DK2571879T3 - Heterobiaryl-cyclohexyl-tetraazabenzo[e]azulener - Google Patents

Heterobiaryl-cyclohexyl-tetraazabenzo[e]azulener Download PDF

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DK2571879T3
DK2571879T3 DK11715545.7T DK11715545T DK2571879T3 DK 2571879 T3 DK2571879 T3 DK 2571879T3 DK 11715545 T DK11715545 T DK 11715545T DK 2571879 T3 DK2571879 T3 DK 2571879T3
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benzo
chloro
tetraaza
cyclohexyl
dihydro
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Cosimo Dolente
Patrick Schnider
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Hoffmann La Roche
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Claims (13)

1. Forbindelse med formlen I
hvor R1 er valgt fra gruppen bestående af i) H, ii) -Ci-e-alkyl, usubstitueret eller substitueret med 1 til 5 substituenter individuelt valgt fra gruppen bestående af OH, halogen, cyano og Ci-6-alkoxy, iii) -S(0)2-Ci-6-alkyl, hvor Ci-6-alkyl er usubstitueret eller substitueret med 1 til 5 substituenter individuelt valgt fra gruppen bestående af OH, halogen, cyano og Ci-6-alkoxy, iv) -C(0)-Ci-6-alkyl, hvor Ci-6-alkyl er usubstitueret eller substitueret med 1 til 5 substituenter individuelt valgt fra gruppen bestående af OH, halogen, cyano og Ci-6-alkoxy, v) -C(0)0-Ci-6-alkyl, hvor Ci-e-alkyl er usubstitueret eller substitueret med 1 til 5 substituenter individuelt valgt fra gruppen bestående af OH, halogen, cyano og Ci-6-alkoxy; vi) cycloalkyl, usubstitueret eller substitueret med 1 til 5 substituenter individuelt valgt fra gruppen bestående af OH, halogen, cyano, Ci-6-alkyl og Ci-6-alkoxy, vii) -StOMCHzVNRR11, hvor q er 0 eller 1, R1 og RM er hver individuelt valgt fra gruppen bestående af H og Ci-e-alkyl, eller R' og R" danner sammen med det nitrogenatom til hvilket de er bundet en 3- til 7-leddet heterocyclyl omfattende ét eller to heteroatomer individuelt valgt fra N, O og S, og hvilken heterocyclyl er usubstitueret eller substitueret med 1 til 5 substituenter individuelt valgt fra gruppen bestående af oxo, halogen, Ci-6-alkyl og Ci-6-alkoxy, viii) -(CH2)r-NRmRiv, hvor r er 1, 2 eller 3, RiM og Riv er hver individuelt valgt fra gruppen bestående af H og Ci-e-alkyl, eller Rm og Riv danner sammen med det nitrogenatom til hvilket de er bundet en 3- til 7-leddet heterocyclyl omfattende ét eller to heteroatomer individuelt valgt fra N, O og S, og hvilken heterocyclyl er usubstitueret eller substitueret med 1 til 5 substituenter individuelt valgt fra gruppen bestående af oxo, halogen, Ci-6-alkyl og Ci-6-alkoxy, og ix) -C(0)(CH2)s-NRvRvi, hvor s er 1, 2 eller 3, Rv og Rvi er hver individuelt valgt fra gruppen bestående af H og Ci-6-alkyl, eller Rv og Rvi danner sammen med det nitrogenatom til hvilket de er bundet en 3- til 7-leddet heterocyclyl omfattende ét eller to heteroatomer individuelt valgt fra N, O og S, og hvilken heterocyclyl er usubstitueret eller substitueret med 1 til 5 substituenter individuelt valgt fra gruppen bestående af oxo, halogen, Ci-6-alkyl og Ci-e-alkoxy; R2 er halogen; R3 er heterobiaryl, usubstitueret eller substitueret med 1-5 substituenter individuelt valgt fra gruppen bestående af OH, halogen, cyano, Ci-6-alkyl, Ci-e-alkoxy, halogen-Ci-6-alkyl, halogen-Ci-e-alkoxy og hydroxy-Ci-6-alkyl; eller et farmaceutisk acceptabelt salt deraf.
