HRP20170401T1 - SUPSTITUIRANI BENZOAZEPINI KAO MODULATORI TOLL-u SLIČNIH RECEPTORA - Google Patents

SUPSTITUIRANI BENZOAZEPINI KAO MODULATORI TOLL-u SLIČNIH RECEPTORA Download PDF

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HRP20170401T1
HRP20170401T1 HRP20170401TT HRP20170401T HRP20170401T1 HR P20170401 T1 HRP20170401 T1 HR P20170401T1 HR P20170401T T HRP20170401T T HR P20170401TT HR P20170401 T HRP20170401 T HR P20170401T HR P20170401 T1 HRP20170401 T1 HR P20170401T1
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James Jeffry Howbert
Robert Hershberg
Laurence E. Burgess
Hong Woon Yang
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Ventirx Pharmaceuticals, Inc.
Array Biopharma, Inc.
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Claims (16)

1. Spoj s formulom I: [image] , ili njegova farmaceutski prihvatljiva sol, naznačen time što [image] je dvostruka veza ili jednostruka veza; R2 i R3 se neovisno bira između H i nesupstituiranog ili supstituiranog C1-C6 alkila, gdje C1-C6 alkil može biti supstituiran s halogenom, C1-C6 alkilom, C1-C6 alkoksi, keto, amino, alkilamino, dialkilamino, trifluormetilom, arilom, heteroarilom ili hidroksilom, ili R2 i R3, zajedno s atomom ugljika na kojeg su vezani, tvore 3 do 7-eročlani zasićeni karbocikl, ili R3 i jedan od Ra ili Rb, zajedno s atomima na koje su vezani, tvore 5-7-eročlani heterociklički prsten; R7 se bira iz skupine koju čine: [image] , [image] , [image] , [image] , [image] , [image] i [image] ; n je 0, 1, 2 ili 3; svakog R8 se neovisno bira između nesupstituiranog ili supstituiranog C1-C6 alkoksi, halogena, trihalogenmetila, nesupstituiranog ili supstituiranog C1-C6 alkoksikarbonila, nitro, nesupstituiranog ili supstituiranog karbonilamino, nesupstituiranog ili supstituiranog sulfonamida, nesupstituiranog ili supstituiranoig heterocikla, koji se sastoji od 1 ili 2 5- ili 6-eročlana prstena i 1-4 heteroatoma, koje se bira između N, O i S, i [image] , gdje svaki od navedenih C1-C6 alkila, C1-C6 alkoksi, C1-C6 alkoksikarbonila, karbonilamino i sulfonamida može neovisno biti supstituiran s halogenom, C1-C6 alkilom, C1-C6 alkoksi, keto, amino, C1-C6 alkilamino, di(C1-C6 alkil)amino, trifluormetilom, arilom, heteroarilom ili hidroksilom; gdje navedeni heterocikl može biti supstituiran s jednom ili više skupina, koje se neovisno bira između C1-C6 alkila, C1-C6 alkoksi, halogena, hidroksi, cijano, nitro, amino, mono(C1-C6)alkilamino, di(C1-C6)alkilamino, C2-C6 alkenila, C2-C6 alkinila, C1-C6 halogenalkila, C1-C6 halogenalkoksi, amino (C1-C6)alkila, mono (C1-C6)alkilamino(C1-C6)alkila ili di(C1-C6)alkilamino(C1-C6)alkila; R9 je nesupstituirani ili supstituirani C1-C6 alkil, nesupstituirani ili supstituirani C1-C6 alkoksi ili -NRhRj, gdje svaki od navedenih C1-C6 alkila i C1-C6 alkoksi može neovisno biti supstituiran s halogenom, C1-C6 alkilom, C1-C6 alkoksi, keto, amino, C1-C6 alkilamino, di(C1-C6 alkil)amino, trifluormetilom, arilom, heteroarilom ili hidroksilom; svaki od Rf i Rg je, neovisno, H, ili C1-C6 alkil, koji može biti supstituiran s halogenom, C1-C6 alkilom, C1-C6 alkoksi, keto, amino, C1-C6 alkilamino, di(C1-C6 alkil)amino, trifluormetilom, arilom, heteroarilom ili hidroksilom, ili Rf i Rg, zajedno s atomom dušika na kojeg su vezani, tvore heterocikl, koji se sastoji od 1 ili 2 5- ili 6-eročlana prstena i izborno 1-3 dodatna