloalkyl-0-, som er substitueret med en eller, hvor det er muligt, to, tre eller flere substituenter valgt blandt halogen, hydroxy og Ci-4alkyl-0-; -NH-CO-NH-Ar1; -NH-CO-NH- Ci_6alkyl og -NH-CO-NH-C3_6cycloalkyl ; R3 og R4 hver uafhængigt betegner hydrogen, Ci^alkyl, Ci^alkyl, som er substitueret med Ci_4alkyl-0-, morpholinyl eller piperazinyl; eller C3_6cycloalkyl; R5, R6 og R7 hver uafhængigt betegner hydrogen, Ci^alkyl, C3_ 6cycloalkyl eller Ci^alkyl, som er substitueret med Ci_4alkyl-0- , C3-6cycloalkyl, phenyl eller pyridyl; R8 betegner hydrogen, Ci_6alkyl eller C3_6cycloalkyl; R9 og R10 hver uafhængigt betegner hydrogen, Ci-6alkyl, C3-6cycloalkyl; Ar1 og Ar2 hver uafhængigt betegner phenyl, som eventuelt er substitueret med en eller, hvor det er muligt, to eller flere substituenter valgt blandt halogen, cyano, amino, Ci-4alkyl, Ci-4alkyl-0-, halogen-Ci_4alkyl, polyhalogen-Ci_4alkyl, C3-6cycloalkyl, hydroxy-Ci-4alkyl, Ci-4alkyloxyCi-4alkyl og polyhydroxy-Ci_4alkyl ; Het1 og Het2 hver uafhængigt betegner piperidinyl, piperazinyl, pyrrolidinyl eller azetidinyl; Het3 betegner morpholinyl, pyrrolidinyl, piperazinyl eller piperidinyl, hvor nævnte Het3 eventuelt er substitueret med en eller, hvor det er muligt, to eller flere substituenter valgt blandt halogen, cyano, amino, Ci_4alkyl, halogen-Ci_4alkyl, polyhalogen-Ci_4alkyl, C3-6cycloalkyl, hydroxy-Ci_4alkyl, Ci_4alkyloxyCi_4alkyl og polyhydroxy-Ci_4alkyl; Het4 betegner morpholinyl, pyrrolidinyl, piperazinyl eller piperidinyl, hvor nævnte Het4 eventuelt er substitueret med en eller, hvor det er muligt, to eller flere substituenter valgt blandt halogen, cyano, amino, Ci-4alkyl, halogen-Ci-4alkyl, polyhalogen-Ci-4alkyl, C3_6cycloalkyl, hydroxy-Ci_4alkyl, Ci-4alkyloxyCi-4alkyl og polyhydroxy-Ci-4alkyl; Het5, Het6 og Het7 hver uafhængigt betegner morpholinyl, pyrrolidinyl, piperazinyl eller piperidinyl, hvor hvert af nævnte Het5, Het6 og Het7 uafhængigt og eventuelt er substitueret med en eller, hvor det er muligt, to eller flere substituenter valgt blandt halogen, cyano, amino, Ci-4alkyl, halogen-Ci_4alkyl, polyhalogen-Ci-4alkyl, C3_6cycloalkyl, hydroxy-Ci-4alkyl, Ci-4alkyloxyCi-4alkyl og polyhydroxy-Ci-4alkyl.
