OCTAHYDRO-CYCLOBUTA[1,2-c;3,4-c']DIPYRROL-2-YL

Abstract

The invention provides novel compounds having the general formula (I)

##STR00001##

wherein R.sup.1, Y and R.sup.2 are as described herein, compositions including the compounds and methods of using the compounds.

Claims

1. Compounds of formula (I) ##STR00137## wherein R.sup.1 is substituted quinolinyl, substituted 1,2,3,4-tetrahydroquinolinyl, substituted isoquinolinyl, substituted 1,2,3,4-tetrahydroisoquinolinyl, substituted 9H-carbazolyl, substituted chromanyl, substituted indolyl, substituted naphthyl, substituted oxazolyl, substituted phenyl, substituted phenylalkyl, substituted phenylcycloalkyl, substituted phenoxyalkyl, substituted phenylalkoxy, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridazinyl, substituted pyridazinylalkyl, substituted pyridazinylalkenyl, substituted pyridazinylalkynyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl, substituted pyridinonyl, substituted pyridinonylalkyl, substituted pyridinonylalkenyl, substituted pyridinonylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl, substituted tetralinyl or substituted tetralinonyl, wherein substituted quinolinyl, substituted 1,2,3,4-tetrahydroquinolinyl, substituted isoquinolinyl, substituted 1,2,3,4-tetrahydroisoquinolinyl, substituted 9H-carbazolyl, substituted chromanyl, substituted indolyl, substituted naphthyl, substituted oxazolyl, substituted phenyl, substituted phenylalkyl, substituted phenylcycloalkyl, substituted phenoxyalkyl, substituted phenylalkoxy, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridazinyl, substituted pyridazinylalkyl, substituted pyridazinylalkenyl, substituted pyridazinylalkynyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl, substituted pyridinonyl, substituted pyridinonylalkyl, substituted pyridinonylalkenyl, substituted pyridinonylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl, substituted tetralinyl and substituted tetralinonyl are substituted with R.sup.6, R.sup.7 and R.sup.8; Y is C(O) or S(O).sub.2; R.sup.2 is substituted pyridinyl, substituted phenyl or is selected from the ring systems A, B and C, wherein substituted pyridinyl and substituted phenyl are substituted with one substituted aminosulfonyl, wherein substituted aminosulfonyl is substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl and alkoxyalkyl; ##STR00138## R.sup.3, R.sup.4 and R.sup.5 are independently selected from H, alkyl, halogen, haloalkyl and alkoxy; R.sup.6, R.sup.7 and R.sup.8 are independently selected from H, halogen, cyano, cyanoalkyl, alkyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, alkylsulfonyl, furanyl, tetrahydropyranyl, phenyl, substituted phenyl, phenylalkoxy, substituted phenylalkoxy, pyridinyl, substituted pyridinyl, pyrrolyl, substituted pyrrolyl, pyrrolydinyl and substituted pyrrolydinyl, wherein substituted phenyl, substituted phenylalkoxy, substituted pyridinyl, substituted pyrrolyl and substituted pyrrolydinyl are substituted with one to three halogen; or pharmaceutically acceptable salts.

2. A compound according to claim 1, wherein R.sup.1 is substituted quinolinyl, substituted 1,2,3,4-tetrahydroquinolinyl, substituted isoquinolinyl, substituted 1,2,3,4-tetrahydroisoquinolinyl, substituted 9H-carbazolyl, substituted chromanyl, substituted indolyl, substituted naphthyl, substituted oxazolyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylalkoxy, substituted phenylalkenyl, substituted pyridazinyl, substituted pyridinyl, substituted pyridinonyl, substituted tetralinyl or substituted tetralinonyl, wherein substituted quinolinyl, substituted 1,2,3,4-tetrahydroquinolinyl, substituted isoquinolinyl, substituted 1,2,3,4-tetrahydroisoquinolinyl, substituted 9H-carbazolyl, substituted chromanyl, substituted indolyl, substituted naphthyl, substituted oxazolyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylalkoxy, substituted phenylalkenyl, substituted pyridazinyl, substituted pyridinyl, substituted pyridinonyl, substituted tetralinyl and substituted tetralinonyl are substituted with R.sup.6, R.sup.7 and R.sup.8.

3. A compound according to claim 1 or 2, wherein R.sup.1 is substituted quinolinyl, substituted indolyl, substituted naphthyl, substituted phenylalkoxy, substituted phenylalkenyl or substituted pyridinyl, wherein substituted quinolinyl, substituted indolyl, substituted naphthyl, substituted phenylalkoxy, substituted phenylalkenyl and substituted pyridinyl are substituted with R.sup.6, R.sup.7 and R.sup.8.

4. A compound according to any one of claim 1 to 3, wherein R.sup.1 is substituted quinolinyl, substituted indolyl, substituted naphthyl or substituted pyridinyl, wherein substituted quinolinyl, substituted indolyl, substituted naphthyl and substituted pyridinyl are substituted with R.sup.6, R.sup.7 and R.sup.8.

5. A compound according to any one of claim 1 to 4, wherein R.sup.2 is selected from the ring systems A and C.

6. A compound according to any one of claim 1 to 5, wherein R.sup.2 is the ring system A.

7. A compound according to any one of claim 1 to 6, wherein Y is C(O).

8. A compound according to any one of claim 1 to 7, wherein R.sup.3, R.sup.4 and R.sup.5 are independently selected from H and halogen.

9. A compound according to any one of claim 1 to 8, wherein R.sup.3, R.sup.4 and R.sup.5 are H.

10. A compound according to any one of claim 1 to 9, wherein R.sup.6 is H, halogen, cyano, cyanoalkyl, alkyl, haloalkyl, cycloalkylalkoxy, alkoxy, alkoxyalkyl, haloalkoxy, alkoxyalkoxy, phenyl, phenylalkoxy or phenyl substituted with one to three halogen.

11. A compound according to anyone of claim 1 to 10, wherein R.sup.6 is alkoxy, haloalkoxy or alkoxyalkoxy.

12. A compound according to any one of claim 1 to 11, wherein R.sup.7 is H, halogen, alkyl, cycloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, furanyl or tetrahydropyranyl.