2. Forbindelse ifølge krav 1, hvor R1 er valgt fra gruppen bestående af i) H, ii) -Ci-e-alkyl, iii) -S(0)2-Ci-e-alkyl, iv) -C(0)0-Ci-e-alkyl, v) cycloalkyl, vi) -(CH2)r-NRiNRiv, hvor r er 1, 2 eller 3, RiN og Riv er hver individuelt valgt fra gruppen bestående af H og Ci-6-alkyl, og vii) -C(0)(CH2)s-NRvRvi, hvor s er 1, 2 eller 3, Rv og Rvi er hver individuelt valgt fra gruppen bestående af H og Ci-e-alkyl,
3. Forbindelse ifølge et hvilket som helst af kravene 1-2, hvor R1 er valgt fra gruppen bestående af -Ci-6-alkyl, cycloalkyl, -(CH2)2-N(Ci-6-alkyl)2 og -C(0)(CH2)-N(Ci-6-alkyl)2.
4. Forbindelse ifølge et hvilket som helst af kravene 1-3, hvor R1 er valgt fra gruppen bestående af methyl, cyclobutyl, methyl-2-ethylamin og l-oxo-2-(dimethylamino)-ethyl.
5. Forbindelse ifølge et hvilket som helst af kravene 1-4, hvor R2 er chlor.
6. Forbindelse ifølge et hvilket som helst af kravene 1-5, hvor R3 er heterobiaryl, usubstitueret eller substitueret med 1-2 halogen.
7. Forbindelse ifølge et hvilket som helst af kravene 1-6, hvor R3 er benzo[c/]isoxazolyl, isoxazolo[4,5-b]pyridinyl, isoxazolo[5,4-b]pyridinyl, benzo[c/]isothiazolyl, isothiazolo[4,5-b]pyridinyl eller 4-isothiazolo[5,4-c]pyridinyl, hver usubstitueret eller substitueret med 1-2 halogen.
8. Forbindelse ifølge et hvilket som helst af kravene 1-7, valgt fra gruppen bestående af c/s-l-(4-benzo[c/]isoxazol-3-yl-cyclohexyl)-8-chlor-4F/,6F/-2,3,5,10b- tetraaza-benzo[e]azulen-5-carboxylsyre-tert-butylester, trans- l-(4-benzo[c/]isoxazol-3-yl-cyclohexyl)-8-chlor-4F/, 6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-carboxylsyre-tert-butylester, c/s-l-(4-benzo[c/]isoxazol-3-yl-cyclohexyl)-8-chlor-5,6-dihydro-4/-/-2,3,5,10b-tetraaza-benzo[e]azulen, c/'s-l-(4-benzo[c/]isoxazol-3-yl-cyclohexyl)-8-chlor-5-methyl-5,6-dihydro- 4H-2,3,5,10b-tetraaza-benzo[e]azulen, trans- l-(4-benzo[c/]isoxazol-3-yl-cyclohexyl)-8-chlor-5,6-dihydro-4AY-2,3,5,10b-tetraaza-benzo[e]azulen, trans- l-(4-benzo[c/]isoxazol-3-yl-cyclohexyl)-8-chlor-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, frans-8-chlor-l-[4-(6-fluor-benzo[c/]isoxazol-3-yl)-cyclohexyl]-4tf,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-carboxylsyre-tert-butylester, irans-8-chlor-l-[4-(6-fluor-benzo[c/]isoxazol-3-yl)-cyclohexyl]-5,6-dihydro- 4H-2,3,5,10b-tetraaza-benzo[e]azulen, frans-8-chlor-l-[4-(6-fluor-benzo[c/]isoxazol-3-yl)-cyclohexyl]-5-methyl- 5.6- dihydro-4F/-2,3,5,10b-tetraaza-benzo[e]azulen, frans-8-chlor-l-[4-(5-fluor-benzo[c/]isoxazol-3-yl)-cyclohexyl]-4F/,6F/-2,3,5,10b-tetraaza-benzo[e]azulen-5-carboxylsyre-tert-butylester, frans-8-chlor-l-[4-(5-fluor-benzo[c/]isoxazol-3-yl)-cyclohexyl]-5,6-dihydro- 4F/-2,3,5,10b-tetraaza-benzo[e]azulen, frans-8-chlor-l-[4-(5-fluor-benzo[c/]isoxazol-3-yl)-cyclohexyl]-5-methyl- 