HRP20180029T1 - Derivati oktahidro-ciklobuta[1,2-c;3,4-c']dipirola kao inhibitori autotaksina - Google Patents

Derivati oktahidro-ciklobuta[1,2-c;3,4-c']dipirola kao inhibitori autotaksina Download PDF

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HRP20180029T1
HRP20180029T1 HRP20180029TT HRP20180029T HRP20180029T1 HR P20180029 T1 HRP20180029 T1 HR P20180029T1 HR P20180029T T HRP20180029T T HR P20180029TT HR P20180029 T HRP20180029 T HR P20180029T HR P20180029 T1 HRP20180029 T1 HR P20180029T1
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carbonyl
octahydro
cyclobuta
substituted
dipyrrol
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Patrizio Mattei
Daniel Hunziker
Patrick DI GIORGIO
Jérôme HERT
Markus Rudolph
Lisha Wang
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F. Hoffmann - La Roche Ag
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Claims (15)

1. Spojevi, naznačeni time, da imaju formulu (I) [image] u kojoj R1 je supstituirani kinolinil, supstituirani 1,2,3,4-tetrahidrokinolinil, supstituirani izokinolinil, supstituirani 1,2,3,4-tetrahidroizokinolinil, supstituirani 9H-karbazolil, supstituirani kromanil, supstituirani indolil, supstituirani naftil, supstituirani oksazolil, supstituirani fenil, supstituirani fenil-C1-C7-alkil, supstituirani fenil-C3-C8-cikloalkil, supstituirani fenoksi-C1-C7-alkil, supstituirani fenil-C1-C7-alkoksi, supstituirani fenil-C2-C7-alkenil, supstituirani fenilalkinil, supstituirani piridazinil, supstituirani piridazinil-C1-C7-alkil, supstituirani piridazinil-C2-C7-alkinil, supstituirani piridazinlalkinil, supstituirani piridinil, supstituirani piridinil-C1-C7-alkil, supstituirani piridinil-C2-C7-alkenil, supstituirani piridinilalkinil, supstituirani piridinonil, supstituirani piridinonil-C1-C7-alkil, supstituirani piridinonil-C2-C7-alkinil, supstituirani piridinonilalkinil, supstituirani tiofenil, supstituirani tiofenil-C1-C7-alkil supstituirani tiofenil-C2-C7-alkenil, supstituirani tiofenilalkinil, supstituirani tetralinil ili supstituirani tetralinonil, pri čemu su supstituirani kinolinil, supstituirani 1,2,3,4-tetrahidrokinolinil, supstituirani izokinolinil, supstituirani 1,2,3,4-tetrahidroizokinolinil, supstituirani 9H-karbazolil, supstituirani kromanil, supstituirani indolil, supstituirani naftil, supstituirani oksazolil, supstituirani fenil, supstituirani fenil-C1-C7-alkil, supstituirani fenil-C3-C8-cikloalkil, supstituirani fenoksi-C1-C7-alkil, supstituirani fenil-C1-C7-alkoksi, supstituirani fenil-C2-C7-alkenil, supstituirani fenilalkinil, supstituirani piridazinil, supstituirani piridazinil-C1-C7-alkil, supstituirani piridazinil-C2-C7-alkenil, supstituirani piridazinilalkinil, supstituirani piridinil, supstituirani piridinil-C1-C7-alkil, supstituirani piridinil-C2-C7-alkenil, supstituirani piridinilalkinil, supstituirani piridinonil, supstituirani piridinonil-C1-C7-alkil, supstituirani piridinonil-C2-C7-alkenil, supstituirani