3. Forbindelse ifølge krav 1 eller 2, hvor: Y betegner -Ci-6alkyl-NR3-CO-Ci-6alkyl-; -Ci-galkyl-CO-Het1-Ci_6alkyl-; -Ci_6alkyl-Het2-CO-NR4-Ci_6alkyl- eller -Ci_6alkyl-NR3-CO-Ci-6alkyl-NR4-CO-Ci-6alkyl-; hvor hvert -Ci_6alkyl- i en hvilken som helst af -Ci_6alkyl-NR3-CO-Ci_6alkyl-; -Ci_6alkyl-C0-Het1-Ci_6alkyl-; -Ci-6alkyl-Het2-CO-NR4-Ci-6alkyl- eller -Ci_ 6alkyl-NR3-CO-Ci-6alkyl-NR4-CO-Ci-6alkyl- eventuelt og uafhængigt er substitueret med en substituent valgt blandt hydroxy og phenyl; X1 betegner en direkte binding, -0- eller -Ci-4alkyl-NR6-, hvor -Ci_4alkyl-delen er direkte bundet til phenylringen; X2 betegner en direkte binding eller -Ci_4alkyl-NR7-, hvor -Ci_ 4alkyl-delen er direkte bundet til pyrrolopyrimidinringsysternet; Q betegner hydrogen; R1 og R2 hver uafhængigt betegner hydrogen; halogen; Ci-4alkyl-0-; Het4; Ci_6alkyl, som er substitueret med et eller, hvor det er muligt, to eller tre halogenatomer; Ci_4alkyl-0-, som er substitueret med en eller, hvor det er muligt, to, tre eller flere substituenter valgt blandt phenyl og C3_6cycloalkyl; -NH-CO-NH-Ar1 eller -NH-CO-NH-C3_6cycloalkyl; R3 og R4 hver uafhængigt betegner hydrogen, Ci_4alkyl eller C3_ 6cycloalkyl ; R5, R6 og R7 hver uafhængigt betegner hydrogen, Ci_4alkyl eller Ci-4alkyl, som er substitueret med Ci-4alkyl-0-, C3_6cycloalkyl, phenyl eller pyridyl; R8 betegner hydrogen; Ar1 betegner phenyl, som eventuelt er substitueret med en eller, hvor det er muligt, to eller flere substituenter valgt blandt halogen og Ci-4alkyl-0-; Het1 og Het2 hver uafhængigt betegner piperidinyl eller pyrrolidiny1 ; Het4 betegner morpholinyl, hvor nævnte Het4 eventuelt er substitueret med en eller, hvor det er muligt, to eller flere substituenter valgt blandt halogen, cyano, amino, Ci-4alkyl, halogen-Ci_4alkyl, polyhalogen-Ci-4alkyl, C3_6cycloalkyl, hydroxy-Ci-4alkyl, Ci-4alkyloxyCi-4alkyl og polyhydroxy-Ci-4alkyl.
4. Forbindelse ifølge krav 1 eller 2, hvor: Y betegner -Ci_6alkyl-NR3-CO-Ci_6alkyl; hvor hvert -Ci_6alkyl- i -Ci-6alkyl-NR3-CO-Ci_6alkyl- er eventuelt og uafhængigt substitueret med en substituent valgt blandt hydroxy og phenyl; X1 betegner -0-; X2 betegner -Ci-4alkyl-NR7-, hvor -Ci-4alkyl-delen er direkte bundet til pyrrolopyrimidinringsystemet; Q betegner hydrogen; R1 og R2 hver uafhængigt betegner hydrogen; halogen; Ci-4alkyl-0-; Ci-6alkyl, som er substitueret med et eller, hvor det er muligt, to eller tre halogenatomer; Ci-4alkyl-0-, som er substitueret med phenyl; -NH-CO-NH-Ar1 eller -NH-CO-NH-C3-6cycloalkyl ; R3 betegner hydrogen, Ci-4alkyl eller C3-6cycloalkyl; R7 betegner hydrogen, Ci-4alkyl eller Ci-4alkyl, som er substitueret med C3_6cycloalkyl eller phenyl; R8 betegner hydrogen; Ar1 betegner phenyl, som eventuelt er substitueret med en eller flere Ci-4alkyl-0-.
