HRP20171075T1 - Piridiloksiindol-inhibitori za vegf-r2 i njihova uporaba u liječenju bolesti - Google Patents

Piridiloksiindol-inhibitori za vegf-r2 i njihova uporaba u liječenju bolesti Download PDF

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HRP20171075T1
HRP20171075T1 HRP20171075TT HRP20171075T HRP20171075T1 HR P20171075 T1 HRP20171075 T1 HR P20171075T1 HR P20171075T T HRP20171075T T HR P20171075TT HR P20171075 T HRP20171075 T HR P20171075T HR P20171075 T1 HRP20171075 T1 HR P20171075T1
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yloxy
pyrimidin
indole
amide
carboxylic acid
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Gerald David Artman Iii
Jason Matthew Elliott
Nan JI
Donglei Liu
Fupeng Ma
Nello Mainolfi
Erik Meredith
Karl Miranda
James J. Powers
Chang Rao
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Novartis Ag
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Claims (16)

1. Spoj, naznačen time, da ima sljedeću formulu : [image] ili njegova sol, u kojoj R1 je vodik ili C1-C6alkil; R3 je vodik ili C1-C6alkil; R5 je vodik ili halogen; R7 je vodik ili C1-C6alkil; X je O ili S; R8 je odabran iz skupine koju čine vodik i C1-C4alkil; R9 je odabran iz skupine koju čine (CH2)nNHR13, (CR11R12)nheterocikl, (CR11R12)nOR15, (CH2)nS(O)mR17 i (CH2)nS(O)mN(R18)2; Ar2 je peteročlani heteroaril koji ima jedan atom dušika u prstenu i nijedan ili jedan dodatni heteroatom prstena odabran od N i O, te je pritom navedena heteroaril-skupina nesupstituirana ili je supstituirana s jednom ili dvije skupine neovisno odabrane iz skupine koju čine C1-C4alkil, C1-C4haloalkil, C1-C4alkoksi, C1-C4haloalkoksi, halogen, amino, aminoC1-C4alkil, mono- i di-C1-C4alkilaminoC1-C4alkil, mono- i di-C1-C4alkilamino, hidroksil, CO2C1-C4alkil, fenilC0-C4alkil, C3-C6cikloalkilC0-C2alkil, aminosulfonil, te mono- i di-C1-C4alkilaminosulfonil; m je 0, 1, ili 2; n je 1 ili 2; R11 i R12 su isti ili različiti i neovisno su odabrani prilikom svakog pojavljivanja, iz skupine koju čine vodik i C1-C4alkil; R13 je vodik, C1-C4alkil, hidroksiC1-C4alkil, ili C3-C6cikloalkil; R15 je vodik ili C1-C4alkil; R17 je C1-C4alkil; i R18 je neovisno odabran prilikom svakog pojavljivanja, iz skupine koju čine vodik, metil ili etil.
2. Spoj prema zahtjevu 1, naznačen time, da ima sljedeću formulu V: [image] V i njegove soli, u kojoj R9 je odabran iz skupine koju čine CH2NHR13, CH2OR15, i CH2S(O)2 N(R18)2; R13 je odabran iz skupine koju čine vodik, C1-C4alkil, i hidroksiC1-C4alkil.
3. Spoj prema zahtjevu 1, naznačen time, da R8 je vodik.
4. Spoj prema zahtjevu 1, ili njegova sol, naznačen/a time, da R1 je vodik, metil ili etil; R3 je vodik; R5 je vodik, fluor ili klor; R9 je odabran iz skupine koju čine CH2NHR13, CH2heterocikl, CH2OR15, i CH2S(O)2R17; te Ar2 je peteročlani heteroaril koji ima jedan atom dušika u prstenu i nijedan ili jedan heteroatom prstena odabran od N i O, te je pritom navedena heteroaril-skupina nesupstituirana ili supstituirana s jednom ili dvije skupine neovisno odabrane iz skupine koju čine C1-C4alkil, C1-C4haloalkil, halogen, hidroksil, fenil, i C3-C6cikloalkil;
5. Spoj prema bilo kojem od zahtjeva 1-4 ili njegova sol, naznačen/a time, da Ar2 je skupina sljedeće formule: [image] u kojoj R22 je odabran od sljedećih C1-C4alkil, C3-C6cikloalkil, C1-C4haloalkil, fenil; i Z je O, NH ili N(C1-C4alkil).
6. Spoj prema bilo kojem od zahtjeva 1-5, naznačen time, da R22 je odabran od sljedećih C1-C4alkil, C3-C6cikloalkil, 1-metil-C3-C6cikloalkil, i C1-2haloalkil; te Z je O ili NH.
7. Spoj prema bilo kojem od zahtjeva 1-6, naznačen time, da R22 je odabran od sljedećih izopropil, tert-butil, ciklopropil, ciklobutil, 1-metil-ciklopropil, 1-trifluorometil-ciklopropil, 1-etil-ciklopropil, 1-metilciklobutil, 1-etilciklobutil, i trifluorometil; te Z je O.