5.6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, frans-8-chlor-l-(4-isoxazolo[4,5-b]pyridin-3-yl-cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-carboxylsyre-tert-butylester, irans-8-chlor-l-(4-isoxazolo[4,5-d]pyndin-3-yl-cyclohexyl)-5,6-dihydro- 4H-2,3,5,10b-tetraaza-benzo[e]azulen, frans-8-chlor-l-(4-isoxazolo[4,5-b]pyridin-3-yl-cyclohexyl)-5-methyl-5,6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, frans-8-chlor-l-(4-isoxazolo[5,4-b]pyridin-3-yl-cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-carboxylsyre-tert-butylester, frans-8-chlor-l-(4-isoxazolo[5,4-b]pyridin-3-yl-cyclohexyl)-5,6-dihydro- 4H-2,3,5,10b-tetraaza-benzo[e]azulen, frans-8-chlor-l-(4-isoxazolo[5,4-b]pyridin-3-yl-cyclohexyl)-5-methyl-5,6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, trans- l-(4-benzo[of]isothiazol-3-yl-cyclohexyl)-8-chlor-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-carboxylsyre-tert-butylester, trans-l-(4-benzo[c/]isothiazol-3-yl-cyclohexyl)-8-chlor-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, irans-l-(4-benzo[c/]isothiazol-3-yl-cyclohexyl)-8-chlor-5-methyl-5,6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, trans-l-(4-benzo[c/]isothiazol-3-yl-cyclohexyl)-8-chlor-5-cyclobutyl-5,6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, trans-{2-[l-(4-benzo[c/]isothiazol-3-yl-cyclohexyl)-8-chlor-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-ethyl>-methyl-amin, trans-l-[l-(4-benzo[c/]isothiazol-3-yl-cyclohexyl)-8-chlor-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-ethanon, trans-l-[l-(4-benzo[c/]isothiazol-3-yl-cyclohexyl)-8-chlor-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-2-dimethylamino-ethanon, trans-l-(4-benzo[d]isothiazol-3-yl-cyclohexyl)-8-chlor-5-methansulfonyl- 5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, frans-8-chlor-l-(4-isothiazolo[4,5-b]pyridin-3-yl-cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-carboxylsyre-tert-butylester, frans-8-chlor-l-(4-isothiazolo[4,5-b]pyridin-3-yl-cyclohexyl)-5,6-dihydro- 4H-2,3,5,10b-tetraaza-benzo[e]azulen, frans-8-chlor-l-(4-isothiazolo[4,5-b]pyridin-3-yl-cyclohexyl)-5-methyl-5,6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, frans-8-chlor-l-(4-isothiazolo[5,4-c]pyridin-3-yl-cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-carboxylsyre-tert-butylester, frans-8-chlor-l-(4-isothiazolo[5,4-c]pyridin-3-yl-cyclohexyl)-5,6-dihydro- 4H-2,3,5,10b-tetraaza-benzo[e]azulen, frans-8-chlor-l-(4-isothiazolo[5,4-c]pyridin-3-yl-cyclohexyl)-5-methyl-5,6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, c/'s-l-(4-benzo[c/]isothiazol-3-yl-cyclohexyl)-8-chlor-4H,6H-2,3,5,10b- tetraaza-benzo[e]azulen-5-carboxylsyre-tert-butylester, c/s-l-(4-benzo[c/]isothiazol-3-yl-cyclohexyl)-8-chlor-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, og c/s-l-(4-benzo[c/]isothiazol-3-yl-cyclohexyl)-8-chlor-5-methyl-5,6-dihydro- 4H-2,3,5,10b-tetraaza-benzo[e]azulen, eller et farmaceutisk acceptabelt salt deraf.