5. Forbindelse ifølge krav 1 eller 2, hvor: Y betegner -Ci_6alkyl-NR3-CO-Ci_6alkyl-; hvor hvert -Ci_6alkyl- i -Ci_6alkyl-NR3-CO-Ci_6alkyl- er eventuelt og uafhængigt substitueret med en substituent valgt blandt hydroxy og phenyl; X1 betegner -0-; X2 betegner -Ci_4alkyl-NR7-, hvor -Ci_4alkyl-delen er direkte bundet til pyrrolopyrimidinringsystemet; Q betegner hydrogen; R1 og R2 hver uafhængigt betegner hydrogen; halogen eller Ci_ 4alkyl-0-; R3 betegner hydrogen, Ci-4alkyl eller C3_6cycloalkyl; R7 betegner hydrogen, Ci-4alkyl eller Ci-4alkyl, som er substitueret med C3_6cycloalkyl eller phenyl; R8 betegner hydrogen.
6. Forbindelse ifølge krav 1 eller 2, hvor: Y betegner -Ci-6alkyl-NR3-CO-Ci_6alkyl-; hvor hvert -Ci-6alkyl- i -Ci-6alkyl-NR3-CO-Ci-6alkyl- er usubstitueret; X1 betegner -0-; X2 betegner -Ci-4alkyl-NR7-; Q betegner hydrogen; R1 og R2 hver uafhængigt betegner hydrogen; halogen eller Ci_ 4alkyl-0-; R3 betegner Ci-4alkyl; R7 betegner Ci-4alkyl; R8 betegner hydrogen.
7. Forbindelse ifølge krav 1, hvor: R1 og R2 hver uafhængigt betegner hydrogen; halogen; Ci-4alkyl-0-; Het4; Ci_6alkyl, som er substitueret med et eller, hvor det er muligt, to eller tre halogenatomer; Ci-4alkyl-0-, som er substitueret med en eller, hvor det er muligt, to, tre eller flere substituenter valgt blandt phenyl og C3_6cycloalkyl; -NH-CO-NH-Ar1 eller -NH-CO-NH-C3_6cycloalkyl.
8. Forbindelse ifølge krav 1 valgt blandt: 2.3, 15, 16, 17, 18, 19, 2 0-octahydro-10-methoxy-15,19-dimethyl- 7,ll-metheno-llH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 2,15,16,17,18,19-hexahydro-15,18-dimethyl-3H-ll,7-metheno-12-oxa-2,3,5,6,15,18-hexaazacycloheptadec[1,2,3-cd]inden-14(13H)-on, 2.3, 15, 16,17,18,19,2 0-octahydro-10-methoxy-15-methyl-19-(phenylmethyl)-7,ll-metheno-llH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, N-(2,3, 13, 14, 15,16,17,18,19,20-decahydro-15,19-dimethyl-14-oxo-11,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-1O-yl)-N'-(4-methoxyphenyl)-urea, 10-ethoxy-2,3,15,16,17,18,19,20-octahydro-15,19-dimethyl-7,lime t heno- 1 IH- 12 -oxa-2 , 3,5,6,15,19-hexaazacyclooctadec[1,2,3— cd]inden-14(13H)-on, 2,3,15,16,17,18,19,20-octahydro-15,19-dimethyl-10-(phenylmethoxy)-7,ll-metheno-llH-12-oxa-2,3,5, 6, 15, 19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 2.3, 15, 16, 17, 18,19,2 0-octahydro-10-methoxy-19-methyl-15-(1-methylethyl)-7,ll-metheno-llH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 2.3, 15, 16, 17, 18, 19, 2 0-octahydro-10-methoxy-15-methyl-7,lime theno-1IH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3- cd]inden-14(13H) -on, N-cyclopentyl-N(2,3,13,14,15,16,17,18,19, 2 0-decahydro-15, 19-dimethyl-14-oxo-ll,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-10-yl)-urea, N-(3-chlorphenyl)-Ν' -(2,3,13,14,15,16,17,18,19,2O-decahydro- 15.19- dimethyl-14-oxo-ll,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-1O-yl)-urea, 