piridinonilalkinil, supstituirani tiofenil, supstituirani tiofenil-C1-C7-alkil, supstituirani tiofenil-C2-C7-alkenil, supstituirani tiofenilalkinil, supstituirani tetralinil i supstituirani tetralinonil zamijenjeni s R6, R7 i R8; Y je -C(O)- ili-S(O)2-; R2 je supstituirani piridinil, supstituirani fenil ili je odabran iz prstenastih sustava A, B i C, pri čemu su supstituirani piridinil i supstituirani fenil zamijenjeni s jednim supstituiranim aminosulfonilom, pri čemu je supstituirani aminosulfonil zamijenjen na dušikovom atomu s jednim do dva supstituenta neovisno odabrana između H, C1-C7-alkila, C3-C8-cikloalkila, C3-C8-cikloalkil-C1-C7-alkila, hidroksi-C1-C7-alkila i C1-C7-alkoksi-C1-C7-alkila; [image] R3, R4 i R5 su neovisno odabrani između H, C1-C7-alkila, halogena, halo-C1-C7-alkila i C1-C7-alkoksi; R6, R7 i R8 su neovisno odabrani iz skupine koju čine H, halogen, cijano, cijano-C1-C7-alkil, C1-C7-alkil, hidroksi-C1-C7-alkil, haloalkil, hidroksihalo-C1-C7-alkil, C3-C8-cikloalkil, C3-C8-cikloalkil-C1-C7-alkil, C3-C8-cikloalkil-C1-C7-alkoksi, C3-C8-cikloalkoksi, C3-C8-cikloalkoksi-C1-C7-alkil, C3-C8-cikloalkil-C1-C7-alkoksi-C1-C7-alkil, C1-C7-alkoksi, C1-C7-alkoksi-C1-C7-alkil, halo-C1-C7-alkoksi, C1-C7-alkoksihalo-C1-C7-alkil, C1-C7-alkoksi-C1-C7-alkoksi, C1-C7-alkoksi-C1-C7-alkoksi-C1-C7-alkil, C1-C7-alkilsulfonil, furanil, tetrahidropiranil, fenil, supstituirani fenil, fenil-C1-C7-alkoksi, supstituirani fenil-C1-C7-alkoksi, piridinil, supstituirani piridinil, pirolil, supstituirani pirolil, pirolidinil i supstituirani pirolidinil, pri čemu su supstituirani fenil, supstituirani fenilalkoksi, supstituirani piridinil, supstituirani pirolil i supstituirani pirolidinil zamijenjeni s jednim do tri halogena; ili farmaceutski prihvatljive soli.
2. Spoj prema zahtjevu 1, naznačen time, da R1 je supstituirani kinolinil, supstituirani 1,2,3,4-tetrahidrokinolinil, supstituirani izokinolinil, supstituirani 1,2,3,4-tetrahidroizokinolinil, supstituirani 9H-karbazolil, supstituirani kromanil, supstituirani indolil, supstituirani naftil, supstituirani oksazolil, supstituirani fenil, supstituirani fenil-C1-C7-alkil, supstituirani fenoksi-C1-C7-alkil, supstituirani fenil-C1-C7-alkoksi, supstituirani fenil-C2-C7-alkenil, supstituirani piridazinil, supstituirani piridinil, supstituirani piridinonil, supstituirani tetralinil ili supstituirani tetralinonil, pri čemu su supstituirani kinolinil, supstituirani 1,2,3,4-tetrahidrokinolinil, supstituirani izokinolinil, supstituirani 1,2,3,4-tetrahidroizokinolinil, supstituirani 9H-karbazolil, supstituirani kromanil, supstituirani indolil, supstituirani naftil, supstituirani oksazolil, supstituirani fenil, supstituirani fenil-C1-C7-alkil, supstituirani fenoksi-C1-C7-alkil, supstituirani fenil-C1-C7-alkoksi, supstituirani fenil-C2-C7-alkenil, supstituirani piridazinil, supstituirani piridinil, supstituirani piridinonil, supstituirani tetralinil i supstituirani tetralinonil zamijenjeni s R6, R7 i R8.
