DK3074400T3 - Octahydro-cyclobuta[1,2-c;3,4-c']dipyrrol derivater som autotaxin inhibitorer - Google Patents

Octahydro-cyclobuta[1,2-c;3,4-c']dipyrrol derivater som autotaxin inhibitorer Download PDF

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DK3074400T3
DK3074400T3 DK14805527.0T DK14805527T DK3074400T3 DK 3074400 T3 DK3074400 T3 DK 3074400T3 DK 14805527 T DK14805527 T DK 14805527T DK 3074400 T3 DK3074400 T3 DK 3074400T3
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carbonyl
cyclobuta
octahydro
substituted
methanone
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Daniel Hunziker
Giorgio Patrick Di
Markus Rudolph
Patrizio Mattei
Lisha Wang
Jérôme Hert
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Hoffmann La Roche
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Claims (15)

1. Forbindelser med formlen (I)
hvor R1 er substitueret quinolinyl, substitueret 1,2,3,4-tetrahydroquinolinyl, substitueret isoquinolinyl, substitueret 1,2,3,4-tetrahydroisoquinolinyl, substitueret 9H-carbazolyl, substitueret chromanyl, substitueret indolyl, substitueret naphthyl, substitueret oxazolyl, substitueret phenyl, substitueret phenyl-(Ci-C7)-alkyl, substitueret phenyl-(C3-C8)-cycloalkyl, substitueret phenoxy-(Ci-C7)-alkyl, substitueret phenyl-(Ci-C7)-alkoxy, substitueret phenyl-(C2-C7)-alkenyl, substitueret phenylalkynyl, substitueret pyridazinyl, substitueret pyridazinyl-(Ci-C7)-alkyl, substitueret pyridazinyl-(C2-C7)-alkenyl, substitueret pyridazinlalkynyl, substitueret pyridinyl, substitueret pyridinyl-(Ci-C7)-alkyl, substitueret pyridinyl-(C2-C7)-alkenyl, substitueret pyridinylalkynyl, substitueret pyridinonyl, substitueret pyridinonyl-(Ci-C7)-alkyl, substitueret pyridinonyl-(C2-C7)-alkenyl, substitueret pyridinonylalkynyl, substitueret thiophenyl, substitueret thiophenyl-(Ci-C7)-alkyl substitueret thiophenyl-(C2-C7)-alkenyl, substitueret thiophenylalkynyl, substitueret tetralinyl eller substitueret tetralinonyl, hvor substitueret quinolinyl, substitueret 1,2,3,4-tetrahydroquinolinyl, substitueret isoquinolinyl, substitueret 1,2,3,4-tetrahydroisoquinolinyl, substitueret 9H-carbazolyl, substitueret chromanyl, substitueret indolyl, substitueret naphthyl, substitueret oxazolyl, substitueret phenyl, substitueret phenyl-(Ci-C7)-alkyl, substitueret phenyl-(C3-C8)-cycloalkyl, substitueret phenoxy-(Ci-C7)-alkyl, substitueret phenyl-(Ci-C7)-alkoxy, substitueret phenyl-(C2-C7)-alkenyl, substitueret phenylalkynyl, substitueret pyridazinyl, substitueret pyridazinyl-(Ci-C7)-alkyl, substitueret pyridazinyl-(C2-C7)-alkenyl, substitueret pyridazinylalkynyl, substitueret pyridinyl, substitueret pyridinyl-(Ci-C7)-alkyl, substitueret pyridinyl-(C2-C7)-alkenyl, substitueret pyridinylalkynyl, substitueret pyridinonyl, substitueret pyridinonyl-(Ci-C7)-alkyl, substitueret pyridinonyl-(C2-C7)-alkenyl, substitueret pyridinonylalkynyl, substituerett hiophenyl, substitueret thiophenyl-(Ci-C7)-alkyl, substitueret