HRP20150701T1 - Spojevi dihidropirolonaftiridinona kao inhibitori jak - Google Patents

Spojevi dihidropirolonaftiridinona kao inhibitori jak Download PDF

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HRP20150701T1
HRP20150701T1 HRP20150701TT HRP20150701T HRP20150701T1 HR P20150701 T1 HRP20150701 T1 HR P20150701T1 HR P20150701T T HRP20150701T T HR P20150701TT HR P20150701 T HRP20150701 T HR P20150701T HR P20150701 T1 HRP20150701 T1 HR P20150701T1
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naphthyridin
oxopyrrolo
dihydropyrrolo
methyl
butanamide
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HRP20150701TT
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Qing Dong
John David Lawson
Michael B. Wallace
Toufike Kanouni
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Takeda Pharmaceutical Company Limited
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Claims (15)

1. Spoj s formulom I [image] ili njegova farmaceutski prihvatljiva sol, naznačen time da: G1 je odabran iz skupine koja sadrži N i CR8; R1 je odabran iz skupine koja sadrži proizvoljno supstituiran C3-8 cikloalkil, proizvoljno supstituiran C3-6 heterocikloalkil, proizvoljno supstituiran C5-14 aril, proizvoljno supstituiran C1-10 heteroaril, te proizvoljno supstituiran C1-6 alkil; R2 i R3 su svaki neovisno odabrani iz skupine koju čine vodik i proizvoljno supstituiran C1-4 alkil, ili R2, R3, i atom ugljika na koji su vezani tvore karbonil; R4 je odabran iz skupine koja sadrži vodik, proizvoljno supstituiran C1-4 alkil, proizvoljno supstituiran C1-4 alkoksi, halo, hidroksi, i amino; R5 je odabran iz skupine koja sadrži vodik, proizvoljno supstituiran C1-4 alkil, C3-8 cikloalkil, i halo; R6 i R7 su svaki neovisno odabrani iz skupine koju čine vodik i proizvoljno supstituiran C1-4 alkil, ili R6, R7, i atom ugljika na koji su vezani tvore karbonil; R8 je odabran iz skupine koja sadrži vodik, proizvoljno supstituiran C1-6 alkil, proizvoljno supstituiran C1-4 alkoksi, C1-9 amid, C1-5 oksikarbonil, cijano, proizvoljno supstituiran C3-8 cikloalkil, proizvoljno supstituiran C5-14 aril, proizvoljno supstituiran C1-10 heteroaril, te halo, pri čemu se C5-14 aril odnosi na monociklički ili policiklički nezasićeni, konjugirani ugljikovodik koji ima aromatski karakter i obuhvaća fenil, bifenil, indenil, ciklopentadienil, fluorenil i naftil; te uz uvjet da se ne više od jednog karbonila tvori od R2 i R3 i R6 i R7.
2. Spoj ili farmaceutski prihvatljiva sol prema zahtjevu 1, naznačen time da svaki od R4 i R5 su vodik.
3. Spoj ili farmaceutski prihvatljiva sol prema bilo kojem od prethodnih zahtjeva, naznačen time da G1 je CR8.
4. Spoj ili farmaceutski prihvatljiva sol prema bilo kojem od prethodnih zahtjeva, naznačen time da G1 je CR8 i R8 je odabran od vodika, halo, te proizvoljno od supstituiranog C1-6 alkila.
5. Spoj ili farmaceutski prihvatljiva sol prema zahtjevu 4, naznačen time da G1 je CR8 i R8 je odabran od vodika, halo, te C1-4 alkila.
6. Spoj ili farmaceutski prihvatljiva sol prema bilo kojem od zahtjeva 1 do 5, naznačen time da R1 je proizvoljno supstituiran C1-6 alkil.
7. Spoj ili farmaceutski prihvatljiva sol prema bilo kojem od zahtjeva 1 do 6 naznačen time da R2, R3, i atom ugljika na koji su vezani tvore karbonil.