13. A compound according to any one of claim 1 to 12, wherein R.sup.7 is H or halogen.

14. A compound according to any one of claim 1 to 13, wherein R.sup.8 is H or alkyl.

15. A compound according to any one of claim 1 to 14, wherein R.sup.8 is H.

16. A compound according to any one of claims 1 to 15, selected from [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(6-chloro-naphthalen-2-yl)-methanone; 1-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-propan-1-one; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(4-fluoro-biphenyl-4-yl)-methanone; (E)-1-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-propenone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(6-bromo-naphthalen-2-yl)-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(6-methoxy-naphthalen-2-yl)-methanone; (E)-1-[(3aS,3bS,6aR,6bR)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-propenone; 6-[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrole-2-carbonyl]-naphthalene-2-carbonitrile; 1-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-2-(4-trifluoromethoxy-phenoxy)-ethanone; 1-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-2-(2-isopropyl-phenoxy)-ethanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(5-trifluoromethoxy-1H-indol-2-yl)-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(6-trifluoromethoxy-1H-indol-2-yl)-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-naphthalen-2-yl-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(6-methyl-naphthalen-2-yl)-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(7-methyl-naphthalen-2-yl)-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(6-phenyl-naphthalen-2-yl)-methanone; (6-bromo-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(4-chloro-biphenyl-4-yl)-methanone; (4-chloro-biphenyl-4-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-methanone; [(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(5-trifluoromethoxy-1H-indol-2-yl)-methanone; [(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(6-trifluoromethoxy-1H-indol-2-yl)-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(3-methoxy-naphthalen-2-yl)-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(1-methoxy-naphthalen-2-yl)-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(1H-indol-2-yl)-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(1-methyl-1H-indol-2-yl)-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(4-cyclopropylmethoxy-naphthalen-2-yl)-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(4-methoxy-naphthalen-2-yl)-methanone; 2-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrole-2-carbonyl]-1H-indole-5-carbonitrile; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(3-methoxy-phenyl)-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(4-methoxy-quinolin-2-yl)-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-methanone; [(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(1,2,3,4-tetrahydro-naphthalen-2-yl)-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(1-methyl-5-trifluoromethoxy-1H-indol-2-yl)-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(6-chloro-1H-indol-2-yl)-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(6-chloro-1-methyl-1H-indol-2-yl)-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(6-methyl-1H-indol-2-yl)-methanone; {2-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrole-2-carbonyl]-indol-1-yl}-acetonitrile; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(1-isobutyl-1H-indol-2-yl)-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-quinolin-2-yl-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-isoquinolin-3-yl-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(1H-indol-6-yl)-methanone; 3-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrole-2-carbonyl]-3,4-dihydro-2H-naphthalen-1-one; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-chroman-2-yl-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(1H-indol-5-yl)-methanone; (4-methoxy-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-[6-(4-chloro-phenyl)-pyridin-3-yl]-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(1-methoxy-isoquinolin-3-yl)-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(4-methyl-quinolin-2-yl)-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(5-chloro-1H-indol-2-yl)-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-[4-(2-methoxy-ethoxy)-naphthalen-2-yl]-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(7-phenyl-naphthalen-2-yl)-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(4-ethoxy-naphthalen-2-yl)-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(4-isopropoxy-naphthalen-2-yl)-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(4-benzyloxy-1H-indol-6-yl)-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(5,6,7,8-tetrahydro-naphthalen-2-yl)-methanone; [(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-methanone; [(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-[1-(3-methoxy-propyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-[1-(2-methoxy-ethoxy)-isoquinolin-3-yl]-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(1-cyclopropylmethoxy-isoquinolin-3-yl)-methanone; (4-isopropoxy-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-[1-(2,2,2-trifluoro-ethoxy)-isoquinolin-3-yl]-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(4-isopropoxy-1H-indol-6-yl)-methanone; 4-[(3aS,3bS,6aR,6bR)-5-(4-isopropoxy-naphthalene-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrole-2-carbonyl]-benzenesulfonamide; [6-(4-chloro-phenyl)-pyridin-3-yl]-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-methanone; (1-cyclopropylmethoxy-isoquinolin-3-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(4-isopropoxy-1-methyl-1H-indol-6-yl)-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(4-ethoxy-quinolin-2-yl)-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(4-isopropoxy-quinolin-2-yl)-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(6-chloro-9H-carbazol-2-yl)-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-[4-(2-methoxy-ethoxy)-quinolin-2-yl]-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(4-isopropoxy-7-trifluoromethyl-quinolin-2-yl)-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(4-cyclopropylmethoxy-quinolin-2-yl)-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-[5-(4-chloro-phenyl)-pyridin-2-yl]-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(1-ethoxy-isoquinolin-3-yl)-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(1-ethyl-4-isopropoxy-1H-indol-6-yl)-methanone; 6-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrole-2-carbonyl]-3-(4-chloro-phenyl)-1H-pyridin-2-one; 1-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(7-chloro-4-ethoxy-quinolin-2-yl)-methanone; (7-chloro-4-ethoxy-quinolin-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(4-isopropoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanone; (1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[4-(2-methoxy-ethoxy)-7-trifluoromethyl-quinoline-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl}-methanone; (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-6-trifluoromethyl-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(4-ethoxy-1-ethyl-1H-indol-5-yl)-methanone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-[1-ethyl-4-(2,2,2-trifluoro-ethoxy)-1H-indol-5-yl]-methanone; 5-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrole-2-carbonyl]-pyridine-2-sulfonic acid amide; (1H-benzotriazol-5-yl)-{(3aS,3bR,6a S,6bR)-5-[4-(2,2,2-trifluoro-ethoxy)-quinoline-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl}-methanone; (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[4-ethoxy-1-(2,2,2-trifluoro-ethyl)-1H-indole-6-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl}-methanone; (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(5-chloro-4-cyclopropylmethoxy-pyridine-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-methanone; (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-methanone; (3,4-dimethyl-phenyl)-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-5,6,7,8-tetrahydro-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-methanone; (1H-benzotriazol-5-yl)-[(3aS,3bS,6aR,6bR)-5-(4-chloro-biphenyl-3-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-methanone; (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-7-methoxy-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-methanone; [(3aS,3bS,6aR,6bR)-5-(4-Ethoxy-6-trifluoromethyl-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-methanone; [(3aS,3bS,6aR,6bR)-5-(1-ethoxy-isoquinoline-3-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-methanone; (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-methanone; (1H-benzotriazol-5-yl)-{(3aS,3bR,6a S,6bR)-5-[5-cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl}-methanone; (1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[6-cyclopropyl-5-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl}-methanone]dipyrrol-2-yl}-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(6-chloro-4-ethoxy-quinolin-2-yl)-methanone; (1H-benzotriazol-5-yl)-{(3aS,3bR,6a S,6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-5-trifluoromethyl-pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl}-methanone; (1H-benzotriazol-5-yl)-{(3aS,3bR,6a S,6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl}-methanone; (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl}-methanone; (1H-benzotriazol-5-yl)-{(3aS,3bS,6a R,6bR)-5-[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl}-methanone; (1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl}-methanone; [(3aS,3bR,6aS,6bR)-5-(6-cyclopropylmethoxy-pyridazine-3-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(3,4-dimethyl-phenyl)-methanone; (1H-benzotriazol-5-yl)-{(3aS,3bS,6a R,6bR)-5-[5-bromo-2-methyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl}-methanone; (1H-benzotriazol-5-yl)-{(3aS,3bS,6a R,6bR)-5-[5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl}-methanone; (1H-benzotriazol-5-yl)-{(3aS,3bS,6a R,6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-5-trifluoromethyl-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl}-methanone; (1H-benzotriazol-5-yl)-{(3aS,3bS,6a R,6bR)-5-[5-(tetrahydro-pyran-4-yl)-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl}-methanone; (1H-benzotriazol-5-yl)-{(3aS,3bR,6a S,6bR)-5-[4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl}-methanone; (1H-benzotriazol-5-yl)-{(3aS,3bS,6a R,6bR)-5-[5-furan-2-yl-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl}-methanone; (1H-benzotriazol-5-yl)-{(3aS,3bS,6a R,6bR)-5-[5-chloro-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl}-methanone; [(3aS,3bR,6aS,6bR)-5-(4-ethoxy-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(4-fluoro-1H-benzotriazol-5-yl)-methanone; {(3aS,3bS,6aR,6bR)-5-[5-methanesulfonyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl}-phenyl-methanone; (3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrole-2-carboxylicacid 4-trifluoromethoxy-benzyl ester; (3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrole-2-carboxylic acid 3,5-dichloro-benzyl ester; (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4-fluoro-biphenyl-4-sulfonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-methanone; (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(6-chloro-naphthalene-2-sulfonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone; and pharmaceutically acceptable salts thereof.