3. Spoj prema bilo kojem od zahtjeva 1 do 2, naznačen time, da je R2 odabran iz prstenastih sustava A i C.
4. Spoj prema bilo kojem od zahtjeva 1 do 3, naznačen time, da R2 predstavlja prstenasti sustav A.
5. Spoj prema bilo kojem od zahtjeva 1 do 4, naznačen time, da Y je -C(O)-.
6. Spoj prema bilo kojem od zahtjeva 1 do 5, naznačen time, da su R3, R4 i R5 neovisno odabrani od H i halogena.
7. Spoj prema bilo kojem od zahtjeva 1 do 6, naznačen time, da R6 je H, halogen, cijano, cijano-C1-C7-alkil, C1-C7-alkil, halo-C1-C7-alkil, C3-C8-cikloalkil-C1-C7-alkoksi, C1-C7-alkoksi, C1-C7-alkoksi-C1-C7-alkil, halo-C1-C7-alkoksi, C1-C7-alkoksi-C1-C7-alkoksi, fenil, fenil-C1-C7-alkoksi ili fenil zamijenjen s jednim do tri halogena.
8. Spoj prema bilo kojem od zahtjeva 1 do 7, naznačen time, da R7 je H, halogen, C1-C7-alkil, C3-C8-cikloalkil, C1-C7-alkoksi, halo-C1-C7-alkoksi, C1-C7-alkilsulfonil, furanil ili tetrahidropiranil.
9. Spoj prema bilo kojem od zahtjeva 1 do 8, naznačen time, da R8 je H ili C1-C7-alkil.
10. Spoj prema bilo kojem od zahtjeva 1 do 9, naznačen time, da je odabran iz skupine koju čine: [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(6-kloro-naftalen-2-il)-metanon; 1-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-3-(4-trifluorometoksi-fenil)-propan-1-on; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(4'-fluoro-bifenil-4-il)-metanon; (E)-1-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-3-(4-trifluorometoksi-fenil)-propenon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(6-bromo-naftalen-2-il)-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(6-metoksi-naftalen-2-il)-metanon; (E)-1-[(3aS,3bS,6aR,6bR)-5-((R)-4,5,6,7-tetrahidro-1H-benzotriazol-5-karbonil)oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-3-(4-trifluorometoksi-fenil)-propenon; 6-[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-karbonil]-naftalen-2-karbonitril; 1-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-2-(4-trifluorometoksi-fenoksi)-etanon; 1-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-2-(2-izopropil-fenoksi)-etanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(5-trifluorometoksi-1H-indol-2-il)-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(6-trifluorometoksi-1H-indol-2-il)-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-naftalen-2-il-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(6-metil-naftalen-2-il)-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(7-metil-naftalen-2-il)-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(6-fenil-naftalen-2-il)-metanon; (6-bromo-naftalen-2-il)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahidro-1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(4'-kloro-bifenil-4-il)-metanon; (4'-kloro-bifenil-4-il)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahidro-1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-metanon; [(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahidro-1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(5-trifluorometoksi-1H-indol-2-il)-metanon; [(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahidro-1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(6-trifluorometoksi-1H-indol-2-il)-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(3-metoksi-naftalen-2-il)-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(1-metoksi-naftalen-2-il)-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(1H-indol-2-il)-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(1-metil-1H-indol-2-il)-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(4-ciklopropilmetoksi-naftalen-2-il)-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(4-metoksi-naftalen-2-il)-metanon; 