HRP20210300T1 - Heterociklički amidi kao inhibitori kinaze - Google Patents

Heterociklički amidi kao inhibitori kinaze Download PDF

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HRP20210300T1
HRP20210300T1 HRP20210300TT HRP20210300T HRP20210300T1 HR P20210300 T1 HRP20210300 T1 HR P20210300T1 HR P20210300T T HRP20210300T T HR P20210300TT HR P20210300 T HRP20210300 T HR P20210300T HR P20210300 T1 HRP20210300 T1 HR P20210300T1
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alkyl
optionally substituted
halo
cycloalkyl
substituted
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HRP20210300TT
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Niall Andrew ANDERSON
Deepak BANDYOPADHYAY
Alain Claude-Marie Daugan
Frederic G. DONCHE
Patrick M. Eidam
Nicolas Eric Faucher
Nicolas S. GEORGE
Philip Anthony Harris
Jae U. Jeong
Bryan W. King
Clark A. Sehon
Gemma Victoria White
David Duff WISNOSKI
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Glaxosmithkline Intellectual Property Development Limited
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Claims (26)

1. Spoj prema formuli (I): [image] naznačen time, što: R1 je (C1-C4)alkoksi-CH2-, fenil(C1-C4)alkoksi-CH2- ili supstituirana ili nesupstituirana (C2-C6)alkil, (C2-C4)alkinil, (C3-C6)cikloalkil, (C3-C6)cikloalkil-(C1-C4)-alkil grupa ili supstituirana ili nesupstituirana heterocikloalkilna grupa sa 5 do 6 članova koja je opcionalno dodatno supstituirana s halogenom ili (C1-C4)alkilom, naznačeno time, što je predmetna supstituirana (C2-C6)alkilna, (C3-C6)cikloalkilna, (C3-C6)cikloaklil-alkilna grupa ili heterocikloalkilna grupa sa 5 do 6 članova supstituirana s 1, 2 ili 3 supstituenta zasebno odabrana iz hidroksila, (benziloksi)karbonil)amino, cijano, halogena, (C1-C4)alkila, halo(C1-C4)alkoksi-(C1-C4)alkil-CO-, (C1-C4)alkoksi-CO-, (C1-C4)alkilNHCO-, ((C1-C4)alkil)((C1-C4)alkil)NCO-, halo(C1-C4)alkil-CO-, opcionalno supstituiranog (C3-C6)cikloalkil-CO-, opcionalno supstituiranog (C3-C6)cikloalkil-(C1-C4)alkil-CO-, opcionalno supstituiranog fenil-CO, opcionalno supstituiranog fenil-SO2-, opcionalno supstituiranog fenil(C1-C4)alkil-CO-, opcionalno supstituiranog heteroaril-CO- sa 5 do 6 članova, te opcionalno supstituiranog heteroaril-CO- sa 9 do 10 članova, naznačeno time, što je predmetni opcionalno supstituirani (C3-C6)cikloalkil-CO-, opcionalno supstituirani (C3-C6)ciloalkil-(C1-C4)alkil-CO-, opcionalno supstituirani fenil-CO-, opcionalno supstituirani fenil-SO2-, opcionalno supstituirani fenil(C1-C4)alkil-CO-, opcionalno supstituirani heteroaril sa 5 do 6 članova ili opcionalno supstituirani heteroaril-CO- s 9 do 10 članova opcionalno supstituiran s 1 ili 2 supstituenta zasebno odabrana iz halogena, cijano, (C1-C4)alkila, (C1-C4)alkoksija, (C1-C4)alkil-CO-, halo(C1-C4)alkila, halo(C1-C4)alkil-CO-, (C3-C6)cikloalkila i heterocikloalkila sa 5 do 6 članova; ili predmetna supstituirana (C2-C4)alkinilna, (C3-C6)cikloalkilna ili heterocikloalkilna grupa sa 5 do 6 članova je supstituirana s opcionalno supstituiranim