heteroatoma, koje se bira između N, O i S; svaki od Rh i Rj je, neovisno, H, C1-C6 alkil, koji može biti supstituiran s halogenom, C1-C6 alkilom, C1-C6 alkoksi, keto, amino, C1-C6 alkilamino, di(C1-C6 alkil)amino, trifluormetilom, arilom, heteroarilom ili hidroksilom, ili C6-C10 aril, koji može biti supstituiran s jednim ili više supstituenata, koje se neovisno bira između halogena, C1-C6 alkila, C1-C6 alkoksi, trifluormetila, arila, heteroarila i hidroksil, ili Rh i Rj, zajedno s atomom dušika na kojeg su vezani, tvore heterocikl, koji se sastoji od 1 ili 2 5- ili 6-eročlana prstena i izborno 1-3 dodatna heteroatoma, koje se bira između N, O i S; R11 je H, nesupstituirani ili supstituirani C1-C6 alkilkarbonil, nesupstituirani ili supstituirani C1-C6 alkoksikarbonil, karbonil supstituiran 3-7-eročlanim karbociklilom ili karbonil supstituiran 5-7-eročlanim heterociklilom, GDJE navedeni C1-C6 alkilkarbonil ili C1-C6 alkoksikarbonil može biti supstituiran s halogenom, C1-C6 alkilom, C1-C6 alkoksi, keto, amino, C1-C6 alkilamino, di(C1-C6 alkil)amino, trifluormetilom, arilom, heteroarilom ili hidroksilom; R4 je H, halogen, nesupstituirani C1-C6 alkil, ili -C(O)NRcRd, ili -C(O)OR10; Rc i Rd se neovisno bira između H i nesupstituiranog ili supstituiranog C1-C6 alkila, gdje C1-C6 alkil može biti supstituiran s aminokarbonilom ili hidroksilom; R10 se bira između H i C1-C6 alkila, gdje alkil može biti supstituiran s jednim ili više -OH; Ra i Rb se neovisno bira između H, nesupstituiranog ili supstituiranog C1-C6 alkila, nesupstituiranog ili supstituiranog C2-C6 alkenila, nesupstituiranog ili supstituiranog C2-C6 alkinila, nesupstituiranog ili supstituiranog C1-C6 alkoksi, amino supstituiranog C1-C6 alkoksikarbonilom, te Re, gdje C1-C6 alkil može biti supstituiran s jednim ili više -OR10 ili Re, gdje svaki od navedenih C2-C6 alkenila, C2-C6 alkinila i C1-C6 alkoksi može biti supstituiran s halogenom, C1-C6 alkilom, C1-C6 alkoksi, keto, amino, C1-C6 alkilamino, di(C1-C6 alkil)amino, trifluormetilom, arilom, heteroarilom ili hidroksilom; ili R3 i jedan od Ra i Rb, zajedno s atomima na koje su vezani, tvore 5-7-eročlani heterociklički prsten; Re se bira između -NH2, -NH(C1-C6 alkila) i -N(C1-C6 alkila)2; i R1 je odsutan kada [image] je dvostruka veza, ili kada [image] je jednostruka veza, R1 je H, ili je R1 vezan s jednim od Ra ili Rb kako bi tvorili zasićeni, djelomično nezasićeni ili nezasićeni 5-7-člani heterociklički prsten, a drugi od Ra ili Rb može biti vodik ili po potrebi odsutan zbog nezasićenosti prstena; uz uvjet da: kada je R7 [image] , R4 nije -COOR10, gdje je R10 C1-C6 alkil, ili -CONRcRd, gdje je i Rc i Rd nesupstituirani C1-C6 alkil, i Ra i Rb se ne bira oba između H, nesupstituiranog C1-C6 alkila i Re, gdje "aril" je jednovalentni aromatski karbociklički radikal s jednim prstenom, više prstena, ili više kondenziranih prstena, gdje je najmanje jedan prsten aromatski, koji može biti supstituiran s jednim ili više supstitutenata, koje se neovisno bira između halogena, C1-C6 alkila, C1-C6 alkoksi, trifluormetila, arila, heteroarila i hidroksi, a "heteroaril" je jednovalentni aromatski radikal od 5-, 6- ili 7-eročlanih prstena i uklučuje sustav kondenziranih prstena (od kojih je najmanje jedan aromatski) s 5-10 atoma koji sadrži najmanje jedan, a do četiri heteroatoma, koje se bira između dušika, kisika i sumpora.