thiophenyl-(C2-C7)-alkenyl, substitueret thiophenylalkynyl, substitueret tetralinyl og substitueret tetralinonyl er substitueret med R6, R7 og R8 Y er -C(O)- eller -S(0)2-; R2 er substitueret pyridinyl, substitueret phenyl eller er valgt blandt ringsystemerne A, B og C, hvor substitueret pyridinyl og substitueret phenyl er substitueret med én substitueret aminosulfonyl, hvor substitueret aminosulfonyl er substitueret på nitrogenatomet med en eller to substituenter, der er uafhængigt valgt blandt H, (Ci-C7)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(Ci-C7)-alkyl, hydroxy-(Ci-C7)-alkyl og (Ci-C7)-alkoxy-(Ci-C7)-alkyl;
R3, R4 og R5 er uafhængigt valgt blandt H, (Ci-C7)-alkyl, halogen, halogen-(Ci-C7)-alkyl og (Ci-C7)-alkoxy; R6, R7 og R8 er uafhængigt valgt blandt H, halogen, cyano, cyano-(Ci-C7)-alkyl, (Ci-C7)-alkyl, hydroxy-(Ci-C7)-alkyl, halogenalkyl, hydroxyhalogen-(Ci-C7)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(Ci-C7)-alkyl, (C3-C8)-cycloalkyl-(Ci-C7)-alkoxy, (C3-C8)-cycloalkoxy, (C3-C8)-cycloalkoxy-(Ci-C7)-alkyl, (C3-C8)-cycloalkyl-(Ci-C7)-alkoxy-(Ci-C7)-alkyl, (Ci-C7)-alkoxy, (Ci-C7)-alkoxy-(Ci-C7)-alkyl, halogen-(Ci-C7)-alkoxy, (Ci-C7)-alkoxyhalogen-(Ci-C7)-alkyl, (Ci-C7)-alkoxy-(Ci-C7)-alkoxy, (Ci-C7)-alkoxy-(Ci-C7)-alkoxy-(Ci-C7)-alkyl, (Ci-C7)-alkylsulfonyl, furanyl, tetrahydropyranyl, phenyl, substitueret phenyl, phenyl-(Ci-C7)-alkoxy, substitueret phenyl-(Ci-C7)-alkoxy, pyridinyl, substitueret pyridinyl, pyrrolyl, substitueret pyrrolyl, pyrrolydinyl og substitueret pyrrolydinyl, hvor substitueret phenyl, substitueret phenylalkoxy, substitueret pyridinyl, substitueret pyrrolyl og substitueret pyrrolydinyl er substitueret med et til tre halogenatomer; eller farmaceutisk acceptable salte.
2. Forbindelse ifølge krav 1, hvor R1 er substitueret quinolinyl, substitueret 1,2,3,4-tetrahydroquinolinyl, substitueret isoquinolinyl, substitueret 1,2,3,4-tetrahydroisoquinolinyl, substitueret 9H-carbazolyl, substitueret chromanyl, substitueret indolyl, substitueret naphthyl, substitueret oxazolyl, substitueret phenyl, substitueret phenyl(Ci-C7)-alkyl, substitueret phenoxy-(Ci-C7)-alkyl, substitueret phenyl-(Ci-C7)-alkoxy, substitueret phenyl-(C2-C7)-alkenyl, substitueret pyridazinyl, substitueret pyridinyl, substitueret pyridinonyl, substitueret tetralinyl eller substitueret tetralinonyl, hvor substitueret quinolinyl, substitueret 1,2,3,4-tetrahydroquinolinyl, substitueret isoquinolinyl, substitueret 1,2,3,4-tetrahydroisoquinolinyl, substitueret 9H-carbazolyl, substitueret chromanyl, substitueret indolyl, substitueret naphthyl, substitueret oxazolyl, substitueret phenyl, substitueret phenyl-(Ci-C7)-alkyl, substitueret phenoxy-(Ci-C7)-alkyl, substitueret phenyl-(Ci-C7)-alkoxy, substitueret phenyl-(C2-C7)-alkenyl, substitueret pyridazinyl, substitueret pyridinyl, substitueret pyridinonyl, substitueret tetralinyl og substitueret tetralinonyl er substitueret med R6, R7 og R8.