17. A compound according to any one of claims 1 to 16, selected from (E)-1-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-propenone; (4-isopropoxy-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-methanone; 4-[(3aS,3bS,6aR,6bR)-5-(4-isopropoxy-naphthalene-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrole-2-carbonyl]-benzenesulfonamide; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(4-isopropoxy-1-methyl-1H-indol-6-yl)-methanone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-[4-(2-methoxy-ethoxy)-quinolin-2-yl]-methanone; (1H-benzotriazol-5-yl)-{(3aS,3bS,6a R,6bR)-5-[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl}-methanone; (3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrole-2-carboxylicacid 4-trifluoromethoxy-benzyl ester; and pharmaceutically acceptable salts thereof.

18. A process to prepare a compound according to any one of claims 1 to 17 comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III), wherein R.sup.1, R.sup.2, A and Y are as defined above. ##STR00139##

19. A compound according to any one of claims 1 to 17 for use as therapeutically active substance.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 and a therapeutically inert carrier.

21. The use of a compound according to any one of claims 1 to 17 for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection.

22. A compound according to any one of claims 1 to 17 for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection.

23. The use of a compound according to any one of claims 1 to 17 for the preparation of a medicament for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection.

24. A method for the treatment or prophylaxis a condition selected from the group consisting of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection, which method comprises administering an effective amount of a compound according to any one of claims 1 to 17.

25. A compound according to any one of claims 1 to 17, when manufactured according to a process of claim 18.

26. The invention as hereinbefore described.

Description

EXAMPLES

[0316] All examples and intermediates were prepared under nitrogen atmosphere if not specified otherwise.

Abbreviations

[0317] aq.=aqueous; CAS-RN=Chemical Abstracts Service Registry Number; e.r.=enantiomeric ratio; HPLC=high performance liquid chromatography; MS=mass spectrum; NMR=nuclear magnetic resonance spectrum; sat.=saturated

Example 1

[(3aS,3bS,6aR,6bR)-5-(1H-Benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(6-chloro-naphthalen-2-yl)-methanone

[0318] ##STR00019##

[0319] To a solution of (3aS,3bS,6aR,6bR)-decahydro-cyclobuta[1,2-c;3,4-c]dipyrrole (intermediate 1; 30 mg, 217 mol) in N,N-dimethylformamide (3.5 ml) were added N-methylmorpholine (110 mg, 1.09 mmol), 6-chloro-naphthalene-2-carboxylic acid (CAS-RN 5042-97-7; 44.9 mg, 217 mol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluoro-phosphate (82.5 mg, 217 mol). After stirring for 8 h at room temperature 1H-benzo[d][1,2,3]triazole-5-carboxylic acid (35.4 mg, 217 mol, Eq: 1.00) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluoro-phosphate (82.5 mg, 217 mol) were added, then after 16 h the reaction mixture was partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel; gradient dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (51 mg, 50%). Off-white solid, MS: 472.5 (M+H)+.

[0320] The following examples were produced in analogy to example 1, replacing 6-chloro-naphthalene-2-carboxylic acid and 1H-benzo[d][1,2,3]triazole-5-carboxylic acid by carboxylic acid 1 and carboxylic acid 2, respectively.