9. Forbindelse ifølge et hvilket som helst af kravene 1-8, valgt fra gruppen bestående af c/'s-l-(4-benzo[of]isoxazol-3-yl-cyclohexyl)-8-chlor-4H,6H-2,3,5,10b- tetraaza-benzo[e]azulen-5-carboxylsyre-te/t-butylester, frans-l-(4-benzo[c/]isoxazol-3-yl-cyclohexyl)-8-chlor-4H,6H-2,3,5,10b- tetraaza-benzo[e]azulen-5-carboxylsyre-tert-butylester, c/s-l-(4-benzo[c/]isoxazol-3-yl-cyclohexyl)-8-chlor-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, c/s-l-(4-benzo[c/]isoxazol-3-yl-cyclohexyl)-8-chlor-5-methyl-5,6-dihydro- 4H-2,3,5,10b-tetraaza-benzo[e]azulen, trans-l-(4-benzo[c/]isoxazol-3-yl-cyclohexyl)-8-chlor-5,6-dihydrc>-4H-2,3,5,10b-tetraaza-benzo[e]azulen, trans-l-(4-benzo[c/]isoxazol-3-yl-cyclohexyl)-8-chlor-5-methyl-5,6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, trans-8-chlor-l-[4-(6-fluor-benzo[c/]isoxazol-3-yl)-cyclohexyl]-4tY,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-carboxylsyre-tert-butylester, trans-8-chlor-l-[4-(6-fluor-benzo[of]isoxazol-3-yl)-cyclohexyl]-5,6-dihydro- 4H-2,3,5,10b-tetraaza-benzo[e]azulen, trans-8-chlor-l-[4-(6-fluor-benzo[cf]isoxazol-3-yl)-cyclohexyl]-5-methyl- 5.6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, trans-8-chlor-l-[4-(5-fluor-benzo[c/]isoxazol-3-yl)-cyclohexyl]-4AY,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-carboxylsyre-tert-butylester, trans-8-chlor-l-[4-(5-fluor-benzo[c/]isoxazol-3-yl)-cyclohexyl]-5,6-dihydro- 4H-2,3,5,10b-tetraaza-benzo[e]azulen, trans-8-chlor-l-[4-(5-fluor-benzo[c/]isoxazol-3-yl)-cyclohexyl]-5 -methyl- 5.6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, trans-8-chlor-l-(4-isoxazolo[4,5-b]pyridin-3-yl-cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-carboxylsyre-tert-butylester, trans-8-chlor-l-(4-isoxazolo[4,5-b]pyridin-3-yl-cyclohexyl)-5,6-dihydro- 4H-2,3,5,10b-tetraaza-benzo[e]azulen, irans-8-chlor-l-(4-isoxazolo[4,5-b]pyridin-3-yl-cyclohexyl)-5-methyl-5,6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, frans-8-chlor-l-(4-isoxazolo[5,4-b]pyridin-3-yl-cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-carboxylsyre-tert-butylester, trans-8-chlor-l-(4-isoxazolo[5,4-b]pyridin-3-yl-cyclohexyl)-5,6-dihydro- 4H-2,3,5,10b-tetraaza-benzo[e]azulen, frans-8-chlor-l-(4-isoxazolo[5,4-b]pyridin-3-yl-cyclohexyl)-5-methyl-5,6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, trans- l-(4-benzo[c/]isothiazol-3-yl-cyclohexyl)-8-chlor-4H, 6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-carboxylsyre-tert-butylester, trans- l-(4-benzo[c/]isothiazol-3-yl-cyclohexyl)-8-chlor-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, trans- l-(4-benzo[c/]isothiazol-3-yl-cyclohexyl)-8-chlor-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, trans-l-(4-benzo[cf]isothiazol-3-yl-cyclohexyl)-8-chlor-5-cyclobutyl-5,6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, trans-{2-[l-(4-benzo[c/]isothiazol-3-yl-cyclohexyl)-8-chlor-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-ethyl}-methyl-amin, frans-l-[l-(4-benzo[c/]isothiazol-3-yl-cyclohexyl)-8-chlor-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-ethanon, frans-l-[l-(4-benzo[c/]isothiazol-3-yl-cyclohexyl)-8-chlor-4H,6H- 2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-2-dimethylamino-ethanon, trans-l-(4-benzo[c/]isothiazol-3-yl-cyclohexyl)-8-chlor-5-methansulfonyl- 