2. Spoj u skladu s patentnim zahtjevom 1, naznačen time što je spoj formule II [image] , ili njegova farmaceutski prihvatljiva sol, gdje R7 se bira iz skupine koju čine: [image] , [image] , [image] , [image] i [image] ; n je 0, 1, 2 ili 3; svakog R8 se neovisno bira između nesupstituiranog ili supstituiranog C1-C6 alkila, nesupstituiranog ili supstituiranog C1-C6 alkoksi, halogena, trihalogenmetila, nesupstituiranog ili supstituiranog C1-C6 alkoksikarbonila, nesupstituiranog ili supstituiranog karbonilamino, nesupstituiranog ili supstituiranog sulfonamida, nesupstituiranog ili supstituiranog heterocikla, koji se sastoji od 1 ili 2 5- ili 6-eročlana prstena i 1-4 heteroatoma, koje se bira između N, O i S, i [image] , gdje svaki od navedenih C1-C6 alkila, C1-C6 alkoksi, C1-C6 alkoksikarbonila, karbonilamino i sulfonamida može neovisno biti supstituiran s halogenom, C1-C6 alkilom, C1-C6 alkoksi, keto, amino, C1-C6 alkilamino, di(C1-C6 alkil)amino, trifluormetilom, arilom, heteroarilom ili hidroksilom; gdje navedeni heterocikl može biti supstituiran s jednom ili više skupina, koje se neovisno bira između C1-C6 alkila, C1-C6 alkoksi, halogena, hidroksi, cijano, nitro, amino, mono(C1-C6)alkilamino, di(C1-C6)alkilamino, C2-C6 alkenila, C2-C6 alkinila, C1-C6 halogenalkila, C1-C6 halogenalkoksi, amino (C1-C6)alkila, mono (C1-C6)alkilamino(C1-C6)alkila ili di(C1-C6)alkilamino(C1-C6)alkila; R9 je nesupstituirani ili supstituirani C1-C6 alkil, nesupstituirani ili supstituirani C1-C6 alkoksi ili -NRhRi, gdje svaki od navedenih C1-C6 alkila i C1-C6 alkoksi može neovisno biti supstituiran s halogenom, C1-C6 alkilom, C1-C6 alkoksi, keto, amino, C1-C6 alkilamino, di(C1-C6 alkil)amino, trifluormetilom, arilom, heteroarilom ili hidroksilom; svaki od Rf i Rg je, neovisno, H, ili C1-C6 alkil, koji može biti supstituiran s halogenom, C1-C6 alkilom, C1-C6 alkoksi, keto, amino, C1-C6 alkilamino, di(C1-C6 alkil)amino, trifluormetilom, arilom, heteroarilom ili hidroksilom; ili Rf i Rg, zajedno s atomom dušika na kojeg su vezani, tvore heterocikl, koji se sastoji od 1 ili 2 5- ili 6-eročlana prstena i izborno 1-3 dodatna heteroatoma, koje se bira između N, O i S; svaki od Rh i Ri je, neovisno, H, ili C1-C6 alkil, koji može biti supstituiran s halogenom, C1-C6 alkilom, C1-C6 alkoksi, keto, amino, C1-C6 