fenilom, heteroarilom sa 5 do 6 članova ili hteroarilnom grupom sa 9 članova, naznačeno time, što je predmetna fenilna grupa, heteroarilna grupa sa 5 do 6 članova ili heteoarilna grupa sa 9 članova opcionalno supstituirana s 1 ili 2 supstituenta zasebno odabrana iz halogena, (C1-C4)alkila, (C1-C4)alkil-CO-, halo(C1-C4)alkila i halo(C1-C4)alkil-CO-; R2 je supstituirana ili nesupstituirana fenilna, (C3-C6)cikloalkilna, heterocikloalkilna grupa koja sadrži kisik sa 5 do 6 članova, heteroarilna grupa sa 5 do 6 članova, heteroarilna grupa sa 9 članova, karbociklička arilna grupa sa 9 do 10 članova ili heterociklička arilna grupa sa 9 do 10 članova, naznačen time, što je predmetna supstituirana fenilna, (C3-C6)ciklaolkilna, heterocikloalkilna grupa sa 5 do 6 članova, heteroarilna grupa sa 5 do 6 članova, heteroarilna grupa sa 9 članova, karbociklička arilna grupa sa 9 do 10 članova ili heterociklička arilna grupa sa 9 do 10 članova supstituirana s 1, 2 ili 3 supstituenta zasebno odabrana iz halogena, (C1-C4)alkila, halo(C1-C4)alkila, (C1-C4)alkoksija, halo(C1-C4)alkoksija i cijano; R3 je H ili halogen; ili njegova sol, pod uvjetom da spoj nije cikloheksil(5-fenil-4,5-dihidro-1H-pirazol-1-il)metanon ili 2,2-dimetil-1-(5-fenil-4,5-dihidro-1H-pirazol-1-il)butan-1on.
2. Spoj ili njegova sol prema patentnom zahtjevu 1, naznačen time, što: R1 je supstituirana ili nesupstituirana (C2-C6)alkilna, (C4-C6)cikloalkilna, (C4-C6)cikloalkil-alkil- ili heterocikloalkilna grupa sa 5 do 6 članova, naznačen time, što je predmetna (C2-C6)alkilna, (C4-C6)cikloalkilna, (C4-C6)cikloalkil-alkil- ili heterocikloalkilna grupa sa 5 do 6 članova supstituirana s 1, 2 ili 3 supstituenta zasebno odabrana iz hidroksila, (benziloksi)karbonil)amino, halogena, (C1-C4)alkila, halo(C1-C4)alkila, (C1-C4)alkil-CO-, halo(C1-C4)alkil-CO- i opcionalno supstituiranog heteroaril-CO- sa 5 do 6 članova, naznačeno time, što je predmetni opcionalno supstituirani heteroaril-CO- sa 5 do 6 članova opcionalno supstituiran s 1 ili 2 supstituenta zasebno odabrana iz (C1-C4)alkila, (C1-C4)alkil-CO-, halo(C1-C4)alkila i halo(C1-C4)alkil-CO-, ili predmetni (C4-C6)cikloalkil ili-ili heterocikloalkilna grupa sa 5 do 6 članova je supstituirana sa opcionalno supstituiranom fenilnom grupom, heteroarilnom grupom sa 5 do 6 članova ili heteroarilnom grupom sa 9 članova opcionalno supstituiranom sa 1 ili 2 supstituenta zasebno odabrana iz halogena, (C1-C4)alkila, (C1-C4)alkil-CO-, halo(C1-C4)alkila i halo(C1-C4)alkil-CO-; R2 je supstituirana ili nesupstituirana fenilna, (C3-C6)cikloalkilna, heterocikloalkilna grupa koja sadrži kisik sa 5 do 6 članova, heteroarilna grupa sa 5 do 6 članova ili heteroarilna grupa sa 9 članova, naznačen time, što je supstituirana fenilna, (C3-C6)cikloalkilna, hetercikloalkilna grupa koja sadrži kisika sa 5 do 6 članova, hteroarilna grupa sa 5 do 6 članova ili heteroarilna grupa sa 9 članova supstituirana s 1, 2 ili 3 supstituenta zasebno odabrana iz halo, (C1-C4)alkila, halo(C1-C4)alkila, (C1-C4)alkoksija i cijano; i R3 je H.