8. Spoj prema bilo kojem od prethodnih zahtjeva, naznačen time, da R7 je vodik.
9. Spoj prema zahtjevu 1 ili njegova sol, naznačen/a time, da je odabran/a od sljedećih: 5-(6-benziloksimetil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina- (5-trifluorometil-2H-pirazol-3-il)-amid; 5-(6-hidroksimetil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina- (5-trifluorometil-1H-pirazol-3-il)-amid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina- (5-trifluorometil-2H-pirazol-3-il)-amid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina- (5-tert-butil-izoksazol-3-il)-amid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina- (3-tert-butil-izoksazol-5-il)-amid; 4-fluoro-5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina- (5-tert-butil-izoksazol-3-il)-amid; 4-fluoro-5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina- (5-tert-butil-1H-pirazol-3-il)-amid; 5-(6-benziloksimetil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-tert- butil-1H-pirazol-3-il)-amid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-tert- butil-2H-pirazol-3-il)-amid; 4-fluoro-5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina- (5-trifluorometil-1H-pirazol-3-il)-amid; {6-[1-(5-tert-butil-izoksazol-3-ilkarbamoil)-4-fluoro-2-metil-1H-indol-5-iloksi]- pirimidin-4-ilmetil}-metil-karbaminska kiselina-tert-butil-ester; 4-fluoro-2-metil-5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-tert-butil-izoksazol-3-il)-amid; 5-(6-hidroksimetil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-[5-(1-metil-ciklopropil)-izoksazol-3-il]-amid; 5-(6-hidroksimetil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-ciklopropil-izoksazol-3-il)-amid; 5-(6-hidroksimetil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-izopropil-1H-pirazol-3-il)-amid; 5-(6-hidroksimetil-pirimidin-4-iloksi)-4-metil-indol-1-karboksilna kiselina-(5-izopropil-1H-pirazol-3-il)-amid; 5-(6-hidroksimetil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-izopropil-izoksazol-3-il)-amid; 5-(6-hidroksimetil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-[5-(1-trifluorometil-ciklopropil)-izoksazol-3-il]-amid; 5-(6-tetrazol-1-ilmetil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-[5-(1-metil-ciklopropil)-izoksazol-3-il]-amid; 5-(6-tetrazol-2-ilmetil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-[5-(1-metil-ciklopropil)-izoksazol-3-il]-amid; 5-(6-tetrazol-2-ilmetil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-ciklopropil-izoksazol-3-il)-amid; 5-(6-tetrazol-2-ilmetil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-izopropil-izoksazol-3-il)-amid; 5-(6-tetrazol-1-ilmetil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-izopropil-izoksazol-3-il)-amid; 5-(6-tetrazol-1-ilmetil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-ciklopropil-izoksazol-3-il)-amid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-[5-(1-metil ciklopropil)-izoksazol-3-il]-amid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-ciklopropil-1H-pirazol-3-il)-amid; 5-(6-dimetilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-izopropil-1H-pirazol-3-il)-amid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(1-tert-butil-1H-pirazol-3-il)-amid; 5-(6-ciklopropilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-izopropil-1H-pirazol-3-il)-amid; 5-(6-etilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-izopropil-1H-pirazol-3-il)-amid; 5-(6-propilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-izopropil-1H-pirazol-3-il)-amid; 5-[6-(izopropilamino-metil)-pirimidin-4-iloksi]-indol-1-karboksilna kiselina-(5-izopropil-1H-pirazol-3-il)-amid; 5-(6-ciklobutilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-izopropil-1H-pirazol-3-il)-amid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-ciklopropil-1-metil-1H-pirazol-3-il)-amid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(1-metil-5-trifluorometil-1H-pirazol-3-il)-amid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-[5-metil-1-(2,2,2-trifluoro-etil)-1H-pirazol-3-il]-amid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-izopropil-izoksazol-3-il)-amid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-ciklopropil-izoksazol-3-il)-amid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-[5-(1-trifluorometil-ciklopropil)-1H-pirazol-3-il]-amid; 5-{6-[(2-metoksi-etilamino)-metil]-pirimidin-4-iloksi}-indol-1-karboksilna