8. Spoj ili farmaceutski prihvatljiva sol prema zahtjevu 7, naznačen time da svaki od R6 i R7 je vodik.
9. Spoj ili farmaceutski prihvatljiva sol prema bilo kojem od zahtjeva 1 do 6 naznačen time da R6, R7, i atom ugljika na koji su vezani tvore karbonil.
10. Spoj ili farmaceutski prihvatljiva sol prema zahtjevu 9, naznačen time da svaki od R2 i R3 je vodik.
11. Spoj prema zahtjevu 1, naznačen time da je odabran je skupine koju čine: tert-butil 4-(5-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)piperidin-1-karboksilat; 4-(piperidin-4-il)-3,4-dihidropirolo[4,3,2-de][2,6]naftiridin-5(1H)-on; 3-okso-3-(4-(5-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)piperidin-1-il)propannitril; tert-butil 4-metil-4-(5-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)piperidin-1-karboksilat; 4-(4-metilpiperidin-4-il)-3,4-dihidropirolo[4,3,2-de][2,6]naftiridin-5(1H)-on; 3-(4-metil-4-(5-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)piperidin-1-il)-3-oksopropannitril; tert-butil 4-etil-4-(5-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)piperidin-1-karboksilat; 4-(4-etilpiperidin-4-il)-3,4-dihidropirolo[4,3,2-de][2,6]naftiridin-5(1H)-on; 3-(4-etil-4-(5-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)piperidin-1-il)-3-oksopropannitril; 4-(pentan-3-il)-3,4-dihidropirolo[4,3,2-de][2,6]naftiridin-5(1H)-on; 4-(1-ciklopropil-3-hidroksipropil)-3,4-dihidropirolo[4,3,2-de][2,6]naftiridin-5(1H)-on; tert-butil 3-((5-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)metil)pirolidin-1-karboksilat; 4-(pirolidin-3-ilmetil)-3,4-dihidropirolo[4,3,2-de][2,6]naftiridin-5(1H)-on; tert-butil 3-(5-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)piperidin-1-karboksilat; 4-(piperidin-3-il)-3,4-dihidropirolo[4,3,2-de][2,6]naftiridin-5(1H)-on; 4-(4-etil-1-propionilpiperidin-4-il)-3,4-dihidropirolo[4,3,2-de][2,6]naftiridin-5(1H)-on; 4-(4-etil-1-(pirimidin-4-il)piperidin-4-il)-3,4-dihidropirolo[4,3,2-de][2,6]naftiridin-5(1H)-on; (S)-4-(1-okso-1-(pirolidin-1-il)butan-2-il)-4,5-dihidropirolo[4,3,2-de][2,6]naftiridin-3(1H)-on; (R)-4-(1-okso-1-(pirolidin-1-il)butan-2-il)-4,5-dihidropirolo[4,3,2-de][2,6]naftiridin-3(1H)-on; (R)-4-(3-metil-1-okso-1-(pirolidin-1-il)butan-2-il)-4,5-dihidropirolo[4,3,2-de][2,6]naftiridin-3(1H)-on; (R)-4-(4-metil-1-okso-1-(pirolidin-1-il)pentan-2-il)-4,5-dihidropirolo[4,3,2-de][2,6]naftiridin-3(1H)-on; (R)-N-ciklopentil-3-metil-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)butanamid; (2R,3R)-N-ciklopentil-3-metil-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)pentanamid; (2R,3S)-N-ciklopentil-3-metil-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)pentanamid; (R)-N-ciklopentil-2-ciklopropil-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)acetamid: (R)-N-ciklopentil-3,3-dimetil-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)butanamid; (R)-N,2-diciklopentil-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)acetamid; (R)-N-ciklopentil-4,4,4-trifluoro-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)butanamid; (R)-N-ciklopentil-3-hidroksi-3-metil-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)butanamid; (R)-2-(6-kloro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-3-cijano-N-ciklopentilpropanamid; N-ciklopentil-1-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)ciklopentankarboksamid; (R)-2-(6-kloro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-N-(cijanometil)-3-metilbutanamid; 