HRP20140147T1 - 3-supstituirani derivati hinolina ili hinoksalina i njihova uporaba kao inhibitora fosfatidilinozitol 3-kinaze (pi3k) - Google Patents

3-supstituirani derivati hinolina ili hinoksalina i njihova uporaba kao inhibitora fosfatidilinozitol 3-kinaze (pi3k) Download PDF

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HRP20140147T1
HRP20140147T1 HRP20140147AT HRP20140147T HRP20140147T1 HR P20140147 T1 HRP20140147 T1 HR P20140147T1 HR P20140147A T HRP20140147A T HR P20140147AT HR P20140147 T HRP20140147 T HR P20140147T HR P20140147 T1 HRP20140147 T1 HR P20140147T1
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nrara
4alkyl
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Yi Chen
Timothy D. Cushing
Xiaolin Hao
Xiao He
Andreas Reichelt
Robert M. Rzasa
Jennifer Seganish
Youngsook Shin
Dawei Zhang
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Amgen Inc.
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Claims (10)

1. Spoj koji ima strukturu: [image] ili bilo koja njegova farmaceutski prihvatljiva sol, u kojima: X1 je C(R9) ili N; X2 je C(R10) ili N; Y je N(R11), O ili S; n je 0, 1, 2 ili 3; R1je direktno-vezani ili kisikom-vezani zasićeni, djelomično zasićeni ili nezasićeni 5-, 6- ili 7-člani monocikličan prsten koji sadrži 0, 1, 2, 3 ili 4 atoma izabrana od N, O i S, ali koji ne sadrži više od jednog O ili S, gdje su dostupni atomi ugljika prstena supstituirani sa 0, 1 ili 2 okso ili tiokso grupe, gdje je prsten supstituiran sa 0 ili 1 R2supstituentom, i prsten je dodatno supstituiran sa 0, 1, 2 ili 3 supstituenta nezavisno izabrana iz grupe koju čine halo, nitro, cijano, C1-4alkil, OC1-4alkil, OC1-4haloalkil, NHC1-4alkil, N(C1-4alkil)C1-4alkili C1-4haloalkil; R2 je izabran iz grupe koju čine halo, C1-4haloalkil, cijano, nitro, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRa, -C(=NRa)NRaRa,-ORa, -OC(=O)Ra, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O)2Ra, -C2-6alkilNRaRa, -OC2-6alkilORa, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Ra, -S(=O)2N(Ra)C(=O)ORa, -S(=O)2N(Ra)C(=O)NRaRa,-NRaRa, -N(Ra)C(=O)Ra, -N(Ra)C(=O)ORa, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O)2Ra, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkilNRaRai -NRaC2-6alkilORa; ili R2 je izabran iz grupe koju čine C1-6alkil, fenil, benzil, heteroaril, heterociklus, -(C1-3alkil)heteroaril, -(C1-3alkil)heterociklus, -O(C1-3alkil)heteroaril, -O(C1-3alkil)heterociklus, -NRa(C1-3alkil)heteroaril, -NRa(C1-3alkil)heterociklus, -(C1-3alkil)fenil,- O(C1-3alkil)fenili -NRa(C1-3alkil)fenil, od kojih su svi supstituirani sa 0, 1, 2 ili 3 supstituenta izabrana iz grupe koju čine C1-4haloalkil,OC1-4alkil, Br, Cl, F, I i C1-4alkil; R3 je izabran iz grupe koju čine H, halo, C1-4haloalkil, cijano, nitro, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRa, -C(=NRa)NRaRa,-ORa, -OC(=O)Ra, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O)2Ra, -OC2-6alkilNRaRa, -OC2-6alkilORa, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Ra, -S(=O)2N(Ra)C(=O)ORa, -S(=O)2N(Ra)C(=O)NRaRa,-NRaRa, -N(Ra)C(=O)Ra, -N(Ra)C(=O)ORa, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O)2Ra, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkilNRaRa, -NRaC2-6alkilORa, C1-6alkil, fenil, benzil, heteroarili heterociklus, gdje su C1-6alkil, fenil, benzil, heteroariliheterociklusdodatno supstituirani sa 0, 1, 2 ili 3 supstituenta izabrana iz grupe koju čine C1-6haloalkil, OC1-6alkil, Br, Cl, F, I i C1-6alkil; R4je, nezavisno, u svakom slučaju, halo, nitro, cijano, C1-4alkil, OC1-4alkil, OC1-4haloalkil, NHC1-4alkil, N(C1-4alkil)C1-4alkil