HRP20191826T1 - Derivati n-piridinil acetamida kao inhibitori wnt signalnog puta - Google Patents

Derivati n-piridinil acetamida kao inhibitori wnt signalnog puta Download PDF

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HRP20191826T1
HRP20191826T1 HRP20191826TT HRP20191826T HRP20191826T1 HR P20191826 T1 HRP20191826 T1 HR P20191826T1 HR P20191826T T HRP20191826T T HR P20191826TT HR P20191826 T HRP20191826 T HR P20191826T HR P20191826 T1 HRP20191826 T1 HR P20191826T1
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substituted
cancer
compound according
compound
haloalkyl
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HRP20191826TT
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Inder Bhamra
Matilda Bingham
Richard TESTAR
Louise SARGENT
Craig DONOGHUE
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Redx Pharma Plc
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Priority claimed from GBGB1417829.7A external-priority patent/GB201417829D0/en
Priority claimed from GBGB1511387.1A external-priority patent/GB201511387D0/en
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Publication of HRP20191826T1 publication Critical patent/HRP20191826T1/hr
Publication of HRP20191826T4 publication Critical patent/HRP20191826T4/hr

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Claims (19)

1. Spoj formule (I): pri čemu het 1 predstavlja 5-člani sustav heterocikličkog prstena koji je odabran između nesupstituiranog ili supstituiranog: pirazola, imidazola, oksazola, izoksazola, izotiazola, tiofena, furana, triazola, oksadiazola i tiadiazola, i kada je supstituiran prsten sustav je supstituiran s 1, 2, i 3 skupine koje su neovisno odabrane pri svakom pojavljivanju od: halo, C1-4 alkila, C1-4 haloalkila, -ORA2, -NRA2RB2, -CN, -SO2RA2, i C3-6 cikloalkil; het 1 je oko het2 i u -(CR1R2)mC(O)NR3-, gdje je het2 i -(CR1R2)mC(O)NR3 su povezane s ne-susjednih atoma na het1; het2 je 5 ili 6 člani heterociklični prsten koji može biti nesupstituiran ili supstituiran, a kada je supstituiran prsten je supstituiran s 1, 2 ili 3 skupine koje su neovisno odabrane pri svakom pojavljivanju od: halo, C1-4 alkil, C1-4 haloalkil, -ORA1, -NRA1RB1, -CN, -NO2, -NRA1C(O)RB1, -C(O)NRA1RB1, -NRA1SO2RB1, -SO2NRA1RB1, -SO2RA1, -C(O)RA1, -C(O)ORA1 i C3-6 cikloalkil; het3 je 5 ili 6 člani heterociklični prsten ili fenilni prsten koji može biti nesupstituiran ili supstituiran, a kada je supstituiran prsten je supstituiran s 1, 2 ili 3 skupine koje su neovisno odabrane i pri svakom pojavljivanju od: halo, C1-4 alkil, C1-4 haloalkil, -ORA1, -NRA1RB1, -CN, -NO2, -NRA1C(O)RB1,-C(O)NRA1RB1, -NRA1SO2RB1, -SO2NRA1RB1, -SO2RA1, -C(O)RA1, -C(O)ORA1 i C3-6 cikloalkil; R1 i R2 su nezavisno odabrani, a pri svakom pojavljivanju od: H, halo, C1-4 alkil, C1-4 haloalkil, ORA3, -NRA3RB3 i C3-6 cikloalkil; R3 je odabran od: H, C1-4 alkil, C1-4 haloalkil, i C3-6 cikloalkil; R4 je neovisno odabran pri svakom pojavljivanju od: halo, C1-4 alkil, C1-4 haloalkil, -CN, -ORA4,-NRA4RB4, -SO2RA4, C3-6 cikloalkil i C3-6 halocikloalkil; m je odabran od 1, 2 ili 3; n je odabran od 0, 1 ili 2; i RA1, RB1, RA2, RB2, RA3, RB3, RA4 i RB4 se pri svakom pojavljivanju neovisno bira i od: H, C1-4 -alkil, C1-4 haloalkil.
2. Spoj u skladu s patentnim zahtjevom 1, naznačen time , da spoj je spoj prema formuli (IIa) ili (III): ili pri čemu X1 i X2 su odabrani između CR6 i N; i R5 i R6 su, pri svakom pojavljivanju, nezavisno odabrani za: H, halo, C1-4 alkil, C1-4 haloalkil,-ORA2, -NRA2RB2, -CN, -SO2RA2, i C3-6 cikloalkil.
3. Spoj prema zahtjevu 1 ili patentnom zahtjevu 2 formule (IIa), pri čemu het1 predstavlja 5- člani heterociklički prstenasti sustav koji je (A) ili (B): (A) Odabran od nesupstituiranog ili supstituiranog: pirazola, imidazola, i triazola; ili (B) odabran između nesupstituiranog ili supstituiranog: imidazola, pirazola ili tiofena.
4. Spoj iz bilo kojeg prethodnog zahtjeva, naznačen time, da: het2 je 5 ili 6 člani heterociklični prsten koji može biti nesupstituiran ili supstituiran, a kada je supstituiran prsten je supstituiran s 1, 2 ili 3 skupine koje su odabrane od: halo, C1-4 alkil, C1-4 haloalkil,-ORA1, -NO2, -NRA1C(O)RB1, -NRA1SO2RB1, -SO2NRA1RB1, -SO2RA1, -C(O)RA1, -C(O)ORA1 i C3-6 cikloalkil; pod uvjetom da ako het2 nije piridil; ili het2 predstavlja prsten odabran od nesupstituiranog ili supstituiranog: pirazola, imidazola, piridina, pirazina, pirimidina, piridazina, pirana, tetrahidropirana, dihidropirana, piperidina, piperazina, morfolina, tiomorfolina, oksazina, dioksina, dioksana, tiazina, oksatiana i ditiana.