TABLE-US-00002 carboxylic carboxylic MS, Ex. Systematic Name acid 1 acid 2 m/e 1.001 1-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro- 4-(trifluoro- 1H-benzo[d]- 500.6 cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-propan-1-one methoxy)- [1,2,3]triazole- (M + H).sup.+ [00020] hydrocinnamic acid (CAS-RN 886499-74-7) 5-carboxylic acid 1.002 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro- 4- 1H-benzo[d]- 482.5 cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-(4-fluoro-biphenyl-4-yl)-methanone fluorobiphenyl- [1,2,3]triazole- (M + H).sup.+ [00021] 4-carboxylic acid (CAS-RN 5731- 10-2) 5-carboxylic acid 1.003 (E)-1-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro- 4-(trifluoro- 1H-benzo[d]- 498.5 cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-propenone methoxy)- [1,2,3]triazole- (M + H).sup.+ [00022] cinnamic acid (CAS-RN 199679-35-1) 5-carboxylic acid 1.004 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro- 6-bromo-2- 1H-benzo[d]- 514.8 cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-(6-bromo-naphthalen-2-yl)-methanone naphthoic acid [1,2,3]triazole- (M H).sup. [00023] (CAS-RN 5773- 80-8) 5-carboxylic acid 1.005 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro- 6-methoxy-2- 1H-benzo[d] 468.7 cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-(6-methoxy-naphthalen-2-yl)-methanone naphthoic acid [1,2,3]triazole- (M + H).sup.+ [00024] (CAS-RN 2471- 70-7) 5-carboxylic acid 1.006 (E)-1-[(3aS,3bS,6aR,6bR)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)- 4-(trifluoro- (+)-(R)- 502.7 octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)- methoxy)- 4,5,6,7- (M + H).sup.+ propenone cinnamic acid tetrahydro-1H- [00025] (CAS-RN 199679-35-1) benzo[d]- [1,2,3]triazole- 5-carboxylic acid (intermediate 11) 1.007 6-[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro- 6-cyano-2- 1H-benzo[d]- 463.5 cyclobuta[1,2-c; 3,4-c]dipyrrole-2-carbonyl]-naphthalene-2-carbonitrile naphthoic acid [1,2,3]triazole- (M + H).sup.+ [00026] (CAS-RN 5159- 60-4) 5-carboxylic acid 1.008 1-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro- 2-(4-(trifluoro- 1H-benzo[d]- 502.4 cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-2-(4-trifluoromethoxy-phenoxy)-ethanone methoxy)- [1,2,3]triazole- (M + H).sup.+ [00027] phenoxy)acetic acid (CAS-RN 72220-50-9) 5-carboxylic acid 1.009 1-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro- 2-(2-isopropyl- 1H-benzo[d]- 460.4 cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-2-(2-isopropyl-phenoxy)-ethanone phenoxy)acetic [1,2,3]triazole- (M + H).sup.+ [00028] acid (CAS-RN 25141-58-6) 5-carboxylic acid 1.010 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro- 5-(trifluoro- 1H-benzo[d]- 511.0 cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-(5-trifluoromethoxy-1H-indol- methoxy)-1H- [1,2,3]triazole- (M + H).sup.+ 2-yl)-methanone indole-2- 5-carboxylic [00029] carboxylic acid (CAS-RN 175203-84-6) acid 1.011 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro- 6-(trifluoro- 1H-benzo[d]- 511.7 cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-(6-trifluoromethoxy-1H- methoxy)-1H- [1,2,3]triazole- (M + H).sup.+ indol-2-yl)-methanone indole-2- 5-carboxylic [00030] carboxylic acid (CAS-RN 923259-70-5) acid 1.012 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro- 2-naphthoic acid 1H-benzo[d]- 438.7 cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-naphthalen-2-yl-methanone (CAS-RN 93- [1,2,3]triazole- (M + H).sup.+ [00031] 09-4) 5-carboxylic acid 1.013 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro- 6-methyl-2- 1H-benzo[d]- 452.6 cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-(6-methyl-naphthalen-2-yl)-methanone naphthoic acid [1,2,3]triazole- (M + H).sup.+ [00032] (CAS-RN 5774- 08-3) 5-carboxylic acid 1.014 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro- 7-methyl-2- 1H-benzo[d]- 452.7 cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-(7-methyl-naphthalen-2-yl)-methanone naphthoic acid [1,2,3]triazole- (M + H).sup.+ [00033] (CAS-RN 5159- 64-8) 5-carboxylic acid 1.015 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro- 6-phenyl-2- 1H-benzo[d]- 514.6 cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-(6-phenyl-naphthalen-2-yl)-methanone naphthoic acid [1,2,3]triazole- (M + H).sup.+ [00034] (CAS-RN 855207-53-3) 5-carboxylic acid 1.016 (6-bromo-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7- 6-bromo-2- (+)-(R)- 520.5 tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; naphthoic acid 4,5,6,7- (M + H).sup.+ 3,4-c]dipyrrol-2-yl]-methanone (CAS-RN 5773- tetrahydro-1H- [00035] 80-8) benzo[d]- [1,2,3]triazole- 5-carboxylic acid (intermediate 11) 1.017 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro- 4- 1H-benzo[d]- 498.6 cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-(4-chloro-biphenyl-4-yl)-methanone chlorobiphenyl- [1,2,3]triazole- (M + H).sup.+ [00036] 4-carboxylic acid (CAS-RN 5748-41-4) 5-carboxylic acid 1.018 (4-chloro-biphenyl-4-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H- 4- (+)-(R)- 502.5 benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol- chlorobiphenyl- 4,5,6,7- (M + H).sup.+ 2-yl]-methanone 4-carboxylic tetrahydro-1H- [00037] acid (CAS-RN 5748-41-4) benzo[d]- [1,2,3]triazole- 5-carboxylic acid (intermediate 11) 1.019 [(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)- 5-(trifluoro- (+)-(R)- 515.7 octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-(5-trifluoromethoxy-1H-indol-2-yl)- methoxy)-1H- 4,5,6,7- (M + H).sup.+ methanone indole-2- tetrahydro-1H- [00038] carboxylic acid (CAS-RN 175203-84-6) benzo[d]- [1,2,3]triazole- 5-carboxylic acid (intermediate 11) 1.020 [(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)- 6-(trifluoro- (+)-(R)- 515.7 octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-(6-trifluoromethoxy-1H-indol- methoxy)-1H- 4,5,6,7- (M + H).sup.+ 2-yl)-methanone indole-2- tetrahydro-1H- [00039] carboxylic acid (CAS-RN 923259-70-5) benzo[d]- [1,2,3]triazole- 5-carboxylic acid (intermediate 11) 1.021 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3-methoxy-2- 1H-benzo[d]- 468.6 3,4-c]dipyrrol-2-yl]-(3-methoxy-naphthalen-2-yl)-methanone naphthoic acid [1,2,3]triazole- (M + H).sup.+ [00040] (CAS-RN 883- 62-5) 5-carboxylic acid 1.022 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 1-methoxy-2- 1H-benzo[d]- 468.6 3,4-c]dipyrrol-2-yl]-(1-methoxy-naphthalen-2-yl)-methanone naphthoic acid [1,2,3]triazole- (M + H).sup.