3. Spoj ili njegova sol, prema patentnom zahtjevu 1, naznačen time, što: R1 je supstituirana ili nesupstituirana (C2-C6)alkilna, (C4-C6)cikloalkilna, (C4-C6)cikloalkil-alkil- ili heterocikloalkilna grupa sa 5 do 6 članova, naznačen time, što je predmetna supstituirana (C2-C6)alkilna, (C4-C6)cikloalkilna, (C4-C6)cikloalkil-alkil- ili heterocikloalkilna grupa sa 5 do 6 članova supstituirana s 1, 2 ili 3 supstituenta zasebno odabrana iz hidroksila, (benziloksi)karbonil)amino, halogena, (C1-C4)alkila, halo(C1-C4)alkila, (C1-C4)alkil-CO-, halo(C1-C4)alki-CO- i opcionalno supstituiranog heteroaril-CO- sa 5 do 6 članova, naznačeno time, što je predmetni opcionalno supstituirani heteroaril-CO- opcionalno supstituiran s 1 ili 2 supstituenta zasebno odabrana iz (C1-C4)alkila, (C1-C4)alkil-CO-, halo(C1-C4)alkila i halo(C1-C4)alkil-CO-, ili predmetna supstituirana (C4-C6)cikloalkilna ili heterocikloalkilna grupa sa 5 do 6 članova je supstituirana s opcionalno supstituiranim fenilom, heteroarilom sa 5 do 6 članova ili heteroarilom sa 9 članova opcionalno supstituiranim s 1 ili 2 supstituenta zasebno odabrana iz halogena, (C1-C4)alkila, (C1-C4)alkil-CO-, halo(C1-C4)alkila i halo(C1-C4)alkil-CO-; R2 je supstituirani ili nesupstituirani fenil, heterocikloalkil koji sadrži kisik sa 5 do 6 članova, naznačen time, što je predmetni supstituirani heterocikloalkil sa 5 do 6 članova supstituiran s 1, 2 ili 3 supstituenta zasebno odabrana iz halo, (C1-C4)alkila, halo(C1-C4)alkila, (C1-C4)alkoksija i cijano; a R3 je H.
4. Spoj ili njegova sol prema bilo kojem patentnom zahtjevu od 1 do 3, koji ima formulu (II): [image]
5. Spoj ili njegova sol prema bilo kojem patentnom zahtjevu od 1 do 4, naznačen time, što je R1 supstituirana ili nesupstituirana heterocikloalkilna grupa sa 5 do 6 članova.
6. Spoj ili njegova sol prema bilo kojem patentnom zahtjevu od 1 do 4, naznačen time, što je R1 supstituirana ili nesupstituirana heterocikloalkilna grupa sa 5 do 6 članova dodatno opcionalno supstituirana s halogenom ili (C1-C4) alkilom.
7. Spoj ili njegova sol prema bilo kojem patentnom zahtjevu od 1 do 4, naznačen time, što je R1 supstituirana piperidinilna grupa, naznačeno time, što je supstituirana piperidinilna grupa supstituirana sa supstituentom odabranim iz (C1-C4)alkil-CO-, halo(C1-C4)alkil-CO-, cijano(C1-C4)alkil-CO-, (C1-C4)alkoksi-(C1-C4)alkil-CO-, (C1-C4)alkilNHCO-, opcionalno supstituiranog (C3-C6)cikloalkil-CO-, opcionalno supstituiranog (C3-C6)cikloalkil-(C1-C4)alkil-CO-, opcionalno supstituiranog fenil-CO-, opcionalno supstituiranog fenil-SO2-, opcionalno supstituiranog fenil(C1-C4)alkil-CO, opcionalno supstituiranog heteroaril-CO sa 5 do 6 članova i opcionalno supstituiranog heteroaril-CO- sa 9 do 10 članova, naznačeno time, što je predmetni opcionalno supstituirani (C3-C6)cikloalkil-CO-, opcionalno supstituirani (C3-C6)cikloalkil-(C1-C4)alkil-CO-, opcionalno supstituirani fenil-CO- opcionalno supstituirani fenil-SO2-, opcionalno supstituirani fenil(C1-C4)alkil-CO-, opcionalno supstituirani heteroaril-CO sa 5 do 6 članova ili opcionalno supstituirani heteroaril-CO- sa 9 do 10 članova opcionalno supstituiran s 1 ili 2 supstituenta zasebno odabrana iz halogena, cijano, (C1-C4)alkila, (C1-C4)alkoksija, (C1-C4)alkil-CO-, halo(C1-C4)alkila, halo(C1-C4)alkil-CO-, (C3-C6)cikloalkila i heterocikloalkila sa 5 do 6 članova.