5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, frans-8-chlor-l-(4-isothiazolo[4,5-b]pyridin-3-yl-cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-carboxylsyre-tert-butylester, frans-8-chlor-l-(4-isothiazolo[4,5-b]pyridin-3-yl-cyclohexyl)-5,6-dihydro- 4H-2,3,5,10b-tetraaza-benzo[e]azulen, frans-8-chlor-l-(4-isothiazolo[4,5-£>]pyridin-3-yl-cyclohexyl)-5-methyl-5,6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, frans-8-chlor-l-(4-isothiazolo[5,4-c]pyridin-3-yl-cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-carboxylsyre-tert-butylester, fra/7s-8-chlor-l-(4-isothiazolo[5,4-c]pyridin-3-yl-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, og frans-8-chlor-l-(4-isothiazolo[5,4-c]pyridin-3-yl-cyclohexyl)-5-methyl-5,6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, eller et farmaceutisk acceptabelt salt deraf.
10. Forbindelse ifølge et hvilket som helst af kravene 1-9, valgt fra gruppen bestående af frans-l-(4-benzo[c/]isoxazol-3-yl-cyclohexyl)-8-chlor-5-methyl-5,6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, frans-8-chlor-l-[4-(6-fluor-benzo[c/]isoxazol-3-yl)-cyclohexyl]-5-methyl- 5.6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, frans-8-chlor-l-[4-(5-fluor-benzo[c/]isoxazol-3-yl)-cydohexyl]-5-methyl- 5.6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, frans-8-chlor-l-(4-isoxazolo[4,5-b]pyridin-3-yl-cyclohexyl)-5-methyl-5,6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, frans-8-chlor-l-(4-isoxazolo[5,4-b]pyridin-3-yl-cyclohexyl)-5-methyl-5,6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, frans-l-(4-benzo[c/]isothiazol-3-yl-cyclohexyl)-8-chlor-5-methyl-5,6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, trans-l-(4-benzo[c/]isothiazol-3-yl-cyclohexyl)-8-chlor-5-cyclobutyl-5,6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, frans-{2-[l-(4-benzo[c/]isothiazol-3-yl-cyclohexyl)-8-chlor-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-ethyl>-methyl-amin, frans-l-[l-(4-benzo[c/]isothiazol-3-yl-cyclohexyl)-8-chlor-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-2-dimethylamino-ethanon, frans-8-chlor-l-(4-isothiazolo[4,5-b]pyridin-3-yl-cyclohexyl)-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, og frans-8-chlor-l-(4-isothiazolo[5,4-c]pyridin-3-yl-cyclohexyl)-5-methyl-5,6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen, eller et farmaceutisk acceptabelt salt deraf. 11. fremgangsmåde til fremstillingen af forbindelsen med formel I ifølge et hvilket som helst af kravene 1-10, omfattende trinnet at omsætte en forbindelse med formel II
med en forbindelse med formel III
for at opnå en forbindelse med formel I, hvor R1, R2 og R3 er som defineret i krav 1.
12. Forbindelse med formel I ifølge et hvilket som helst af kravene 1-10 til anvendelse som terapeutisk aktivstof.
13. Forbindelse med formel I ifølge et hvilket som helst af kravene 1-10 til anvendelse i forebyggelsen eller behandling af dysmenoré, hankøns- eller hunkønsseksualdysfunktion, hypertension, kronisk hjertefejl, uhensigtsmæssig sekretion af vasopressin, levercirrhose, nefrotisk syndrom, angst, depressive lidelser, obsessiv kompulsiv forstyrrelse, autistiske spektrumlidelser, skizofreni, og aggressiv adfærd.
14. Farmaceutisk sammensætning omfattende en forbindelse med formel I ifølge et hvilket som helst af kravene 1-10.
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