3. Forbindelse ifølge et hvilket som helst af kravene 1 til 2, hvor R2 er valgt blandt ringsystemerne A og C.
4. Forbindelse ifølge et hvilket som helst af kravene 1 til 3, hvor R2 er ringsystemet A.
5. Forbindelse ifølge et hvilket som helst af kravene 1 til 4, hvor Y er -C(O)-.
6. Forbindelse ifølge et hvilket som helst af kravene 1 til 5, hvor R3, R4 og R5 er uafhængigt valgt blandt Fl og halogen.
7. Forbindelse ifølge et hvilket som helst af kravene 1 til 6, hvor R6 er H, halogen, cyano, cyano(Ci-C7)-alkyl, (Ci-C7)-alkyl, halogen-(Ci-C7)-alkyl, (C3-Cs)-cycloalkyl-(Ci-C7)-alkoxy, (Ci-C7)-alkoxy, (Ci-C7)-alkoxy-(Ci-C7)-alkyl, halogen-(Ci-C7)-alkoxy, (Ci-C7)-alkoxy-(Ci-C7)-alkoxy, phenyl, phenyl-(Ci-C7)-alkoxy eller phenyl substitueret med et til tre halogenatomer.
8. Forbindelse ifølge et hvilket som helst af kravene 1 til 7, hvor R7 er H, halogen, (Ci-C7)-alkyl, (C3-C8)-cycloalkyl, (Ci-C7)-alkoxy, halogen-(Ci-C7)-alkoxy, (Ci-C7)-alkylsulfonyl, furanyl eller tetrahydropyranyl.
9. Forbindelse ifølge et hvilket som helst af kravene 1 til 8, hvor R8 er Fl eller (Ci-C7)-alkyl.
10. Forbindelse ifølge et hvilket som helst af kravene 1 til 9, der er valgt blandt [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]-(6-chlor-naphthalen-2-yl)-methanon; l-[(3aS,3bR,6aS,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-3-(4-trifluormethoxy-phenyl)-propan-l-on; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(4'-fluor-biphenyl-4-yl)-methanon; (E)-l-[(3aS,3bR,6aS,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro- cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]-3-(4-trifluormethoxy-phenyl)-propenon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(6-brom-naphthalen-2-yl)-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(6-methoxy-naphthalen-2-yl)-methanon; (E)-l-[(3aS,3bS,6aR,6bR)-5-((R)-4,5,6,7-tetrahydro-lH-benzotriazol-5- carbonyl)octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]-3-(4-trifluormethoxy-phenyl)- propenon; 6-[(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-carbonyl]-naphthalen-2-carbonitril l-[(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-2-(4-trifluormethoxy-phenoxy)-ethanon; l-[(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-2-(2-isopropyl-phenoxy)-ethanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(5-trifluormethoxy-lH-indol-2-yl)-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(6-trifluormethoxy-lH-indol-2-yl)-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-naphthalen-2-yl-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(6-methyl-naphthalen-2-yl)-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(7-methyl-naphthalen-2-yl)-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(6-phenyl-naphthalen-2-yl)-methanon; (6-brom-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-lH- benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(4'-chlor-biphenyl-4-yl)-methanon; (4'-chlor-biphenyl-4-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-lH- benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]-methanon; [(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-lH-benzotriazol-5-carbonyl)- octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]-(5-trifluormethoxy-lH-indol-2-yl)- methanon; [(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-lH-benzotriazol-5-carbonyl)- octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]-(6-trifluormethoxy-lH-indol-2-yl)- methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(3-methoxy-naphthalen-2-yl)-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(l-methoxy-naphthalen-2-yl)-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(lH-indol-2-yl)-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(l-methyl-lH-indol-2-yl)-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(4-cyclopropylmethoxy-naphthalen-2-yl)-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(4-methoxy-naphthalen-2-yl)-methanon; 