8. Spoj ili njegova sol prema bilo kojem patentnom zahtjevu od 1 do 4, naznačen time, što je R1 supstituirana piperidinilna grupa, dodatno opcionalno supstituirana s halogenom ili (C1-C4)alkilom, naznačeno time, što je supstituirana piperidinilna grupa supstituirana sa supstituentom odabranim iz (C1-C4)alkil-CO-, halo(C1-C4)alkil-CO-, cijano(C1-C4)alkil-CO-, (C1-C4)alkoksi-(C1-C4)alkil-CO-, (C1-C4)alkilNHCO-, opcionalno supstituiranog (C3-C6)cikloalkil-CO-, opcionalno supstituiranog (C3-C6)cikloalkil-(C1-C4)alkil-CO-, opcionalno supstituiranog fenil-CO-, opcionalno supstituiranog fenil-SO2-, opcionalno supstituiranog fenil(C1-C4)alkil-CO, opcionalno supstituiranog heteroaril-CO sa 5 do 6 članova i opcionalno supstituiranog heteroaril-CO- sa 9 do 10 članova, naznačeno time, što je predmetni opcionalno supstituirani (C3-C6)cikloalkil-CO-, opcionalno supstituirani (C3-C6)cikloalkil-(C1-C4)alkil-CO-, opcionalno supstituirani fenil-CO- opcionalno supstituirani fenil-SO2-, opcionalno supstituirani fenil(C1-C4)alkil-CO-, opcionalno supstituirani heteroaril-CO sa 5 do 6 članova ili opcionalno supstituirani heteroaril-CO- sa 9 do 10 članova opcionalno supstituiran s 1 ili 2 supstituenta zasebno odabrana iz halogena, cijano, (C1-C4)alkila, (C1-C4)alkoksija, (C1-C4)alkil-CO-, halo(C1-C4)alkila, halo(C1-C4)alkil-CO-, (C3-C6)cikloalkila i heterocikloalkila sa 5 do 6 članova.
9. Spoj ili njegova sol prema bilo kojem patentnom zahtjevu od 1 do 4, naznačen time, što je R1 supstituirana piperidin-4-il grupa supstituirana s CH3CO-, CF3CO- ili 1-metil-1H-pirol-2il-CO-.
10. Spoj ili njegova sol prema bilo kojem patentnom zahtjevu od 1 do 4, naznačen time, što je R1 supstituirana piperidinilna grupa, naznačeno time, što je supstituirana piperidinilna grupa opcionalno supstituirana s halogenom ili (C1-C4)alkilom te je dodatno supstituirana s opcionalno supstituiranom fenilnom grupom, heteroarilnom grupom sa 5 do 6 članova ili heteroarilnom grupom sa 9 članova, naznačeno time, što je opcionalno supstituirana fenilna, heteroarilna grupa sa 6 članova ili heteroarilna grupa sa 9 članova opcionalno supstituirana s 1 ili 2 supstituenta zasebno odabrana iz halogena, (C1-C4)alkila, (C1-C4)alkil-CO-, halo(C1-C4)alkila i halo(C1-C4)alkil-CO-.
11. Spoj ili njegova sol prema bilo kojem patentnom zahtjevu od 1 do 10, naznačen time, što je R2 supstituirana ili nesupstituirana fenilna, (C3-C6)cikloalkilna, heterocikloalkilna grupa koja sadrži kisik sa 5 do 6 članova, heteroarilna grupa sa 5 do 6 članova, heteroarilna grupa sa 9 članova, karbociklička arilna grupa sa 9 do 10 članova ili heterociklička arilna grupa sa 9 do 10 članova, naznačeno time, što je predmetna fenilna, (C3-C6)cikloalkilna, heterocikloalkilna grupa koja sadrži kisik sa 5 do 6 članova, heteroarilna grupa sa 5 do 6 članova, heteroarilna grupa sa 9 članova, karbociklička arilna grupa sa 9 do 10 članova ili heterociklička arilna grupa sa 9 do 10 članova supstituirana s 1, 2 ili 3 supstituenta zasebno odabrana iz halogena, (C1-C4)alkila, halo(C1-C4)alkila, (C1-C4)alkoksija, halo(C1-C4)alkoksija i cijano.