10-chlor-2,3,15,16,17,18,19,20-octahydro-15,19-dimethyl-7,lime theno-1IH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3 — cd]inden-14(13H)-on, N-cyclohexyl-N'-(2,3,13,14,15,16,17,18,19,2 O-decahydro-15,19-dimethyl-14-oxo-ll,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-1O-yl)-urea, 10-(cyclopropylmethoxy)-2,3,15,16,17,18,19,20-octahydro-15,19-dimethyl-7,ll-metheno-llH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 10-(cyclopentyloxy)-2,3,15,16,17,18,19,20-octahydro-15,19-dimethyl-7,ll-metheno-llH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, N-cyclopentyl-2-[(2,3,13,14,15,16,17,18,19,2O-decahydro-15,19-dimethyl-14-oxo-7,ll-metheno-llH-12-oxa-2,3,5, 6, 15, 19-hexaazacyclooctadec[1,2,3-cd]inden-1O-yl)oxy]-acetamid, 10-[2-(cyclopentyloxy)ethoxy]-2,3,15,16,17,18,19,20-octahydro- 15.19- dimethyl-ll,7-metheno-7H-12-oxa-2,3,5, 6, 15, 19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 10-(2-ethoxyethoxy)-2,3,15,16,17,18,19,20-octahydro-15,19-dimethyl-ll, 7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 2,3,15,16,17,18,19,20-octahydro-15,19-dimethyl-10-(1-methylethoxy)-11,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 2,3,15,16,17,18,19, 2 0-octahydro-15, 19-dimethyl-10-propoxy-11,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, N- (4-chlorphenyl)-Ν' -(2,3,13,14,15,16,17,18,19,2O-decahydro-15, 19-dimethyl-14-oxo-ll,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-1O-yl)-urea, 4-[[ (2,3, 13, 14, 15, 16, 17, 18, 19,20-decahydro-15,19-dimethyl-14- oxo-11,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-1O-yl)oxy]acetyl]-morpholin, N-cyclohexyl-2-[ (2,3,13,14,15,16,17,18,19,2 0-decahydro-15,19-dimethyl-14-oxo-7,ll-metheno-llH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-1O-yl)oxy]-acetamid, 2,3,15,16,17,18,19,20-octahydro-10-(2-methoxyethoxy)-15,19-dimethyl-7,ll-metheno-llH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 2,3, 15, 16, 17, 18, 19, 2 0-octahydro-15,19-dimethyl-ll,7-metheno-7H-12-oxa-2,3,5,6, 15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, N-cyclopropyl-2-[(2,3,13,14,15,16,17,18,19,20-decahydro-15,19-dimethyl-14-oxo-ll,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-1O-yl)oxy]-acetamid, N-(cyclopropylmethyl)-Ν'-(2,3,13,14,15,16,17,18,19,20-decahydro-15,19-dimethyl-14-oxo-ll,7-metheno-7H-12-oxa- 2.3.5.6.15.19- hexaazacyclooctadec[1,2,3-cd]inden-1O-yl)-urea, 2,3,15,16,17,18,19,2 0-octahydro-10-[2 - (2- methoxyethoxy)ethoxy]-15,19-dimethyl-ll,7-metheno-7H-12-oxa- 2.3.5.6.15.19- hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 2,3,15,16,17,18,19, 2 0-octahydro-10-(2-methoxyethoxy)-15-methyl-11,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 2-[ (2,3,13,14,15,16,17,18,19,2 0-decahydro-15,19-dimethyl-14-oxo-11,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-1O-yl)oxy]-N-(4-methoxyphenyl)-acetamid, 