5. Spoj prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time, da het3 predstavlja aromatski, zasićen ili nezasićen 6-člani heterociklički prsten koji je nesupstituiran ili je supstituiran i sadrži najmanje jedan atom dušika, po izboru gdje je het3 prsten koji se bira između nesupstituiranog ili supstituiranog: pirimidina, pirazina, piridazina, piperazina, dioksina, dioksana, morfolina i tiomorfolina.
6. Spoj prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time, da se R1 i R2 mogu neovisno birati pri svakom pojavljivanju od: H, klora, fluora, metila, etila, tri fluormetila, tri fluoretila, -OCF3, -OH, - OMe, -OEt, -NH2, -NHMe, i -NMe2.
7. Spoj prema bilo kojem od prethodnih patentnih zahtjeva , naznačen time, da R3 predstavlja H ili metil.
8. Spoj u skladu s bilo kojim od prethodnih patentnih zahtjeva, naznačen time, da R4 je nezavisno izabran pri svakom pojavljivanju od: H, klora, fluora, metila, etila, trifluorometila, trifluoroetila, -OCF3, -OH, -OMe, - OEt, -NH2, -NHMe, i -NMe2.
9. Spoj iz bilo kojeg prethodnog zahtjeva, naznačen time, da m je 1.
10. Spoj prema bilo kojem od prethodnih zahtjeva, naznačen time da n je 0.
11. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da je spoj je izabran između:
12. Spoj iz bilo kojeg prethodnog zahtjeva, naznačen time da se upotrebljava kao lijek.
13. Spoj prema bilo kojem od patentnih zahtjeva i od 1 do 11, naznačen time, da je spoj za uporabu u modulaciji Wnt signaliziranja.
14. Spoj prema bilo kojem od zahtjeva 1 do 11, naznačen time, da se upotrebljava u liječenju stanja koje se može modulirati inhibicijom Porcn, opcijski gdje se stanje koje se može liječiti inhibicijom Porcn bira između: karcinoma, sarkoma, melanoma, raka kože, hematoloških tumora, limfoma, karcinoma i leukemije, nadalje opcijski gdje se stanje bira između: karcinoma pločastih stanica jednjaka, karcinoma želuca, glioblastoma, astrocitoma; retinoblastoma, osteosarkoma, hondosarkoma, Ewingova sarkoma, rabdomisarkoma, Wilmova tumora, bazalnocelularnog karcinoma, ne-staničnog karcinoma pluća, tumora mozga, hormonskog refraktornog karcinoms prostate, raks prostate, metastatskog raka dojke, karcinoma dojke, metastatskog karcinoma gušterače, raka gušterače, kolorektalnog karcinoma, raka grlića maternice, pločastog staničnog karcinoma glave i vrata i raka glave i vrata ili pri čemu je stanje odabrano između: kožne fibroze, idiopatske plućne fibroza, bubrežne intersticijska fibroze, fibroze jetre, proteinurije, odbacivanja bubrežnog grafta, osteoartritisa, Parkinsonove bolesti, cistoidnog makularnog edema, cistoidnog makularnog edemapovezanog s uveitisom, retinopatije, dijabetičke retinopatije i retinopatije prijevremenog rođenja.
15. Spoj prema bilo kojem od zahtjeva 1 do 11, naznačen time, da se upotrebljava u liječenju stanja odabranog između: karcinoma, sarkoma, melanoma, raka kože, hematoloških tumora, limfoma, karcinoma i leukemije.
16. Spoj iz zahtjeva 15, naznačen time da je stanje odabrano: karcinoma pločastih stanica jednjaka, raka želuca, glioblastoma, astrocitoma; retinoblastoma, osteosarkoma, hondosarkoma, Ewingova sarkoma, rabdomisarkoma, Wilmova tumora, bazalnocelularnog karcinoma, ne-sitnostaničnog raka pluća, tumora mozga, refraktornog hormonalnog raka prostate, raka prostate, metastatskog karcinoma dojke, raka dojke, metastatskog karcinoma gušterače, raka gušterače, kolorektalnog karcinoma, raka grlića maternice, karcinoma pločastih stanica glave i vrata i raka glave i vrata.
17. Spoj iz zahtjeva 15, naznačen time da je stanje izabrano između: fibroze kože, idiopatske plućne fibroze, intersticijske fibroze bubrega, fibroze jetre, proteinurije, odbacivanja bubrežnih presadaka, osteoartritisa, Parkinsonove bolesti, cistoidnog makularnog edema, cistoidnog makularnog edema povezanog s uveitisom, retinopatije, dijabetičke retinopatije i retinopatije prijevremenog rođenja.
18. Farmaceutska formulacija koja sadrži spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 11 i farmaceutski prihvatljivo pomoćno sredstvo.
19. Farmaceutski pripravak u skladu s patentnim zahtjevom 18, naznačen time što je farmaceutski pripravak kombinirani proizvod koji obuhvaća dodatno farmaceutski aktivno sredstvo.
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