12. Spoj ili njegova sol prema bilo kojem patentnom zahtjevu od 1 do 10, naznačen time, što je R2 nesupstituirani fenil.
13. Spoj ili njegova sol prema bilo kojem patentnom zahtjevu od 1 do 10, naznačen time, što je R2 fenil supstituiran s 1 ili 2 supstituenta zasebno odabrana iz halo, (C1-C4)alkila, halo(C1-C4)alkila, (C1-C4)alkoksija, halo(C1-C4)alkoksija i cijano.
14. Spoj ili njegova sol prema bilo kojem patentnom zahtjevu od 1 do 10, naznačen time, što je R2 opcionalno supstituirani heteroaril sa 6 članova koji sadrži 1 ili 2 heteroatoma dušika, naznačeno time, što je heteroaril opcionalno supstituiran s 1 ili 2 supstituenta zasebno odabrana iz halo, (C1-C4)alkila, halo(C1-C4)alkila i (C1-C4)alkoksija.
15. Spoj ili njegova sol prema bilo kojem patentnom zahtjevu od 1 do 14, naznačen time, što je R3 H.
16. Spoj ili njegova sol prema bilo kojem patentnom zahtjevu od 1 do 15, naznačen time, što je sol farmaceutski prihvatljiva sol.
17. Spoj ili njegova sol prema patentnom zahtjevu 1 koji je (S)-1-(4-(5-(3,5-difluorofenil)-4-5-dihidro-1H-pirazol-1-karbonil)piperidin-1-il)etanon ili njegova farmaceutski prihvatljiva sol.
18. Spoj ili njegova sol prema patentnom zahtjevu 1 koji je (S)-1-(4-(5-(3,5-difluorofenil)-4-5-dihidro-1H-pirazol-1-karbonil)piperidin-1-il)etanon.
19. Farmaceutski pripravak koji obuhvaća spoj ili njegovu farmaceutski prihvatljivu sol prema bilo kojem patentnom zahtjevu od 16 do 18 te jedan ili više farmaceutski prihvatljivih ekscipijensa.
20. Farmaceutski pripravak prema patentnom zahtjevu 19, koji dodatno obuhvaća najmanje jedno terapijski djelatno sredstvo.
21. Spoj ili njegova farmaceutski prihvatljiva sol prema bilo kojem patentnom zahtjevu od 16 do 18, za terapijski primjenu.
22. Spoj ili njegova farmaceutski prihvatljiva sol prema bilo kojem patentnom zahtjevu od 16 do 18 za primjenu u liječenju bolesti ili poremećaja posredovanog kinazom RIP1 odabranog iz upalne bolesti crijeva (uključujući Crohnovu bolest i ulcerozni kolitis), psorijaze, odignuća (i degeneracije) mrežnice, retinitis pigmentose, degeneracije makule, pankreatitisa, atopijskog dermatitisa, artritisa (uključujući reumatoidni artritis, spondiloartritis, giht, juvenilni idiopatski artritis (sistemski oblik juvenilnog idiopatskog artritisa (SoJIA)), psorijatični artritis), sistemskog eritemskog lupusa (SLE), Sjorgenovog sindroma, sistemske sklerodermije, antifosfolipidnog sindroma (APS), vaskulitisa, osteoartritisa, oštećenja / bolesti jetre (nealkoholni steatohepatitis, alkoholni steatohepatitis, autoimuni hepatitis, autoimuna hepatobilijarna bolest, primarni sklerozirajući kolangitis (PSC), toksičnost izazvana acetaminofenom, hepatotoksičnost), oštećenja / ozljede bubrega (nefritis, transplantacija bubrega, kirurški zahvat, primjena nefrotoksičnih lijekova, npr. cisplatina, akutna ozljeda bubrega (AKI)), celijakije, autoimune idiopatske trombocitopenične purpure (autoimuna ITP), odbacivanja transplantata (odbacivanje transplantiranih organa, tkiva i stanica), ishemijske reperfuzijske ozljede solidnih organa, sepse, sindroma