10-(3-ethoxypropoxy)-2,3,15,16,17,18,19,20-octahydro-15,19-dimethyl-ll, 7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 2-[ (2,5,13,14,15,16, 17, 18,19,2 O-decahydro-15,19-dimethyl-14-oxo-11,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-1O-yl)oxy]-N-(3,4,5-trimethoxyphenyl)-acetamid, 10-(difluormethoxy)-2,3,15,16,17,18,19,2 0-octahydro-15, 19-dimethyl-ll, 7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 10-brom-2,3,15,16,17,18,19,20-octahydro-15,19-dimethyl-ll,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3— cd]inden-14(13H)-on, 2.3.15.16.17.18.19.20- octahydro-15,19-dimethyl-10-[2-(1-methylethoxy)ethoxy]-7,ll-metheno-llH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 2.3.15.16.17.18.19.20- octahydro-10-(3-methoxypropoxy)-15,19-dimethyl-7,ll-metheno-llH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 10-[2-[ethyl(2-methoxyethyl)amino]ethoxy]- 2,3, 15, 16, 17, 18,19,2 0-octahydro-15,19-dimethyl-ll,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14 (13H)-on, 2.3.15.16.17.18.19.20- octahydro-10-[3-(4- methoxyphenoxy)propoxy]-15,19-dimethyl-ll,7-metheno-7H-12-oxa- 2.3.5.6.15.19- hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 10-[2-[(4-chlorphenyl)amino]ethoxy]-2,3,15,16,17,18,19,20-octahydro-15,19-dimethyl-ll,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 2,3,15,16,17,18,19,2 0-octahydro-10-[2- [ (2- methoxyethyl) (phenylmethyl) amino]ethoxy]-15,19-dimethyl-7,lime t heno-1 IH-12-oxa-2, 3,5,6,15,19-hexaazacyclooctadec[1,2,3— cd]inden-14(13H)-on, 2.3.15.16.17.18.19.20- octahydro-10-(2-hydroxyethoxy)-15,19-dimethyl-ll, 7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, N-(4-chlorphenyl)-2-[ (2,3,13,14,15,16,17,18,19,2 0-decahydro- 15.19- dimethyl-14-oxo-ll,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-10-yl)oxy]-acetamid, 10-[2-(4-chlorphenoxy)ethoxy]-2,3,15,16,17,18,19,20-octahydro- 15.19- dimethyl-ll,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 10-(2-ethoxyethoxy)-2,3,15,16,17,18,19,20-octahydro-15-methyl- 7,ll-metheno-llH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 10-[3-[(4-chlorphenyl)amino]propoxy]-2,3,15,16,17,18,19,20-octahydro-15,19-dimethyl-7,ll-metheno-llH-12-oxa- 2.3.5.6.15.19- hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 2.3.15.16.17.18.19.20- octahydro-15,19-dimethyl-10-(1-pyrrolidinyl)-11,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 2.3.15.16.17.18.19.20- octahydro-15,19-dimethyl-10-[2-[(1- methyl-lH-imidazol-2-yl)thio]ethoxy]-7,ll-metheno-llH-12-oxa- 2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on og 10-(2-ethoxyethoxy)-2,3,15,16,17,18,19,20-octahydro-2,15,19-trimethyl-7,ll-metheno-llH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on og N- oxidformerne, de farmaceutisk acceptable additionssalte, de kvaternære aminer og de stereokemisk isomere former af sådanne forbindelser.