2-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-karbonil]-1H-indol-5-karbonitril; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(3-metoksi-fenil)-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(4-metoksi-kinolin-2-il)-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-[2-(4-kloro-fenil)-5-metil-oksazol-4-il]-metanon; [(3aS,3bR,6aS,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(1,2,3,4-tetrahidro-naftalen-2-il)-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(1-metil-5-trifluorometoksi-1H-indol-2-il)-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(6-kloro-1H-indol-2-il)-methanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(6-kloro-1-metil-1H-indol-2-il)-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(6-metil-1H-indol-2-il)-metanon; {2-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-karbonil]-indol-1-il}-acetonitril; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(1-izobutil-1H-indol-2-il)-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-kinolin-2-il-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-izokinolin-3-il-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(1H-indol-6-il)-metanon; 3-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-karbonil]-3,4-dihidro-2H-naftalen-1-on; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-kroman-2-il-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(1H-indol-5-il)-metanon; (4-metoksi-naftalen-2-il)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahidro-1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-[6-(4-kloro-fenil)-piridin-3-il]-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(1-metoksi-izokinolin-3-il)-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(4-metil-kinolin-2-il)-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(5-kloro-1H-indol-2-il)-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-[4-(2-metoksi-etoksi)-naftalen-2-il]-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(7-fenil-naftalen-2-il)-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(4-etoksi-naftalen-2-il)-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(4-izopropoksi-naftalen-2-il)-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(4-benziloksi-1H-indol-6-il)-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(5,6,7,8-tetrahidro-naftalen-2-il)-metanon; [(3aS,3bR,6aS,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(4,4-dimetil-1,2,3,4-tetrahidro-naftalen-2-il)-metanon; [(3aS,3bR,6aS,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-[1-(3-metoksi-propil)-1,2,3,4-tetrahidro-kinolin-3-il]-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-[1-(2-metoksi-etoksi)-izokinolin-3-il]-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(1-ciklopropilmetoksi-izokinolin-3-il)-metanon; (4-izopropoksi-naftalen-2-il)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahidro-1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-[1-(2,2,2-trifluoro-etoksi)-izokinolin-3-il]-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(4-izopropoksi-1H-indol-6-il)-metanon; 4-[(3aS,3bS,6aR,6bR)-5-(4-izopropoksi-naftalen-2-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-karbonil]-benzen-sulfonamid; [6-(4-kloro-fenil)-piridin-3-il]-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahidro-1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-metanon; (1-ciklopropilmetoksi-izokinolin-3-il)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahidro-1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(4-izopropoksi-1-metil-1H-indol-6-il)-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(4-etoksi-kinolin-2-il)-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(4-izopropoksi-kinolin-2-il)-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(6-kloro-9H-karbazol-2-il)-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-[4-(2-metoksi-etoksi)-kinolin-2-il]-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(4-izopropoksi-7-trifluorometil-kinolin-2-il)-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(4-ciklopropilmetoksi-kinolin-2-il)-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-[5-(4-kloro-fenil)-piridin-2-il]-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(1-etoksi-izokinolin-3-il)-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(1-etil-4-izopropoksi-1H-indol-6-il)-metanon; 