1-((R)-2-(6-kloro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-3-metilbutanoil)pirolidin-3-karbonitril; (R)-1-(2-(6-kloro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-3-metilbutanoil)piperidin-4-karbonitril; (R)-2-(6-kloro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-N-(4-cijanofenil)-3-metilbutanamid; (R)-2-(6-kloro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H-il)-N-(3-cijanofenil)-3-metilbutanamid; (R)-2-(6-kloro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-N-((S)-1-cijanobutan-2-il)-3-metilbutanamid; (R)-2-(6-kloro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-N-((R)-1-cijanobutan-2-il)-3-metilbutanamid; (R)-1-(2-(6-kloro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-3-metilbutanoil)azetidin-3-karbonitril; (R)-2-(6-kloro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-N-(2-cijanoetil)-3,3-dimetilbutanamid; (R)-1-(2-(6-kloro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-3,3-dimetilbutanoil)azetidin-3-karbonitril; (R)-1-(2-(6-fluoro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-3-metilbutanoil)azetidin-3-karbonitril; (R)-2-(6-fluoro-3-oksopirolo[4,3-,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-3-metilbutanska kiselina; (2R)-2-(6-fluoro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-3-metil-N-(tetrahidrofuran-3-il)butanamid; (R)-2-(6-fluoro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-3-metil-N-(1,1-dioksidotetrahidrotien-3-il)butanamid; (R)-2-(6-fluoro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-3-metil-N-(2-(metilsulfonil)etil)butanamid; (R)-N-(1,1-dioksidotetrahidro-2H-tiopiran-4-il)-2-(6-fluoro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-3-metilbutanamid; 4-{(1R)-1-[(1,1-dioksidotiomorfo-4-il)karbonil]-2-metilpropil}-6-fluoro-4,5-dihidropirolo[4,3,2-de][2,6]naftiridin-3(1H)-on; (R)-N-(ciklopropilmetoksi)-2-(6-fluoro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-3-metilbutanamid; (2R)-N-(3,3-difluorociklopentil)-2-(6-fluoro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-3-metilbutanamid; (R)-3-(fluorometil)-1-(3-metil-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)butanoil)azetidin-3-karbonitril; (R)-1-(2-(6-fluoro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-3-metilbutanoil)-3-metilazetidin-3-karbonitril; (R)-3-metil-1-(3-metil-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)butanoil) azetidin-3 -karbonitril; (R)-4-(1-morfoo-1-oksobutan-2-il)-4,5-dihidropirolo[4,3,2-de][2,6]naftiridin-3(1H)-on; (R)-4-(1-(4-metilpiperazin-1-il)-1-oksobutan-2-il)-4,5-dihidropirolo[4,3,2-de][2,6]naftiridin-3(1H)-on; 4-((2R)-1-(3-hidroksipirolidin-1-il)-1-oksobutan-2-il)-4,5-dihidropirolo[4,3,2-de][2,6]naftiridin-3(1H)-on; (R)-N-ciklopentil-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)butanamid; 4-((2R)-1-(3-(4-fluorofenil)pirolidin-1-il)-1-oksobutan-2-il)-4,5-dihidropirolo[4,3,2-de][2,6]naftiridin-3(1H)-on; 4-((2R)-1-(3-(dimetilamino)pirolidin-1-il)-1-oksobutan-2-il)-4,5-dihidropirolo[4,3,2-de][2,6]naftiridin-3(1H)-on; 4-((2R)-1-(3-(metoksimetil)pirolidin-1-il)-1-oksobutan-2-il)-4,5-dihidropirolo[4,3,2-de][2,6]naftiridin-3(1H)-on; 4-((2R)-1-(3-metilpiperidin-1-il)-1-oksobutan-2-il)-4,5-dihidropirolo[4,3,2-de][2,6]naftiridin-3(1H)-on; (R)-4-(1-(4-(2-hidroksipropan-2-il)piperidin-1-il)-1-oksobutan-2-il)-4,5-dihidropirolo[4,3,2-de][2,6]naftiridin-3(1H)-on; (R)-4-(1-(4-(metilsulfonil)piperazin-1-il)-1-oksobutan-2-il)-4,5-dihidropirolo[4,3,2-de][2,6]naftiridin-3(1H)-on; (R)-4-(1-okso-1-(4-(piridin-2-il)piperazin-1-il)butan-2-il)-4,5-dihidropirolo[4,3,2-de] [2,6]naftiridin-3(1H)-on; (R)-N-ciklopropil-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)butanamid; (R)-N-(ciklopropilmetil)-