+ [00041] (CAS-RN 883- 21-6) 5-carboxylic acid 1.023 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 1H-indole-2- 1H-benzo[d]- 427.5 3,4-c]dipyrrol-2-yl]-(1H-indol-2-yl)-methanone carboxylic acid [1,2,3]triazole- (M + H).sup.+ [00042] (CAS-RN 1477- 50-5) 5-carboxylic acid 1.024 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 1-methyl-1H- 1H-benzo[d]- 441.5 3,4-c]dipyrrol-2-yl]-(1-methyl-1H-indol-2-yl)-methanone indole-2- [1,2,3]triazole- (M + H).sup.+ [00043] carboxylic acid (CAS-RN 16136- 58-6) 5-carboxylic acid 1.025 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 4-(cyclopropyl- 1H-benzo[d]- 508.6 3,4-c]dipyrrol-2-yl]-(4-cyclopropylmethoxy-naphthalen-2-yl)-methanone methoxy)-2- [1,2,3]triazole- (M + H).sup.+ [00044] naphthoic acid 5-carboxylic acid 1.026 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 4-methoxy-2- 1H-benzo[d]- 468.5 3,4-c]dipyrrol-2-yl]-(4-methoxy-naphthalen-2-yl)-methanone naphthoic acid [1,2,3]triazole- (M + H).sup.+ [00045] (CAS-RN 5773-93-3) 5-carboxylic acid 1.027 2-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 5-cyano-1H- 1H-benzo[d]- 452.6 3,4-c]dipyrrole-2-carbonyl]-1H-indole-5-carbonitrile indole-2- [1,2,3]triazole- (M + H).sup.+ [00046] carboxylic acid (CAS-RN 169463-44-9) 5-carboxylic acid 1.028 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3-methoxy- 1H-benzo[d]- 418.5 3,4-c]dipyrrol-2-yl]-(3-methoxy-phenyl)-methanone benzoic acid [1,2,3]triazole- (M + H).sup.+ [00047] (CAS-RN 586- 38-9) 5-carboxylic acid 1.029 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 4-methoxy-2- 1H-benzo[d]- 469.5 3,4-c]dipyrrol-2-yl]-(4-methoxy-quinolin-2-yl)-methanone quinoline- [1,2,3]triazole- (M + H).sup.+ [00048] carboxylic acid (CAS-RN 15733-83-2) 5-carboxylic acid 1.030 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 2-(4- 1H-benzo[d]- 503.6 3,4-c]dipyrrol-2-yl]-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-methanone chlorophenyl)-5- [1,2,3]triazole- (M + H).sup.+ [00049] methyl-1,3- oxazole-4- carboxylic acid (CAS-RN 2940- 23-0) 5-carboxylic acid 1.031 [(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 1,2,3,4- 1H-benzo[d]- 442.7 3,4-c]dipyrrol-2-yl]-(1,2,3,4-tetrahydro-naphthalen-2-yl)-methanone tetrahydro-2- [1,2,3]triazole- (M + H).sup.+ [00050] naphthoic acid (CAS-RN 53440-12-3) 5-carboxylic acid 1.032 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 1-methyl-5- 1H-benzo[d]- 525.7 3,4-c]dipyrrol-2-yl]-(1-methyl-5-trifluoromethoxy-1H-indol-2-yl)-methanone (trifluoro- [1,2,3]triazole- (M + H).sup.+ [00051] methoxy)-1H- indole-2- carboxylic acid (CAS-RN 1257122-42-1) 5-carboxylic acid 1.033 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 6-chloro-1H- 1H-benzo[d]- 461.6 3,4-c]dipyrrol-2-yl]-(6-chloro-1H-indol-2-yl)-methanone indole-2- [1,2,3]triazole- (M + H).sup.+ [00052] carboxylic acid (CAS-RN 16732-75-5) 5-carboxylic acid 1.034 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 6-chloro-1- 1H-benzo[d]- 475.6 3,4-c]dipyrrol-2-yl]-(6-chloro-1-methyl-1H-indol-2-yl)-methanone methyl-1H- [1,2,3]triazole- (M + H).sup.+ [00053] indole-2- carboxylic acid (CAS-RN 680569-83-9) 5-carboxylic acid 1.035 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 6-methyl-1H- 1H-benzo[d]- 441.7 c]dipyrrol-2-yl]-(6-methyl-1H-indol-2-yl)-methanone indole-2- [1,2,3]triazole- (M + H).sup.+ [00054] carboxylic acid (CAS-RN 18474-59-4) 5-carboxylic acid 1.036 {2-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 1-(cyanomethyl)- 1H-benzo[d]- 466.6 3,4-c]dipyrrole-2-carbonyl]-indol-1-yl}-acetonitrile 1H-indole-2- [1,2,3]triazole- (M + H).sup.+ [00055] carboxylic acid (CAS-RN 959089-89-5) 5-carboxylic acid 1.037 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 1-isobutyl-1H- 1H-benzo[d]- 483.7 c]dipyrrol-2-yl]-(1-isobutyl-1H-indol-2-yl)-methanone indole-2- [1,2,3]triazole- (M + H).sup.+ [00056] carboxylic acid (CAS-RN 1020986-39-3) 5-carboxylic acid 1.038 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; quinaldic acid 1H-benzo[d]- 439.5 3,4-c]dipyrrol-2-yl]-quinolin-2-yl-methanone (CAS-RN [1,2,3]triazole- (M + H).sup.+ [00057] 93-10-7) 5-carboxylic acid 1.039 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; isoquinoline-3- 1H-benzo[d]- 439.5 3,4-c]dipyrrol-2-yl]-isoquinolin-3-yl-methanone carboxylic acid [1,2,3]triazole- (M + H).sup.+ [00058] (CAS-RN 6624- 49-3) 5-carboxylic acid 1.040 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- indole-6- 1H-benzo[d]- 427.7 c]dipyrrol-2-yl]-(1H-indol-6-yl)-methanone carboxylic acid [1,2,3]triazole- (M + H).sup.+ [00059] (CAS-RN 1670- 82-2) 5-carboxylic acid 1.041 3-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 4-oxo-1,2,3,4- 1H-benzo[d]- 456.5 3,4-c]dipyrrole-2-carbonyl]-3,4-dihydro-2H-naphthalen-1-one tetrahydro- [1,2,3]triazole- (M + H).sup.+ [00060] naphthalene-2- carboxylic acid (CAS-RN 6566- 40-1) 5-carboxylic acid 1.042 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- chroman-2- 1H-benzo[d]- 444.7 c]dipyrrol-2-yl]-chroman-2-yl-methanone carboxylic acid [1,2,3]triazole- (M + H).sup.+ [00061] (CAS-RN 51939-71-0) 5-carboxylic acid 1.043 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- indole-5- 1H-benzo[d]- 427.6 c]dipyrrol-2-yl]-(1H-indol-5-yl)-methanone carboxylic acid [1,2,3]triazole- (M + H).sup.+ [00062] (CAS-RN 1670- 81-1) 5-carboxylic acid 1.044 (4-methoxy-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H- 4-methoxy-2- (+)-(R)- 472.7 benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-methanone naphthoic acid 4,5,6,7- (M + H).sup.+ [00063] (CAS-RN 5773- 93-3) tetrahydro-1H- benzo[d]- [1,2,3]triazole- 5-carboxylic acid (intermediate 11) 1.045 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 6-(4- 1H-benzo[d]- 499.4 c]dipyrrol-2-yl]-[6-(4-chloro-phenyl)-pyridin-3-yl]-methanone chlorophenyl)- [1,2,3]triazole- (M + H).sup.+ [00064] nicotinic acid (CAS-RN 31676-66-1) 5-carboxylic acid 1.046 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 1-methoxyiso- 1H-benzo[d]- 469.6 c]dipyrrol-2-yl]-(1-methoxy-isoquinolin-3-yl)-methanone quinoline-3- [1,2,3]triazole- (M + H).sup.+ [00065] carboxylic acid (CAS-RN 1094553-95-3) 5-carboxylic acid 1.047 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 4- 1H-benzo[d]- 453.5 c]dipyrrol-2-yl]-(4-methyl-quinolin-2-yl)-methanone methylquinoline- [1,2,3]triazole- (M + H).sup.