ili C1-4haloalkil; R5je, nezavisno, u svakom slučaju, H, halo, C1-6alkil, C1-4haloalkil, ili C1-6alkilsupstituiran sa 1, 2 ili 3 supstituenta izabrana iz grupe koju čine halo, cijano, OH, OC1-4alkil, C1-4alkil, C1-3haloalkil, OC1-4alkil, NH2, NHC1-4alkil, N(C1-4alkil)C1-4alkil; ili obje R5grupe zajedno formiraju C3-6spiroalkilsupstituiran sa 0, 1, 2 ili 3 supstituenta izabrana iz grupe koju čine halo, cijano, OH, OC1-4alkil, C1-4alkil, C1-3haloalkil, OC1-4alkil, NH2, NHC1-4alkil, N(C1-4alkil)C1-4alkil; R6 je izabran iz grupe koju čine H, C1-6haloalkil, Br, Cl, F, I, ORa, NRaRa, C1-6alkil, fenil, benzil, heteroaril i heterociklus, gdje su C1-6alkil, fenil, benzil, heteroarili heterociklus dodatno supstituirani sa 0, 1, 2 ili 3 supstituenta izabrana iz grupe koju čine C1-6haloalkil, OC1-6alkil, Br, Cl, F, I i C1-6alkil; R7 je izabran iz grupe koju čine H, C1-6haloalkil, Br, Cl, F, I, ORa, NRaRa, C1-6alkil, fenil, benzil, heteroarili heterociklus, gdje su C1-6alkil, fenil, benzil, heteroarili heterociklusdodatno supstituirani sa 0, 1, 2 ili 3 supstituenta izabrana iz grupe koju čine C1-6haloalkil, OC1-6alkil, Br, Cl, F, I i C1-6alkil; R8 je izabran iz grupe koju čine H, halo, C1-4haloalkil, cijano, nitro, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRa, -C(=NRa)NRaRa,-ORa, -OC(=O)Ra, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O)2Ra, -OC2-6alkilNRaRa, -OC2-6alkilORa, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Ra, -S(=O)2N(Ra)C(=O)ORa, -S(=O)2N(Ra)C(=O)NRaRa,-NRaRa, -N(Ra)C(=O)Ra, -N(Ra)C(=O)ORa, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O)2Ra, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkilNRaRa, -NRaC2-6alkilORa, C1-6alkil, fenil, benzil, heteroarili heterociklus, gdje su C1-6alkil, fenil, benzil, heteroarili heterociklus dodatno supstituirani sa 0, 1, 2 ili 3 supstituenta izabrana iz grupe koju čine C1-6haloalkil, OC1-6alkil, Br, Cl, F, I i C1-6alkil; R9 je izabran iz grupe koju čine H, halo, C1-4haloalkil, cijano, nitro, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRa, -C(=NRa)NRaRa,-ORa, -OC(=O)Ra, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O)2Ra, -OC2-6alkilNRaRa, -OC2-6alkilORa, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Ra, -S(=O)2N(Ra)C(=O)ORa, -S(=O)2N(Ra)C(=O)NRaRa,-NRaRa, -N(Ra)C(=O)Ra, -N(Ra)C(=O)ORa, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O)2Ra, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkilNRaRa, -NRaC2-6alkilORa, C1-6alkil, fenil, benzil, heteroarili heterociklus, gdje su C1-6alkil, fenil, benzil, heteroarili heterociklus dodatno supstituirani sa 0, 1, 2 ili 3 supstituenta izabrana iz grupe koju čine halo, C1-4haloalkil, cijano, nitro, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Ra, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O)2Ra, -OC2-6alkilNRaRa, -OC2-6alkilORa, -SRa,-S(=O)Ra, -S(=O)2Ra, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Ra, -S(=O)2N(Ra)C(=O)ORa, -S(=O)2N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Ra, -N(Ra)C(=O)ORa, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O)2Ra, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkilNRaRa, -NRaC2-6alkilORa; ili R9 je zasićen, djelomično zasićen ili nezasićen 5-, 6- ili 7-člani monociklični prsten koji sadrži 0, 1, 2, 3 ili 4 atoma izabrana od N, O i S, ali koji ne sadrži više od jednog O ili S, gdje su dostupni atomi ugljika u prstenu supstituirani sa 0, 1 ili 2 okso ili tiokso grupe,gdje je prsten supstituiran sa 0, 1, 2, 3 ili 4 supstituenta izabrana iz grupe koju čine