9. Forbindelse ifølge krav 1 valgt blandt: 2, 6, 13, 14, 15, 16, 18, 19,20,21,22,23-dodecahydro-10-methoxy-18,22-dimethyl-17H-7,ll-metheno-12-oxa-2,3,5,6,18,22-hexaazacycloheneicos[1,2,3-cd]inden-17-on, 2, 6, 14, 15, 17, 18, 19,20,21,22-decahydro-10-methoxy-17,21-dimethyl-7,ll-metheno-llH-12-oxa-2,3,5,6,17,21-hexaazacycloeicos[1,2,3-cd]inden-16(13H)-on, 10-chlor-2,6,14,15,16,17,19,20,21,22,23,24-dodecahydro-l9,23-dimethyl-7,ll-metheno-llH-12-oxa-2,3,5,6,19,23-hexaazacyclodocos[1,2,3-cd]inden-18(13H)-on, 2, 6, 15, 16, 17, 18, 19, 2 0-octahydro-10-methoxy-15,19-dimethyl- 7.11- metheno-1IH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 2.14, 15, 17, 18, 19,20,21-octahydro-10-methoxy-17,20-dimethyl-6H-11,7-metheno-12-oxa-2,3,5,6,17,2 0-hexaazacyclononadec[1,2,3 — cd]inden-16(13H)-on, 19-ethyl-2,6,15,16,17,18,19,20-octahydro-10-methoxy-15-methyl- 7.11- metheno-llH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 2, 6, 15, 16, 17, 18, 19,2 0-octahydro-15,19-dimethyl-9-(trifluormethyl)-11,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 2.15, 16,17,18, 19-hexahydro-15,18-dimethyl-6H-ll,7-metheno-12-oxa-2,3,5,6,15,18-hexaazacycloheptadec[1,2,3-cd]inden-14(13H)-on, 2,15, 16,17,18,19-hexahydro-10-methoxy-15,18-dimethyl-6H-7,lime theno-12-oxa-2,3,5,6,15,18-hexaazacycloheptadec[1,2,3— cd]inden-14(13H)-on, 10-chlor-2,6,15,16,17,18,19,20-octahydro-15,19-dimethyl-7,lime theno-1IH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3— cd]inden-14(13H)-on, 10-ethoxy-2,6,15,16,17,18,19,20-octahydro-15,19-dimethyl-7,lime theno-1IH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3— cd]inden-14(13H)-on, 2, 6, 15, 16, 17, 18, 19,2 0-octahydro-15,19-dimethyl-10-(phenylmethoxy)-7,ll-metheno-llH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 2, 6, 15, 16, 17, 18, 19, 20-octahydro-10-methoxy-15-methyl-7,lime theno-1IH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 2, 6, 15, 16, 17, 18, 19, 20-octahydro-10-methoxy-15-methyl-19-(phenylmethyl)-7,ll-metheno-llH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 19-(cyclopropylmethyl)-2,6,15,16,17,18, 19, 20-octahydro-10-methoxy-15-methyl-7,ll-metheno-llH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, N- (2,6,13,14,15,16,17,18,19,20-decahydro-15,19-dimethyl-14-oxo-11,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-10-yl)-N'- (4-methoxyphenyl)-urea, 2, 6, 15, 16, 17, 18, 19, 20-octahydro-10-methoxy-19-methyl-15-(1-methylethyl)-7,ll-metheno-llH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, 15-cyclohexyl-2,6,15,16,17,18,19,20-octahydro-10-methoxy-19-methyl-7,ll-metheno-llH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on, N-cyclohexyl-N'-(2,6,13,14,15,16,17,18,19,2 0-decahydro-15,19-dimethyl-14-oxo-ll,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-10-yl)-urea, N-(3-chlorphenyl)-Ν'-(2,6,13,14,15,16,17,18,19,2 O-decahydro-15, 19-dimethyl-14-oxo-ll,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-10-yl)-urea, N-cyclopentyl-N'-(2,6,13,14,15,16,17,18,19,2 0-decahydro-15,19- dimethyl-14-oxo-ll,7-metheno-7H-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-10-yl)-urea og 10-(cyclopropylmethoxy)-2,6,15,16,17,18,19,20-octahydro-15,19-dimethyl-7,ll-metheno-llH-12-oxa-2,3,5,6,15,19-hexaazacyclooctadec[1,2,3-cd]inden-14(13H)-on og W-oxidformerne, de farmaceutisk acceptable additionssalte, de kvaternære aminer og de stereokemisk isomere former af sådanne forbindelser.
10. Farmaceutisk sammensætning, som omfatter en forbindelse ifølge et hvilket som helst af kravene 1-9 og en farmaceutisk acceptabel bærer eller et farmaceutisk acceptabelt fortyndingsmiddel.
11. Forbindelse ifølge et hvilket som helst af kravene 1-9 til anvendelse i medicin.
12. Forbindelse ifølge krav 11 til anvendelse til forebyggelse eller behandling af celleproliferative sygdomme.
13. Forbindelse ifølge krav 12 til anvendelse til forebyggelse eller behandling af cancer.
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