+ [00066] 2-carboxylic acid (CAS-RN 40609- 76-5) 5-carboxylic acid 1.048 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 5-chloroindole-2- 1H-benzo[d]- 461.4 3,4-c]dipyrrol-2-yl]-(5-chloro-1H-indol-2-yl)-methanone carboxylic acid [1,2,3]triazole- (M + H).sup.+ [00067] (CAS-RN 10517- 21-2) 5-carboxylic acid 1.049 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 4-(2- 1H-benzo[d]- 512.4 c]dipyrrol-2-yl]-[4-(2-methoxy-ethoxy)-naphthalen-2-yl]-methanone methoxyethoxy)- [1,2,3]triazole- (M + H).sup.+ [00068] 2-naphthoic acid 5-carboxylic acid 1.050 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 7-phenyl- 1H-benzo[d]- 514.6 c]dipyrrol-2-yl]-(7-phenyl-naphthalen-2-yl)-methanone naphthalene-2- [1,2,3]triazole- (M + H).sup.+ [00069] carboxylic acid (CAS-RN 229006-56-8) 5-carboxylic acid 1.051 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 4-ethoxy- 1H-benzo[d]- 482.6 c]dipyrrol-2-yl]-(4-ethoxy-naphthalen-2-yl)-methanone naphthalene-2- [1,2,3]triazole- (M + H).sup.+ [00070] carboxylic acid (CAS-RN 1368864-77-0) 5-carboxylic acid 1.052 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 4-isopropoxy- 1H-benzo[d]- 496.5 c]dipyrrol-2-yl]-(4-isopropoxy-naphthalen-2-yl)-methanone naphthalene-2- [1,2,3]triazole- (M + H).sup.+ [00071] carboxylic acid (CAS-RN 1368865-02-4) 5-carboxylic acid 1.053 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 4-benzyloxy-1H- 1H-benzo[d]- 533.4 c]dipyrrol-2-yl]-(4-benzyloxy-1H-indol-6-yl)-methanone indole-6- [1,2,3]triazole- (M + H).sup.+ [00072] carboxylic acid (CAS-RN 105265-24-5) 5-carboxylic acid 1.054 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 5,6,7,8- 1H-benzo[d]- 442.5 c]dipyrrol-2-yl]-(5,6,7,8-tetrahydro-naphthalen-2-yl)-methanone tetrahydro-2- [1,2,3]triazole- (M + H).sup.+ [00073] naphthoic acid (CAS-RN 1131- 63-1) 5-carboxylic acid 1.055 [(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 4,4-dimethyl- 1H-benzo[d]- 470.7 c]dipyrrol-2-yl]-(4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-methanone 1,2,3,4- [1,2,3]triazole- (M + H).sup.+ [00074] tetrahydro- naphthalene-2- carboxylic acid (CAS-RN 23204-02-6) 5-carboxylic acid 1.056 [(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 1-(3- 1H-benzo[d]- 515.5 c]dipyrrol-2-yl]-[1-(3-methoxy-propyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-methanone methoxypropyl)- [1,2,3]triazole- (M + H).sup.+ [00075] 1,2,3,4- tetrahydro- quinoline-3- carboxylic acid (intermediate 6) 5-carboxylic acid 1.057 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 1-(2- 1H-benzo[d]- 513.5 c]dipyrrol-2-yl]-[1-(2-methoxy-ethoxy)-isoquinolin-3-yl]-methanone methoxyethoxy)- [1,2,3]triazole- (M + H).sup.+ [00076] isoquinoline-3- carboxylic acid (CAS-RN 1094758-42-5) 5-carboxylic acid 1.058 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 1-(cyclopropyl- 1H-benzo[d]- 509.5 c]dipyrrol-2-yl]-(1-cyclopropylmethoxy-isoquinolin-3-yl)-methanone methoxy)iso- [1,2,3]triazole- (M + H).sup.+ [00077] quinoline-3- carboxylic acid (CAS-RN 1097166-34-1) 5-carboxylic acid 1.059 (4-isopropoxy-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H- 4-isopropoxy- (+)-(R)- 500.7 benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-methanone naphthalene-2- 4,5,6,7- (M + H).sup.+ [00078] carboxylic acid (CAS-RN 1368865-02-4) tetrahydro-1H- benzo[d]- [1,2,3]triazole- 5-carboxylic acid (intermediate 11) 1.060 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 1-(2,2,2- 1H-benzo[d]- 537.6 c]dipyrrol-2-yl]-[1-(2,2,2-trifluoro-ethoxy)-isoquinolin-3-yl]-methanone trifluoroethoxy)- [1,2,3]triazole- (M + H).sup.+ [00079] isoquinoline-3- carboxylic acid (CAS-RN 1096982-79-4) 5-carboxylic acid 1.061 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 4-isopropoxy- 1H-benzo[d]- 485.4 c]dipyrrol-2-yl]-(4-isopropoxy-1H-indol-6-yl)-methanone 1H-indole-6- [1,2,3]triazole- (M + H).sup.+ [00080] carboxylic acid (intermediate 3.3) 5-carboxylic acid 1.062 4-[(3aS,3bS,6aR,6bR)-5-(4-isopropoxy-naphthalene-2-carbonyl)-octahydro- 4-isopropoxy- 4-sulfamoyl- 534.6 cyclobuta[1,2-c; 3,4-c]dipyrrole-2-carbonyl]benzenesulfonamide naphthalene-2- benzoic acid (M + H).sup.+ [00081] carboxylic acid (CAS-RN 1368865-02-4) 1.063 [6-(4-chloro-phenyl)-pyridin-3-yl]-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H- 6-(4- (+)-(R)- 503.4 benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-methanone chlorophenyl)- 4,5,6,7- (M + H).sup.+ [00082] nicotinic acid (CAS-RN 31676-66-1) tetrahydro-1H- benzo[d]- [1,2,3]triazole- 5-carboxylic acid (intermediate 11) 1.064 (1-cyclopropylmethoxy-isoquinolin-3-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7- 1-(cyclopropyl- (+)-(R)- 513.7 tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol- methoxy)iso- 4,5,6,7- (M + H).sup.+ 2-yl]-methanone quinoline-3- tetrahydro-1H- [00083] carboxylic acid (CAS-RN 1097166-34-1) benzo[d]- [1,2,3]triazole- 5-carboxylic acid (intermediate 11) 1.065 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 4-isopropoxy-1- 1H-benzo[d]- 499.7 c]dipyrrol-2-yl]-(4-isopropoxy-1-methyl-1H-indol-6-yl)-methanone methyl-1H- [1,2,3]triazole- (M + H).sup.+ [00084] indole-6- carboxylic acid (intermediate 10) 5-carboxylic acid 1.066 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 4- 1H-benzo[d]- 483.6 c]dipyrrol-2-yl]-(4-ethoxy-quinolin-2-yl)-methanone ethoxyquinoline- [1,2,3]triazole- (M + H).sup.+ [00085] 2-carboxylic acid (CAS-RN 40609- 78-7) 5-carboxylic acid 1.067 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 4-isopropoxy- 1H-benzo[d]- 497.4 c]dipyrrol-2-yl]-(4-isopropoxy-quinolin-2-yl)-methanone quinoline-2- [1,2,3]triazole- (M + H).sup.+ [00086] carboxylic acid (CAS-RN 1406553-19-2) 5-carboxylic acid 1.068 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 6-chloro-9H- 1H-benzo[d]- 511.6 c]dipyrrol-2-yl]-(6-chloro-9H-carbazol-2-yl)-methanone carbazole-2- [1,2,3]triazole- (M + H).sup.+ [00087] carboxylic acid (CAS-RN 58479-49-5) 5-carboxylic acid 1.069 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 4-(2-methoxy- 1H-benzo[d]- 513.4 c]dipyrrol-2-yl]-[4-(2-methoxy-ethoxy)-quinolin-2-yl)-methanone ethoxy)quinoline- [1,2,3]triazole- (M + H).sup.+ [00088] 2-carboxylic acid (CAS-RN 52144- 36-2) 5-carboxylic acid 1.070 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 4-isopropoxy-7- 1H-benzo[d]- 565.4 c]dipyrrol-2-yl]-(4-isopropoxy-7-trifluoromethyl-quinolin-2-yl)-methanone (trifluoro- [1,2,3]triazole- (M + H).sup.