halo,C1-4haloalkil, cijano, nitro, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Ra, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O)2Ra, -OC2-6alkilNRaRa, -OC2-6alkilORa, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Ra, -S(=O)2N(Ra)C(=O)ORa, -S(=O)2N(Ra)C(=O)NRaRa, -NRaRa, -N(RaC(=O)Ra, -N(Ra)C(=O)ORa, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O)2Ra, -N(Ra)S(=O)2NRaRa,-NRaC2-6alkilNRaRai -NRaC2-6alkilORa; R10 je H, C1-3alkil, C1-3haloalkil, cijano, nitro, CO2Ra, C(=O)NRaRa, -C(=NRa)NRaRa, -S(=O)2N(Ra)C(=O)Ra,-S(=O)2N(Ra)C(=O)ORa, -S(=O)2N(Ra)C(=O)NRaRa, S(=O)Rb, S(=O)2Rb ili S(=O)2NRaRa; R11 je H ili C1-4alkil; Raje nezavisno, u svakom slučaju, H ili Rb; i Rbje nezavisno, u svakom slučaju, fenil, benzil ili C1-6alkil, pri čemu su fenil, benzil i C1-6alkil supstituirani sa 0, 1, 2 ili 3 supstituenta izabrana iz grupe koju čine halo, C1-4alkil, C1-3haloalkil, -OC1-4alkil, -NH2, -NHC1-4alkil,-N(C1-4alkil)C1-4alkil; i gdje "Cα-βalkil" označava alkil grupu koja sadrži minimalno α i maksimalno β atoma ugljika u razgranatoj, cikličnoj ili linearnoj vezi ili svaku kombinaciju ova tri, gdje α i β predstavljaju cijele brojeve, i gdje alkilgrupa može takođersadržavati jednu ili dvije dvogube ili trogube veze.
2. Spoj prema patentnom zahtjevu 1, koji ima strukturu: [image]
3. Spoj prema patentnom zahtjevu 1, koji ima strukturu: [image]
4. Spoj prema patentnom zahtjevu 1, koji ima strukturu: [image]
5. Spoj prema patentnom zahtjevu 1, naznačen time što je R3 jednako F, Cl ili Br; i n je 0.
6. Spoj prema patentnom zahtjevu 1, naznačen time što, R1 je fenil supstituiran sa 0 ili 1 R2supstituenta, i fenil je dodatno supstituiran sa 0, 1, 2 ili 3 supstituenta nezavisno izabrana iz grupe koju čine halo, nitro, cijano, C1-4alkil,OC1-4alkil, OC1-4haloalkil, NHC1-4alkil, N(C1-4alkil)C1-4alkili C1-4haloalkil.
7. Spoj prema patentnom zahtjevu 1, naznačen time što, R1 je direktno vezan ili kisikom vezan zasićeni, djelomično zasićeni ili nezasićeni 5-, 6- ili 7-člani monociklični prsten koji sadrži 1, 2, 3 ili 4 atoma izabrana iz grupe koju čine N, O i S, ali koji ne sadrži više od jednog O ili S, gdje su dostupni atomi ugljiku prstena supstituirani sa 0, 1 ili 2 okso ili tiokso grupe, gdje je prsten supstituiran sa 0 ili 1 R2supstituentom, i prsten je dodatno supstituiran sa 0, 1, 2 ili 3 supstituenta nezavisno izabrana iz grupe koju čine halo, nitro, cijano, C1-4alkil, OC1-4alkil, OC1-4haloalkil, NHC1-4alkil, N(C1-4alkil)C1-4alkil i C1-4haloalkil.
8. Spoj prema patentnom zahtjevu 1 za uporabu u liječenju reumatoidnog artritisa, anikoloznog spondilitisa, osteoartritisa, psorijatičkog artritisa, psorijaze, inflamatornih bolesti i autoimunih bolesti, inflamatornih bolesti crijeva, inflamatornih poremećaja očiju, inflamatornih ili nestabilnih poremećaja bešike, bolesti kože sa inflamatornim komponentama, kroničnih inflamatornih stanja, autoimunih bolesti, sustavnog lupus eritematodusa (SLE), miastenije gravis, reumatoidnog artritisa, akutnog diseminiranog encefalomijelitisa, idiopatske trombocitopenijske purpure, multiple skleroze, Sjögrenovog sindroma i autoimune hemolitičke anemije, alergijskih stanja i hipersenzitivnosti.
9. Spoj prema patentnom zahtjevu 1 za uporabu u liječenju kancera, koji su posredovani, zavisni od ili povezani sa aktivnošću p110δ.
10. Farmaceutska kompozicija koja sadrži spoj prema patentnom zahtjevu 1 i farmaceutski prihvatljiv razblaživač ili nosač.
HRP20140147AT 2007-03-23 2014-02-17 3-supstituirani derivati hinolina ili hinoksalina i njihova uporaba kao inhibitora fosfatidilinozitol 3-kinaze (pi3k) HRP20140147T1 (hr)

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