2-[(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-carbonyl]-lH-indol-5-carbonitril; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(3-methoxy-phenyl)-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(4-methoxy-quinolin-2-yl)-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-[2-(4-chlor-phenyl)-5-methyl-oxazol-4-yl]-methanon; [(3aS,3bR,6aS,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(l,2,3,4-tetrahydro-naphthalen-2-yl)-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(l-methyl-5-trifluormethoxy-lH-indol-2-yl)-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(6-chlor-lH-indol-2-yl)-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(6-chlor-l-methyl-lH-indol-2-yl)-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(6-methyl-lH-indol-2-yl)-methanon; {2-[(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro- cyclobuta[l,2-c;3,4-c']dipyrrol-2-carbonyl]-indol-l-yl>-acetonitril; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(l-isobutyl-lH-indol-2-yl)-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-quinolin-2-yl-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-isoquinolin-3-yl-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(lH-indol-6-yl)-methanon; 3-[(3aS,3bR,6aS,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-carbonyl]-3,4-dihydro-2H-naphthalen-l-on; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-chroman-2-yl-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(lH-indol-5-yl)-methanon; (4-methoxy-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro- lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-[6-(4-chlor-phenyl)-pyridin-3-yl]-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(l-methoxy-isoquinolin-3-yl)-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(4-methyl-quinolin-2-yl)-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(5-chlor-lH-indol-2-yl)-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-[4-(2-methoxy-ethoxy)-naphthalen-2-yl]-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(7-phenyl-naphthalen-2-yl)-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(4-ethoxy-naphthalen-2-yl)-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(4-isopropoxy-naphthalen-2-yl)-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(4-benzyloxy-lH-indol-6-yl)-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(5,6,7,8-tetrahydro-naphthalen-2-yl)-methanon; [(3aS,3bR,6aS,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(4,4-dimethyl-l,2,3,4-tetrahydro-naphthalen-2-yl)-methanon; [(3aS,3bR,6aS,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]-[l-(3-methoxy-propyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-[l-(2-methoxy-ethoxy)-isoquinolin-3-yl]-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(l-cyclopropylmethoxy-isoquinolin-3-yl)-methanon; (4-isopropoxy-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro- lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-[l-(2,2,2-trifluor-ethoxy)-isoquinolin-3-yl]-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(4-isopropoxy-lH-indol-6-yl)-methanon; 4-[(3aS,3bS,6aR,6bR)-5-(4-isopropoxy-naphthalen-2-carbonyl)-octahydro- cyclobuta[l,2-c;3,4-c']dipyrrol-2-carbonyl]-benzensulfonamid; [6-(4-chlor-phenyl)-pyridin-3-yl]-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro- lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]-methanon; (l-cyclopropylmethoxy-isoquinolin-3-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7- tetrahydro-lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2- yl]-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(4-isopropoxy-l-methyl-lH-indol-6-yl)-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(4-ethoxy-quinolin-2-yl)-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(4-isopropoxy-quinolin-2-yl)-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(6-chlor-9H-carbazol-2-yl)-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-[4-(2-methoxy-ethoxy)-quinolin-2-yl]-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(4-isopropoxy-7-trifluormethyl-quinolin-2-yl)-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(4-cyclopropylmethoxy-quinolin-2-yl)-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-[5-(4-chlor-phenyl)-pyridin-2-yl]-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(l-ethoxy-isoquinolin-3-yl)-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(l-ethyl-4-isopropoxy-lH-indol-6-yl)-methanon; 