kiselina- (5-ciklopropil-izoksazol-3-il)-amid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(1,5-dimetil-1H-pirazol-3-il)-amid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-[5-(4-metil-tetrahidro-piran-4-il)-izoksazol-3-il]-amid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-[5-(1-metil-ciklopropil)-1H-pirazol-3-il]-amid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(1-izopropil-5-metil-1H-pirazol-3-il)-amid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-[5-(1-trifluorometil-ciklopropil)-izoksazol-3-il]-amid; 5-(6-aminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-[5-(1-trifluorometil-ciklopropil)-izoksazol-3-il]-amid; 5-(6-metilaminometil-pirimidin-4 iloksi)-indol-1-karboksilna kiselina-(5- ciklopropil-1-etil-1H-pirazol-3-il)-amid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(1,5-diciklopropil-1H-pirazol-3-il)-amid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-ciklopropil-1-izopropil-1H-pirazol-3-il)-amid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-[1-metil-5- (1-trifluorometil-ciklopropil)-1H-pirazol-3-il]-amid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-izopropil-1-metil-1H-pirazol-3-il)-amid; 5-[6-(2-metilamino-etil)-pirimidin-4-iloksi]-indol-1-karboksilna kiselina-[5-(1-metil-ciklopropil)-izoksazol-3-il]-amid; 5-[6-(2-dimetilamino-etil)-pirimidin-4-iloksi]-indol-1-karboksilna kiselina-(5-izopropil-1H-pirazol-3-il)-amid; 5-[6-(2-metilamino-etil)-pirimidin-4-iloksi]-indol-1-karboksilna kiselina-(5-izopropil-1H-pirazol-3-il)-amid; 5-{6-[(acetil-metil-amino)-metil]-pirimidin-4-iloksi}-indol-1-karboksilna kiselina- [5-(1-trifluorometil-ciklopropil)-izoksazol-3-il]-amid; 5-{6-[(acetil-metil-amino)-metil]-pirimidin-4-iloksi}-indol-1-karboksilna kiselina-(5-izopropil-izoksazol-3-il)-amid; 5-{6-[2-(acetil-metil-amino)-etil]-pirimidin-4-iloksi}-indol-1-karboksilna kiselina- (5-izopropil-1H-pirazol-3-il)-amid; 5-[6-(2-metoksi-etoksimetil)-pirimidin-4-iloksi]-indol-1-karboksilna kiselina-[5-(1-metil-ciklopropil)-izoksazol-3-il]-amid; tert-butil-(4-(1-(5-ciklopropil-1-etil-1H-pirazol-3-ilkarbamoil)-1H-indol-5-iloksi)pirimidin-2-il)metil(metil)karbamat; N-(5-ciklopropil-1-etil-1H-pirazol-3-il)-5-(2-((metilamino)metil)pirimidin-4-iloksi)- 1H-indol-1-karboksamid; 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-izopropil-1H-pirazol-3-il)-amid; ili 4-fluoro-2-metil-5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-tert-butil-izoksazol-3-il)-amid.
10. Spoj prema zahtjevu 1, naznačen time, da je to 5-(6-hidroksimetil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-[5-(1-trifluorometil-ciklopropil)-izoksazol-3-il]-amid ili njegova sol.
11. Spoj prema zahtjevu 1, naznačen time, da je to 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina-(5-ciklopropil-1-metil-1H-pirazol-3-il)-amid ili njegova sol.
12. Spoj prema zahtjevu 1, naznačen time, da je to 5-(6-metilaminometil-pirimidin-4-iloksi)-indol-1-karboksilna kiselina- (1-metil-5-trifluorometil-1H-pirazol-3-il)-amid ili njegova sol.
13. Farmaceutski sastav, naznačen time, da obuhvaća najmanje jedan spoj prema bilo kojem od zahtjeva 1-12 i najmanje jedan nosač.
14. Kombinacija, posebno farmaceutska kombinacija, naznačena time, da obuhvaća terapeutski učinkovitu količinu spoja prema bilo kojem od zahtjeva 1-12 te jedno ili više dodatnih terapeutski djelotvornih sredstava.
15. Spoj prema bilo kojem od zahtjeva 1-12, ili njegova sol, naznačen/a time, da, da se upotrebljava kao lijek.
16. Spoj prema bilo kojem od zahtjeva 1-12, ili njegova sol, naznačen/a time, da, da se upotrebljava u liječenju bolesti ovisnih o VEGF-R-receptoru, koje su odabrane od sljedećih: vlažna ili suha makularna degeneracija vezana za dob, geografska atrofija, centralna serozna retinopatija, cistoidni makularni edem, dijabetska retinopatija, proliferativna dijabetska retinopatija, dijabetski makularni edem, rubeosis iridis, retinopatija kod nedonoščadi, okluzije centralne i sporedne retinske vene, upalna/infektivna retinska neovaskularizacija/edem, retinoblastom, melanom, očni tumori, odvajanje retine, miopijska neovaskularizacija, angioidne brazde, Ealsova bolest, ishemijska retinopatija, koroidna ruptura, nošenje kontaktnih leća, suhe oči, blefaritis, distrofije rožnice, ozljeda i prethodne operacije na rožnici, opekotine rožnice, odbacivanje usatka rožnice, imunološka bolest rožnice, i degenerativne bolesti rožnice.
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US20120245187A1 (en) 2012-09-27
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