+ [00089] methyl)quinoline- 2-carboxylic acid (intermediate 2) 5-carboxylic acid 1.071 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 4-(cyclopropyl- 1H-benzo[d]- 509.6 c]dipyrrol-2-yl]-(4-cyclopropylmethoxy-quinolin-2-yl)-methanone methoxy)- [1,2,3]triazole- (M + H).sup.+ [00090] quinoline-2- carboxylic acid (CAS-RN 1275281-11-2) 5-carboxylic acid 1.072 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 5-(4- 1H-benzo[d]- 499.4 c]dipyrrol-2-yl]-[5-(4-chloro-phenyl)-pyridin-2-yl]-methanone chlorophenyl)- [1,2,3]triazole- (M + H).sup.+ [00091] picolinic acid (CAS-RN 87789-85-3) 5-carboxylic acid 1.073 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 1-ethoxyiso- 1H-benzo[d]- 483.4 3,4-c]dipyrrol-2-yl]-(1-ethoxy-isoquinolin-3-yl)-methanone quinoline-3- [1,2,3]triazole- (M + H).sup.+ [00092] carboxylic acid (CAS-RN 1094758-39-0) 5-carboxylic acid 1.074 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 1-ethyl-4- 1H-benzo[d]- 513.7 c]dipyrrol-2-yl]-(1-ethyl-4-isopropoxy-1H-indol-6-yl)-methanone isopropoxy-1H- [1,2,3]triazole- (M + H).sup.+ [00093] indole-6- carboxylic acid (intermediate 2.6) 5-carboxylic acid 1.075 6-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 5-(4- 1H-benzo[d]- 515.6 3,4-c]dipyrrole-2-carbonyl]-3-(4-chloro-phenyl)-1H-pyridin-2-one chlorophenyl)- [1,2,3]triazole- (M + H).sup.+ [00094] 6-oxo-1,6- dihydropyridine- 2-carboxylic acid (intermediate 3.2) 5-carboxylic acid 1.076 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta 7-chloro-4- 1H-benzo[d]- 517.4 [1,2-c; 3,4-c]dipyrrol-2-yl]-(7-chloro-4-ethoxy-quinolin-2-yl)-methanone ethoxyquinoline- [1,2,3]triazole- (M + H).sup.+ [00095] 2-carboxylic acid (intermediate 2.5) 5-carboxylic acid 1.077 (7-chloro-4-ethoxy-quinolin-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H- 7-chloro-4- (+)-(R)- 521.4 benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]methanone ethoxyquinoline- 4,5,6,7- (M + H).sup.+ [00096] 2-carboxylic acid (intermediate 2.5) tetrahydro-1H- benzo[d]- [1,2,3]triazole- 5-carboxylic acid (intermediate 11) 1.078 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 5,6,7,8- 1H-benzo[d]- 500.7 c]dipyrrol-2-yl]-(4-isopropoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanone tetrahydro-2- [1,2,3]triazole- (M + H).sup.+ [00097] naphthoic acid (intermediate 2.4) 5-carboxylic acid 1.079 (1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[4-(2-methoxy-ethoxy)-7-trifluoromethyl- 4-(2- 1H-benzo[d]- 581.7 quinoline-2-carbonyl]-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl}-methanone methoxyethoxy)- [1,2,3]triazole- (M + H).sup.+ [00098] 7-(trifluoro- methyl)quinoline- 2-carboxylic acid (intermediate 2.3) 5-carboxylic acid 1.080 (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-6-trifluoromethyl-quinoline-2- 4-ethoxy-6- 1H-benzo[d]- 551.6 carbonyl)-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-methanone (trifluoromethyl)- [1,2,3]triazole- (M + H).sup.+ [00099] quinoline-2- carboxylic acid (intermediate 2.2) 5-carboxylic acid 1.081 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 4-ethoxy-1-ethyl- 1H-benzo[d]- 499.5 c]dipyrrol-2-yl]-(4-ethoxy-1-ethyl-1H-indol-5-yl)-methanone 1H-indole-6- [1,2,3]triazole- (M + H).sup.+ [00100] carboxylic acid (intermediate 3.1) 5-carboxylic acid 1.082 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4- 1-ethyl-4-(2,2,2- 1H-benzo[d]- 553.4 c]dipyrrol-2-yl]-[1-ethyl-4-(2,2,2-trifluoro-ethoxy)-1H-indol-5-yl]-methanone trifluoroethoxy)- [1,2,3]triazole- (M + H).sup.+ [00101] 1H-indole-6- carboxylic acid (intermediate 2.1) 5-carboxylic acid 1.083 5-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c; 4- 6-sulfamoyl- 522.4 3,4-c]dipyrrole-2-carbonyl]-pyridine-2-sulfonic acid amide ethoxyquinoline- nicotinic acid (M + H).sup.+ [00102] 2-carboxylic acid (CAS-RN 40609- 78-7) (CAS-RN 285135-56-0) 1.084 (1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[4-(2,2,2-trifluoro-ethoxy)-quinoline- 4-(2,2,2- 1H-benzo[d]- 537.4 2-carbonyl]-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl}-methanone trifluoroethoxy)- [1,2,3]triazole- (M + H).sup.+ [00103] quinoline-2- carboxylic acid (CAS-RN 1281584-65-3) 5-carboxylic acid 1.085 (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[4-ethoxy-1-(2,2,2-trifluoro-ethyl)- 4-ethoxy-1-(2,2,2- 1H-benzo[d]- 553.4 1H-indole-6-carbonyl]-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl}-methanone trifluoroethyl)- [1,2,3]triazole- (M + H).sup.+ [00104] 1H-indole-6- carboxylic acid (intermediate 2.9) 5-carboxylic acid 1.086 (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(5-chloro-4-cyclopropylmethoxy-pyridine- 5-chloro-4- 1H-benzo[d]- 493.4 2-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-methanone (cyclopropyl- [1,2,3]triazole- (M + H).sup.+ [00105] methoxy)picolinic acid 5-carboxylic acid 1.087 (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(5-cyclopropyl-6-cyclopropylmethoxy- 5-cyclopropyl-6- 1H-benzo[d]- 499.4 pyridine-2-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-methanone (cyclopropyl- [1,2,3]triazole- (M + H).sup.+ [00106] methoxy)picolinic acid(CAS-RN 1415898-71-3) 5-carboxylic acid 1.088 (3,4-dimethyl-phenyl)-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-5,6,7,8-tetrahydro-quinoline- 4-ethoxy-5,6,7,8- 1H-benzo[d]- 487.7 2-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-methanone tetrahydro- [1,2,3]triazole- (M + H).sup.+ [00107] quinoline-2- carboxylic acid (intermediate 8) 5-carboxylic acid 1.089 (1H-benzotriazol-5-yl)-[(3aS,3bS,6aR,6bR)-5-(4-chloro-biphenyl-3-carbonyl)- 4-chlorobiphenyl- 1H-benzo[d]- 498.6 octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-methanone 3-carboxylic acid [1,2,3]triazole- (M + H).sup.+ [00108] (CAS-RN 4655- 10-1) 5-carboxylic acid 1.090 (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-7-methoxy-quinoline-2- 4-ethoxy-7- 1H-benzo[d]- 513.4 carbonyl)-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-methanone methoxy- [1,2,3]triazole- (M + H).sup.+ [00109] quinoline-2- carboxylic acid (intermediate 2.8) 5-carboxylic acid 1.091 [(3aS,3bS,6aR,6bR)-5-(4-ethoxy-6-trifluoromethyl-quinoline-2-carbonyl)-octahydro- 4-ethoxy-6- 1H-[1,2,3]tri- 552.4 cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-methanone (trifluoromethyl)- azolo[4,5- (M + H).sup.+ [00110] quinoline-2- carboxylic acid (intermediate 2.2) b]pyridine-5- carboxylic acid (CAS-RN 1216149-55-1) 1.092 [(3aS,3bS,6aR,6bR)-5-(1-ethoxy-isoquinoline-3-carbonyl)-octahydro-cyclobuta[1,2-c; 1-ethoxyiso- 1H-[1,2,3]tri- 484.6 3,4-c]dipyrrol-2-yl]-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-methanone quinoline-3- azolo[4,5- (M + H).sup.