alkilamino, di(C1-C6 alkil)amino, trifluormetilom, arilom, heteroarilom ili hidroksilom; ili Rh i Ri, zajedno s atomom dušika na kojeg su vezani, tvore heterocikl, koji se sastoji od 1 ili 2 5- ili 6-eročlana prstena i izborno 1-3 dodatna heteroatoma, koje se bira između N, O i S; R11 je H, nesupstituirani ili supstituirani C1-C6 alkilkarbonil, nesupstituirani ili supstituirani C1-C6 alkoksikarbonil, karbonil supstituiran 3-7-eročlanim karbociklilom ili karbonil supstituiran 5-7-eročlanim heterociklilom, GDJE navedeni C1-C6 alkilkarbonil ili C1-C6 alkoksikarbonil može biti supstituiran s halogenom, C1-C6 alkilom, C1-C6 alkoksi, keto, amino, C1-C6 alkilamino, di(C1-C6 alkil)amino, trifluormetilom, arilom, heteroarilom ili hidroksilom; R4 se bira između H, -C(O)NRcRd, -C(O)OR10, halogenA i nesupstituiranog C1-C6 alkila; Rc i Rd se neovisno bira između H i nesupstituiranog ili supstituiranog C1-C6 alkila, gdje C1-C6 alkil može biti supstituiran s aminokarbonilom ili hidroksilom; R10 je C1-C6 alkil, koji može biti supstituiran s jednim ili više -OH; Ra i Rb se neovisno bira između H, nesupstituiranog ili supstituiranog C1-C6 alkila, nesupstituiranog ili supstituiranog C2-C6 alkenila, nesupstituiranog ili supstituiranog C2-C6 alkinila, nesupstituiranog ili supstituiranog C1-C6 alkoksi, amino supstituiranog C1-C6 alkoksikarbonilom, te Re, gdje C1-C6 alkil može biti supstituiran s jednim ili više -OH, -OR10 ili Re, gdje svaki od navedenih C2-C6 alkenila, C2-C6 alkinila i C1-C6 alkoksi može biti supstituiran s halogenom, C1-C6 alkilom, C1-C6 alkoksi, keto, amino, C1-C6 alkilamino, di(C1-C6 alkil)amino, trifluormetilom, arilom, heteroarilom ili hidroksilom; ili R3 i jedan od Ra ili Rb, zajedno s atomima na koje su vezani, tvore 5-7-eročlani heterociklički prsten; Re se bira između -NH2, -NH(C1-C6 alkila) i -N(C1-C6 alkila)2.
3. Spoj u skladu s patentnim zahtjevom 1 ili 2, naznačen time što je R4 H, halogen, nesupstituirani C1-C6 alkil, C(O)OR10, gdje je R10 alkil, ili -C(O)NRcRd, gdje i Rc i Rd su alkil, ili gdje je najmanje jedan od Rc ili Rd alkil, supstituiran s jednim -OH.
4. Spoj u skladu s bilo kojim od patentnih zahtjeva 1-3, naznačen time što je R4 -C(O)OR10, gdje je R10 etil; ili R4 je -C(O)NRcRd, gdje i Rc i Rd su propil, ili je jedan od Rc i Rd [image] , a drugi je propil.