sistemskog upalnog odgovora (SIRS), cerebrovaskularnog inzulta (moždani udar), infarkta miokarda, ateroskleroze, Huntingtonove bolesti, Alzheimerove bolesti, Parkinsonove bolesti, amiotrofične lateralne skleroze (ALS), neonatalne hipoksične ozljede mozga, ishemijske ozljede mozga, traumatske ozljede mozga, alergijskih oboljenja (uključujući astmu i atopijski dermatitis), opeklina, multiple skleroze, dijabetesa tipa I, Wegenerove granulomatoze, plućne sarkoidoze, Behcetove bolesti, sindroma groznice povezanog s enzimom za konverziju interleukina-1 (ICE, također poznat kao kaspaza-1), kronične opstruktivne plućne bolesti (KOPB), oštećenja izazvanog duhanskim dimom, cistične fibroze, periodičnog sindroma povezanog s receptorom faktora nekroze tumora (TRAPS), neoplastičnog tumora, parodontoze, NEMO-mutacija (mutacije NF-kapa-B esencijalnog modulatornog gena (također poznatog kao IKK gama ili IKKG)), posebno sindroma nedostatka NEMO, nedostatka HOIL-a ((također poznat kao RBCKI) nedostatak hem oksidirane IRP2 ubikvitin ligaze-1), sindroma deficijencije kompleksa linearnog niza lanca ubikvitina (LUBAC), hematoloških maligniteta i maligniteta solidnih organa, bakterijskih infekcija i virusnih infekcija (kao što su gripa, stafilokok i mikobakterije (tuberkuloza)), i lizosomnih bolesti (posebno Gaucherova bolest i uključujući GM2 gangliosidozu, alfa-manosidozu, aspartilglukozaminuriju, bolest skladištenja kolesteril-estera, kronični nedostatak heksosaminidaze A, cistinozu, Danonovu bolest, Fabryjevu bolest, Farberovu bolest, fukozidozu, galaktozijadilozu, GMI gangliozidozu, mukolipidozu, infantilnu bolest skladištenja slobodne sijalične kiseline, juvenilni nedostatak heksosaminidaze A, Krabbeovu bolest, nedostatak lizosomske kisele lipaze, metakromatsku leukodistrofiju, poremećaje mukopolisaharidoze, višestruki nedostatak sulfataza, Niemann-Pickovu bolest, neuronalnu ceroidnu lipofuscinozu, Pompeovu bolest, piknodizostozu, Sandhoffovu bolest, Schindlerovu bolest, bolest skladištenja sijalične kiseline, Tay-Sachs i Wolmanovu bolest), Stevens-Johnsonovog sindroma, toksične epidermalne nekrolize, glaukoma, ozljede kralježnične moždine, duktalnog adenokarcinoma gušterače, hepatocelularnog karcinoma, mezotelioma, melanoma, akutnog zatajenja jetre i zaštite od/ublažavanja zračenja, slušnih poremećaja kao što je gubitak sluha izazvan bukom te lijekova povezanih s ototoksičnošću kao što je cisplatin ili u liječenju stanica ex vivo radi očuvanja vitalnosti i funkcije.
23. Spoj ili njegova farmaceutski prihvatljiva sol prema patentnom zahtjevu 22 za primjenu u liječenju multiple skleroze.
24. Spoj ili njegova farmaceutski prihvatljiva sol prema patentnom zahtjevu 22 za primjenu u liječenju amiotrofične lateralne skleroze (ALS).
25. Spoj ili njegova farmaceutski prihvatljiva sol prema patentnom zahtjevu 22 za primjenu u liječenju Alzheimerove bolesti.
26. Spoj ili njegova farmaceutski prihvatljiva sol prema patentnom zahtjevu 22 za primjenu u liječenju Parkinsonove bolesti.
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