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)butanamid; (R)-N-izobutil-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)butanamid; (R)-N-izobutil-N-metil-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)butanamid; (2R)-N-(1-hidroksipropan-2-il)-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)butanamid; (R)-N-(2-hidroksi-2-metilpropil)-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)butanamid; (R)-N-((S)-2,3-dihidroksipropil)-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)butanamid; (R)-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-N-fenilbutanamid; (R)-N-(1-(metilsulfonil)piperidin-4-il)-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)butanamid; (2R)-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-N-((tetrahidrofuran-2-il)metil)butanamid; (2R)-N-(1-cijanoetil)-2-(6-fluoro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-3-metilbutanamid; (R)-4-(1-(3,3-difluoroazetidin-1-il)-3-metil-1-oksobutan-2-il)-6-fluoro-4,5-dihidropirolo[4,3,2-de][2,6]naftiridin-3 (1H)-on; (R)-4-(1-(1,1-dioksidotiazolidin-3-il)-3-metil-1-oksobutan-2-il)-6-fluoro-4,5-dihidropirolo[4,3,2-de][2,6]naftiridin-3(1H)-on; (R)-2-(6-fluoro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-N,3-dimetil-N-(2-(metilsulfonil)etil)butanamid; (R)-N-(cijanometil)-2-(6-fluoro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-N,3-dimetilbutanamid; (R)-4-(1-(3-(difluorometil)azetidin-1-il)-3-metil-1-oksobutan-2-il)-6-fluoro-4,5-dihidropirolo[4,3,2-de][2,6]naftiridin-3(1H)-on; (R)-1-(3-metil-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)butanoil)azetidin-3-karbonitril; (R)-1-(3,3-dimetil-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)butanoil)azetidin-3-karbonitril; (R)-N-(cijanometil)-3,3-dimetil-2-(3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)butanamid; (S)-1-((R)-2-(6-kloro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-3-metilbutanoil)pirolidin-2-karbonitril; (R)-1-((R)-2-(6-kloro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-3-metilbutanoil)pirolidin-2-karbonitril; (2S,4S)-1-((R)-2-(6-kloro-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)-3-metilbutanoil)-4-fluoropirolidin-2-karbonitril; (R)-1-(3,3-dimetil-2-(6-metil-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)butanoil)azetidin-3-karbonitril; (R)-1-(3-metil-2-(6-metil-3-oksopirolo[4,3,2-de][2,6]naftiridin-4(1H,3H,5H)-il)butanoil)azetidin-3-karbonitril; stereoizomeri bilo kojeg od gore navedenih spojeva; te farmaceutski prihvatljive soli bilo kojeg od gore navedenih stereoizomera ili spojeva.
12. Farmaceutski pripravak, naznačen time da sadrži spoj ili farmaceutski prihvatljivu sol kako je definirano u bilo kojem od patentnih zahtjeva 1 do 11, te farmaceutski prihvatljivu pomoćnu tvar.
13. Spoj ili farmaceutski prihvatljiva sol kako je definirano u bilo kojem od patentnih zahtjeva 1 do 11 naznačen time da je za uporabu kao lijek.
14. Spoj ili farmaceutski prihvatljiva sol kako je definirano u bilo kojem od patentnih zahtjeva 1 do 11 naznačen time da je za uporabu kod liječenja bolesti, poremećaja ili stanja koje je odabrano od alergijskog rinitisa, alergijske astme, atopijskog dermatitisa, reumatoidnog artritisa, multiple skleroze, sistemskog eritematoznog lupusa, psorijaze, imunološke trombocitopenične purpure, kronične opstruktivne plućne bolesti, te tromboze.
15. Kombinacija djelotvorne količine spoja ili farmaceutski prihvatljive soli kako je definirano u bilo kojem od patentnih zahtjeva 1 do 11, te barem jednog dodatnog farmakološki aktivnog sredstva.
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