6-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-karbonil]-3-(4-kloro-fenil)-1H-piridin-2-on; 1-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(7-kloro-4-etoksi-kinolin-2-il)-metanon; (7-kloro-4-etoksi-kinolin-2-il)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahidro-1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(4-izopropoksi-5,6,7,8-tetrahidro-naftalen-2-il)-metanon; (1H-benzotriazol-5-il)-{(3aS,3bR,6aS,6bR)-5-[4-(2-metoksi-etoksi)-7-trifluorometil-kinolin-2-karbonil]-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il}-metanon; (1H-benzotriazol-5-il)-[(3aS,3bR,6aS,6bR)-5-(4-etoksi-6-trifluorometil-kinolin-2-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(4-etoksi-1-etil-1H-indol-5-il)-metanon; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-[1-etil-4-(2,2,2-trifluoro-etoksi)-1H-indol-5-il]-metanon; 5-[(3aS,3bR,6aS,6bR)-5-(4-etoksi-kinolin-2-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-karbonil]-piridin-2-amid-sulfonska kiselina; (1H-benzotriazol-5-il)-{(3aS,3bR,6aS,6bR)-5-[4-(2,2,2-trifluoro-etoksi)-kinolin-2-karbonil]-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il}-metanon; (1H-benzotriazol-5-il)-{(3aS,3bS,6aR,6bR)-5-[4-etoksi-1-(2,2,2-trifluoro-etil)-1H-indol-6-karbonil]-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il}-metanon; (1H-benzotriazol-5-il)-[(3aS,3bR,6aS,6bR)-5-(5-kloro-4-ciklopropilmetoksi-piridin-2-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-metanon; (1H-benzotriazol-5-il)-[(3aS,3bR,6aS,6bR)-5-(5-ciklopropil-6-ciklopropilmetoksi-piridin-2-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-metanon; (3,4-dimetil-fenil)-[(3aS,3bR,6aS,6bR)-5-(4-etoksi-5,6,7,8-tetrahidro-kinolin-2-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-metanon; (1H-benzotriazol-5-il)-[(3aS,3bS,6aR,6bR)-5-(4'-kloro-bifenil-3-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-metanon; (1H-benzotriazol-5-il)-[(3aS,3bR,6aS,6bR)-5-(4-etoksi-7-metoksi-kinolin-2-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-metanon; [(3aS,3bS,6aR,6bR)-5-(4-etoksi-6-trifluorometil-kinolin-2-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(1H-[1,2,3]triazolo[4,5-b]piridin-5-il)-metanon; [(3aS,3bS,6aR,6bR)-5-(1-etoksi-izokinolin-3-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(1H-[1,2,3]triazolo[4,5-b]piridin-5-il)-metanon; (1H-benzotriazol-5-il)-[(3aS,3bR,6aS,6bR)-5-(6-ciklopropilmetoksi-5-trifluorometil-piridin-2-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-metanon; (1H-benzotriazol-5-il)-{(3aS,3bR,6a S,6bR)-5-[5-ciklopropil-4-(2,2,2-trifluoro-etoksi)-piridin-2-karbonil]-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il}-metanon; (1H-benzotriazol-5-il)-{(3aS,3bR,6aS,6bR)-5-[6-ciklopropil-5-(2,2,2-trifluoro-etoksi)-piridazin-3-karbonil]-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il}-metanon']dipirol-2-il}-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(6-kloro-4-etoksi-kinolin-2-il)-metanon; (1H-benzotriazol-5-il)-{(3aS,3bR,6a S,6bR)-5-[6-(2,2,2-trifluoro-etoksi)-5-trifluorometil-piridin-2-karbonil]-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il}-metanon; (1H-benzotriazol-5-il)-{(3aS,3bR,6aS,6bR)-5-[6-(2,2,2-trifluoro-etoksi)-piridin-2-karbonil]-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il}-metanon; (1H-benzotriazol-5-il)-{(3aS,3bS,6aR,6bR)-5-[6-(2,2,2-trifluoro-etoksi)-piridin-3-karbonil]-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il}-metanon; (1H-benzotriazol-5-il)-{(3aS,3bS,6aR,6bR)-5-[5-bromo-6-(2,2,2-trifluoro-etoksi)-piridin-3-karbonil]-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il}-metanon; (1H-benzotriazol-5-il)-{(3aS,3bR,6aS,6bR)-5-[5-(2,2,2-trifluoro-etoksi)-piridin-2-karbonil]-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il}-metanon; [(3aS,3bR,6aS,6bR)-5-(6-ciklopropilmetoksi-piridazin-3-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(3,4-dimetil-fenil)-metanon; (1H-benzotriazol-5-il)-{(3aS,3bS,6aR,6bR)-5-[5-bromo-2-metil-6-(2,2,2-trifluoro-etoksi)-