6-[(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-carbonyl]-3-(4-chlor-phenyl)-lH-pyridin-2-on; l-[(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(7-chlor-4-ethoxy-quinolin-2-yl)-methanon; (7-chlor-4-ethoxy-quinolin-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro- lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(4-isopropoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanon; (lH-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[4-(2-methoxy-ethoxy)-7- trifluormethyl-quinolin-2-carbonyl]-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl>- methanon; (lH-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-6-trifluormethyl- quinolin-2-carbonyl)-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotnazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(4-ethoxy-l-ethyl-lH-indol-5-yl)-methanon; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-[l-ethyl-4-(2,2,2-trifluor-ethoxy)-lH-indol-5-yl]-methanon; 5-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-quinolin-2-carbonyl)-octahydro- cyclobuta[l,2-c;3,4-c']dipyrrol-2-carbonyl]-pyridin-2-sulfonsyreamid; (lH-benzotnazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[4-(2,2,2-tnfluor-ethoxy)- quinolin-2-carbonyl]-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl>-methanon; (lH-benzotnazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[4-ethoxy-l-(2,2,2-tnfluor-ethyl)- lH-indol-6-carbonyl]-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl>-methanon; (lH-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(5-chlor-4-cyclopropylmethoxy- pyridin-2-carbonyl)-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]-methanon; (lH-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(5-cyclopropyl-6- cyclopropylmethoxy-pyridin-2-carbonyl)-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2- yl]-methanon; (3,4-dimethyl-phenyl)-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-5,6,7,8-tetrahydro- quinolin-2-carbonyl)-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]-methanon; (lH-benzotriazol-5-yl)-[(3aS,3bS,6aR,6bR)-5-(4'-chlor-biphenyl-3-carbonyl)- octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]-methanon; (lH-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-7-methoxy-quinolin-2- carbonyl)-octahydro-cyclobuta[l,2-c;3,4-c,]dipyrrol-2-yl]-methanon; [(3aS,3bS,6aR,6bR)-5-(4-ethoxy-6-trifluormethyl-quinolin-2-carbonyl)- octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]-(lH-[l,2,3]tnazolo[4,5-b]pyridin-5-yl)- methanon; [(3aS,3bS,6aR,6bR)-5-(l-ethoxy-isoquinolin-3-carbonyl)-octahydro- cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]-(lH-[l,2,3]triazolo[4,5-b]pyndin-5-yl)-methanon; (lH-benzotnazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(6-cyclopropylmethoxy-5- trifluormethyl-pyridin-2-carbonyl)-octahydro-cyclobuta[l,2-c;3,4-c,]dipyrrol-2-yl]- methanon; (lH-benzotriazol-5-yl)-<(3aS,3bR,6aS,6bR)-5-[5-cyclopropyl-4-(2,2,2-trifluor- ethoxy)-pyridin-2-carbonyl]-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl>-methanon; (lH-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[6-cyclopropyl-5-(2,2,2-trifluor- ethoxy)-pyridazin-3-carbonyl]-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl>- methanon]dipyrrol-2-yl>-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(6-chlor-4-ethoxy-quinolin-2-yl)-methanon; (lH-benzotnazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[6-(2,2,2-tnfluor-ethoxy)-5- trifluormethyl-pyridin-2-carbonyl]-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl>- methanon; (lH-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[6-(2,2,2-trifluor-ethoxy)-pyndin- 2- carbonyl]-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl>-methanon; (lH-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[6-(2/2/2-trifluor-ethoxy)-pyridin- 3- carbonyl]-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl>-methanon; (lH-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-brom-6-(2,2,2-trifluor-ethoxy)- pyridin-3-carbonyl]-octahydro-cyclobuta[l,2-c;3,4-c,]dipyrrol-2-yl>-methanon; (lH-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[5-(2/2/2-trifluor-ethoxy)-pyridin- 