5. Spoj u skladu s bilo kojim od patentnih zahtjeva 1-3, naznačen time što je R4 Br, metil ili etil.
6. Spoj u skladu s bilo kojim od patentnih zahtjeva 1-5, naznačen time što je R7 [image] , gdje je n 1, 2 ili 3.
7. Spoj u skladu s bilo kojim od patentnih zahtjeva 1-5, naznačen time što je R7 [image] .
8. Spoj u skladu s bilo kojim od patentnih zahtjeva 1-7, naznačen time što najmanje jedan od Ra i Rb nije vodik; ili je jedan od Ra i Rb alkil, a drugi je vodik; ili je jedan ili više od Ra i Rb alkil, supstituiran s Re; ili su Ra i Rb oba alkil; ili je jedan od Ra i Rb Re, a drugi od Ra i Rb je vodik.
9. Spoj u skladu s bilo kojim od patentnih zahtjeva 1-8, naznačen time što najmanje jedan od R2 i R3 nije vodik; ili R2 i R3 su vezan kako bi tvorili zasićeni karbocikl, po mogućnosti the zasićeni karbocikl je ciklopropil.
10. Spoj u skladu s patentnim zahtjevom 1, naznačen time što je spoj formule III: [image] , ili njegova sol, gdje R2′ i R3′ se neovisno bira između H i nesupstituiranog ili supstituiranog C1-C6 alkila, gdje C1-C6 alkil može biti supstituiran s halogenom, C1-C6 alkilom, C1-C6 alkoksi, keto, amino, alkilamino, dialkilamino, trifluormetilom, arilom, heteroarilom ili hidroksilom, ili R2′ i R3′, zajedno s atomom ugljika na kojeg su vezani, tvore 3 do 7-eročlani zasićeni karbocikl, ili R3′, a jedan od Ra′ ili Rb′, zajedno s atomima na koje su vezani, tvore 5-7-eročlani heterociklički prsten; R4′ je C1-C6 alkil, koji može biti supstituiran s jednim ili više -OH; i Ra′ i Rb′ se neovisno bira između H i nesupstituiranog ili supstituiranog C1-C6 alkila, gdje alkil može biti supstituiran s jednim ili više -OH, ili R3′, a jedan od Ra′ ili Rb″, zajedno s atomima na koje je vezan, tvori 5-7-eročlani heterociklički prsten.
11. Spoj u skladu s patentnim zahtjevom 10, naznačen time što je svaki od R2′ i R3′ H; ili R2′ ili R3′ je nesupstituirani ili supstituirani C1-C6 alkil; ili R2′ ili R3′ je metil; ili R2′ i R3′ su oba metil; ili R2′ i R3′, zajedno s atomom ugljika na kojeg su vezani, tvore 3 do 7-eročlani zasićeni karbocikl, po mogućnosti ciklopropilni prsten.
12. Farmaceutski pripravak, naznačen time što sadrži spoj u skladu s bilo kojim od patentnih zahtjeva 1-11, ili njegovu farmaceutski prihvatljivu sol, kao i farmaceutski prihvatljivu podlogu.
13. Spoj u skladu s patentnim zahtjevom 2, naznačen time što su R7, R4, R2, R3, Ra i Rb kao što je prikazano u Tablici 1: Tablica 1 [image] [image] [image] [image] [image]
14. Spoj u skladu s patentnim zahtjevom 2, naznačen time što se bira između spojeva iz Tablice 1A: Tablica 1A [image] ili njihovih farmaceutski prihvatljivih soli.
15. Spoj, naznačen time što se bira između spojeva [image] ili njihovih farmaceutski prihvatljivih soli.
16. Spoj u skladu s bilo kojim od patentnih zahtjeva 1-11 i 13-15, naznačen time što je namijenjen upotrebi u liječenju stanja koje se bira između raka, bolesti povezane s imunosnim kompleksom, autoimune bolesti, zarazne bolesti, upalnog poremećaja, imunodeficijencije, odbacivanja presatka, reakcije presatka prema domaćinu, alergije, kardiovaskularne bolesti, fibrotične bolesti, astme i sepse.
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