piridin-3-karbonil]-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il}-metanon; (1H-benzotriazol-5-il)-{(3aS,3bS,6aR,6bR)-5-[5-ciklopropil-6-(2,2,2-trifluoro-etoksi)-piridin-3-karbonil]-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il}-metanon; (1H-benzotriazol-5-il)-{(3aS,3bS,6aR,6bR)-5-[6-(2,2,2-trifluoro-etoksi)-5-trifluorometil-piridin-3-karbonil]-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il}-metanon; (1H-benzotriazol-5-il)-{(3aS,3bS,6aR,6bR)-5-[5-(tetrahidropiran-4-il)-6-(2,2,2-trifluoro-etoksi)-piridin-3-karbonil]-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il}-metanon; (1H-benzotriazol-5-il)-{(3aS,3bR,6aS,6bR)-5-[4-(4-kloro-fenil)-5-(2,2,2-trifluoro-etoksi)-piridin-2-karbonil]-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il}-metanon; (1H-benzotriazol-5-il)-{(3aS,3bS,6aR,6bR)-5-[5-furan-2-il-6-(2,2,2-trifluoro-etoksi)-piridin-3-karbonil]-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il}-metanon; (1H-benzotriazol-5-il)-{(3aS,3bS,6aR,6bR)-5-[5-kloro-6-(2,2,2-trifluoro-etoksi)-piridin-3-karbonil]-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il}-metanon; [(3aS,3bR,6aS,6bR)-5-(4-etoksi-kinolin-2-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(4-fluoro-1H-benzotriazol-5-il)-metanon; {(3aS,3bS,6aR,6bR)-5-[5-metansulfonil-6-(2,2,2-trifluoro-etoksi)-piridin-3-karbonil]-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il}-fenil-metanon; (3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-karboksilna kiselina-4-trifluorometoksi-benzilester; (3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-karboksilna kiselina-3,5-dikloro-benzilester; (1H-benzotriazol-5-il)-[(3aS,3bR,6aS,6bR)-5-(4'-fluoro-bifenil-4-sulfonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-metanon; (1H-benzotriazol-5-il)-[(3aS,3bR,6aS,6bR)-5-(6-kloro-naftalen-2-sulfonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(6-trifluorometil-3,4-dihidro-1H-izokinolin-2-il)-metanon; i njihove farmaceutski prihvatljive soli.
11. Spoj prema bilo kojem od zahtjeva 1 do 10, naznačen time, da je odabran iz skupine koju čine: (E)-1-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-3-(4-trifluorometoksi-fenil)-propenon; (4-izopropoksi-naftalen-2-il)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahidro-1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-metanon; 4-[(3aS,3bS,6aR,6bR)-5-(4-izopropoksi-naftalen-2-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-karbonil]-benzensulfonamid; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-(4-izopropoksi-1-metil-1H-indol-6-il)-metanon; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il]-[4-(2-metoksi-etoksi)-kinolin-2-il]-metanon; (1H-benzotriazol-5-il)-{(3aS,3bS,6aR,6bR)-5-[5-bromo-6-(2,2,2-trifluoro-etoksi)-piridin-3-karbonil]-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-il}-metanon; (3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-karbonil)-oktahidro-ciklobuta[1,2-c;3,4-c']dipirol-2-karboksilna kiselina-4-trifluorometoksi-benzilester; i njihove farmaceutski prihvatljive soli.
12. Postupak za proizvodnju spoja prema bilo kojem od zahtjeva 1 do 11, naznačen time, da obuhvaća reakciju spoja formule (II) u prisutnosti spoja formule (III), pri čemu R1, R2, A i Y imaju gore definirano značenje. [image]
13. Spoj prema bilo kojem od zahtjeva 1 do 11, naznačen time, da se upotrebljava kao terapeutski djelatna tvar.
14. Farmaceutski pripravak, naznačen time, da obuhvaća spoj prema bilo kojem od zahtjeva 1 do 11 i terapeutski inertni nosač.
15. Spoj prema bilo kojem od zahtjeva 1 do 11, naznačen time, da se upotrebljava u liječenju ili profilaksi bubrežnih i jetrenih bolesnih stanja, upalnih stanja, poremećaja živčanog sustava, bolesti dišnog sustava, vaskularnih i kardiovaskularnih bolesnih stanja, fibrotičkih bolesti, raka, očnih bolesti, metaboličkih bolesti, kolestatskog i drugih oblika kroničnog pruritusa te akutnog i kroničnog odbacivanja transplantiranog organa.
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