2-carbonyl]-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl>-methanon; [(3aS,3bR,6aS,6bR)-5-(6-cyclopropylmethoxy-pyridazin-3-carbonyl)-octahydro- cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]-(3,4-dimethyl-phenyl)-methanon; (lH-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-brom-2-methyl-6-(2,2,2- trifluor-ethoxy)-pyridin-3-carbonyl]-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl>- methanon; (lH-benzotnazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-cyclopropyl-6-(2,2,2-trifluor- ethoxy)-pyridin-3-carbonyl]-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl>-methanon; (lH-benzotnazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[6-(2,2,2-trifluor-ethoxy)-5- trifluormethyl-pyridin-3-carbonyl]-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl)- methanon; (lH-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-(tetrahydro-pyran-4-yl)-6- (2,2,2-trifluor-ethoxy)-pyridin-3-carbonyl]-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2- yl}-methanon; (lH-benzotriazol-5-yl)-<(3aS,3bR,6aS,6bR)-5-[4-(4-chlor-phenyl)-5-(2,2,2- trifluor-ethoxy)-pyridin-2-carbonyl]-octahydro-cyclobuta[l,2-c;3,4-c,]dipyrrol-2-yl>- methanon; (lH-benzotriazol-5-yl)-<(3aS,3bS,6aR,6bR)-5-[5-furan-2-yl-6-(2,2,2-trifluor- ethoxy)-pyridin-3-carbonyl]-octahydro-cyclobuta[l,2-c;3,4-c,]dipyrrol-2-yl>-methanon; (lH-benzotriazol-5-yl)-<(3aS,3bS,6aR,6bR)-5-[5-chlor-6-(2,2,2-trifluor-ethoxy)- pyridin-3-carbonyl]-octahydro-cyclobuta[l,2-c;3,4-c,]dipyrrol-2-yl>-methanon; [(3aS,3bR,6aS,6bR)-5-(4-ethoxy-quinolin-2-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-yl]-(4-fluor-lH-benzotriazol-5-yl)-methanon; {(3aS,3bS,6aR,6bR)-5-[5-methansulfonyl-6-(2,2,2-trifluor-ethoxy)-pyridin-3- carbonyl]-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl>-phenyl-methanon; (3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-carboxylsyre-4-trifluormethoxy-benzylester; (3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c']dipyrrol-2-carboxylsyre-3,5-dichlor-benzylester; (lH-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4'-fluor-biphenyl-4-sulfonyl)- octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]-methanon; (lH-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(6-chlor-naphthalen-2-sulfonyl)- octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]-(6-trifluormethyl-3,4-dihydro-lH-isoquinolin-2-yl)-methanon; og farmaceutisk acceptable salte deraf.
11. Forbindelse ifølge et hvilket som helst af kravene 1 til 10, der er valgt blandt (E)-l-[(3aS,3bR,6aS,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro- cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl]-3-(4-trifluormethoxy-phenyl)-propenon; (4-isopropoxy-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro- lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2-c;3,4-c,]dipyrrol-2-yl]-methanon; 4-[(3aS,3bS,6aR,6bR)-5-(4-isopropoxy-naphthalen-2-carbonyl)-octahydro- cyclobuta[l,2-c;3,4-c']dipyrrol-2-carbonyl]-benzensulfonamid; [(3aS,3bS,6aR,6bR)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c,]dipyrrol-2-yl]-(4-isopropoxy-l-methyl-lH-indol-6-yl)-methanon; [(3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2- c;3,4-c,]dipyrrol-2-yl]-[4-(2-methoxy-ethoxy)-quinolin-2-yl]-methanon; (lH-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-brom-6-(2,2,2-trifluor-ethoxy)- pyridin-3-carbonyl]-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-yl>-methanon; (3aR,3bS,6aR,6bS)-5-(lH-benzotriazol-5-carbonyl)-octahydro-cyclobuta[l,2-c;3,4-c']dipyrrol-2-carboxylsyre-4-trifluormethoxy-benzylester; og farmaceutisk acceptable salte deraf.
12. Fremgangsmåde til fremstilling af en forbindelse ifølge et hvilket som helst af kravene 1 til 11, hvilken fremgangsmåde omfatter reaktionen afen forbindelse med formlen (II) i nærvær af en forbindelse med formlen (III), hvor R1, R2, A og Y er som defineret ovenfor.
13. Forbindelse ifølge et hvilket som helst af kravene 1 til 11 til anvendelse som terapeutisk aktivt stof.
14. Farmaceutisk sammensætning, der omfatter en forbindelse ifølge et hvilket som helst af kravene 1 til 11 og en terapeutisk inert bærer.
15. Forbindelse ifølge et hvilket som helst af kravene 1 til 11 til anvendelse i behandlingen eller forebyggelsen af nyrelidelser, leverlidelser, inflammatoriske lidelser, lidelser af nervesystemet, lidelser i åndedrætssystemet, vaskulære og cardiovaskulære lidelser, fibrotiske sygdomme, cancer, okulære lidelser, stofskiftelidelser, cholestatisk og andre former for kronisk pruritus og akut og kronisk organtransplantatafstødning.
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