+ [00111] carboxylic acid (CAS-RN 1094758-39-0) b]pyridine-5- carboxylic acid (CAS-RN 1216149-55-1) 1.093 (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(6-cyclopropylmethoxy-5-trifluoromethyl- 6-(cyclopropyl- 1H-benzo[d]- 527.4 pyridine-2-carbonyl)-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-methanone methoxy)-5- [1,2,3]triazole- (M + H).sup.+ [00112] (trifluoromethyl)- picolinic acid (CAS-RN 1415899-19-2) 5-carboxylic acid 1.094 (1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[5-cyclopropyl-4-(2,2,2-trifluoro-ethoxy)- 5-cyclopropyl-4- 1H-benzo[d]- 527.4 pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl}-methanone (2,2,2- [1,2,3]triazole- (M + H).sup.+ [00113] trifluoroethoxy)- picolinic acid 5-carboxylic acid 1.095 (1H-benzotriazol-5-yl)-{(3aS,3bR,6a[6-cyclopropyl-5-(2,2,2-trifluoro-ethoxy)- 6-cyclopropyl-5- 1H-benzo[d]- 528.4 pyridazine-3-carbonyl]-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl}- (2,2,2- [1,2,3]triazole- (M + H).sup.+ methanone]dipyrrol-2-yl}-methanone trifluoroethoxy)- 5-carboxylic [00114] pyridazine-3- carboxylic acid acid 1.096 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c; 6-chloro-4- 1H-benzo[d]- 517.4 3,4-c]dipyrrol-2-yl]-(6-chloro-4-ethoxy-quinolin-2-yl)-methanone ethoxyquinoline- [1,2,3]triazole- (M + H).sup.+ [00115] 2-carboxylic acid (CAS-RN 1355234-15-9) 5-carboxylic acid 1.097 (1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-5- 6-(2,2,2- 1H-benzo[d]- 555.4 trifluoromethyl-pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol- trifluoroethoxy)- [1,2,3]triazole- (M + H).sup.+ 2-yl}-methanone 5- 5-carboxylic [00116] (trifluoromethyl)- picolinic acid acid 1.098 (1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-pyridine-2- 6-(2,2,2- 1H-benzo[d]- 487.7 carbonyl]-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl}-methanone trifluoroethoxy)- [1,2,3]triazole- (M + H).sup.+ [00117] picolinic acid (CAS-RN 1247503-48-5) 5-carboxylic acid 1.099 (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-pyridine-3- 6-(2,2,2- 1H-benzo[d]- 487.7 carbonyl]-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl}-methanone trifluoroethoxy)- [1,2,3]triazole- (M + H).sup.+ [00118] nicotinic acid (CAS-RN 175204-90-7) 5-carboxylic acid 1.100 (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine- 5-bromo-6-(2,2,2- 1H-benzo[d]- 565.5 3-carbonyl]-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl}-methanone trifluoroethoxy)- [1,2,3]triazole- (M + H).sup.+ [00119] nicotinic acid (CAS-RN 1211586-75-2) 5-carboxylic acid 1.101 (1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[5-(2,2,2-trifluoro-ethoxy)-pyridine-2- 5-(2,2,2- 1H-benzo[d]- 487.4 carbonyl]-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl}-methanone trifluoroethoxy)- [1,2,3]triazole- (M + H).sup.+ [00120] picolinic acid (CAS-RN 881409-53-6) 5-carboxylic acid 1.102 [(3aS,3bR,6aS,6bR)-5-(6-cyclopropylmethoxy-pyridazine-3-carbonyl)-octahydro- 6-(cyclopropyl- 1H-benzo[d]- 460.7 cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl]-(3,4-dimethyl-phenyl)-methanone methoxy)- [1,2,3]triazole- (M + H).sup.+ [00121] pyridazine-3- carboxylic acid (CAS-RN 1184404-57-6) 5-carboxylic acid 1.103 (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-bromo-2-methyl-6-(2,2,2-trifluoro- 5-bromo-2- 1H-benzo[d]- 577.7 ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl}-methanone methyl-6-(2,2,2- [1,2,3]triazole- (M H).sup. [00122] trifluoroethoxy)- nicotinic acid 5-carboxylic acid 1.104 (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)- 5-cyclopropyl-6- 1H-benzo[d]- 527.7 pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl}-methanone (2,2,2- [1,2,3]triazole- (M + H).sup.+ [00123] trifluoroethoxy)- nicotinic acid (CAS-RN 1427064-90-1) 5-carboxylic acid 1.105 (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-5- 6-(2,2,2- 1H-benzo[d]- 555.6 trifluoromethyl-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c; 3,4- trifluoroethoxy)- [1,2,3]triazole- (M + H).sup.+ c]dipyrrol-2-yl}-methanone 5-(trifluoro- 5-carboxylic [00124] methyl)nicotinic acid acid 1.106 (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-(tetrahydro-pyran-4-yl)-6-(2,2,2- 5-(tetrahydro-2H- 1H-benzo[d]- 571.7 trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl}- pyran-4-yl)-6- [1,2,3]triazole- (M + H).sup.+ methanone (2,2,2-trifluoro- 5-carboxylic [00125] ethoxy)nicotinic acid (CAS-RN 1427064-92-3) acid 1.107 (1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[4-(4-chloro-phenyl)-5-(2,2,2-trifluoro- 4-(4- 1H-benzo[d]- 597.2 ethoxy)-pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl}-methanone chlorophenyl)-5- [1,2,3]triazole- (M + H).sup.+ [00126] (2,2,2-trifluoro- ethoxy)picolinic acid (CAS-RN 1364677-00-8) 5-carboxylic acid 1.108 (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-furan-2-yl-6-(2,2,2-trifluoro-ethoxy)- 5-(furan-2-yl)-6- 1H-benzo[d]- 553.2 pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl}-methanone (2,2,2-trifluoro- [1,2,3]triazole- (M + H).sup.+ [00127] ethoxy)nicotinic acid 5-carboxylic acid 1.109 (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-chloro-6-(2,2,2-trifluoro-ethoxy)- 5-chloro-6- 1H-benzo[d]- 521.1 pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl}-methanone oxo-1-(2,2,2- [1,2,3]triazole- (M + H).sup.+ [00128] triftriluoroethyl)- 1,6-dihydro- pyridine-3- carboxylic acid (intermediate 3) 5-carboxylic acid 1.110 [(3aS,3bR,6aS,6bR)-5-(4-ethoxy-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c; 4- 4-fluoro-1H- 501.2 3,4-c]dipyrrol-2-yl]-(4-fluoro-1H-benzotriazol-5-yl)-methanone ethoxyquinoline- benzo[d]- (M + H).sup.+ [00129] 2-carboxylic acid (CAS-RN 40609- 78-7) [1,2,3]triazole- 5-carboxylic acid (intermediate 10) 1.111 {(3aS,3bS,6aR,6bR)-5-[5-methanesulfonyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-3- 5- 1H-benzo[d]- 565.2 carbonyl]-octahydro-cyclobuta[1,2-c; 3,4-c]dipyrrol-2-yl}-phenyl-methanone (methylsulfonyl)- [1,2,3]triazole- (M + H).sup.+ [00130] 6-(2,2,2-lrifluoro- ethoxy)nicotinic acid (intermediate 5) 5-carboxylic acid [00131]

Example 2

(3aR,3bS,6aR,6bS)-5-(1H-Benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester

[0321] ##STR00132##

[0322] To a solution of (3aS,3bS,6aR,6bR)-decahydro-cyclobuta[1,2-c;3,4-c]dipyrrole (intermediate 1; 40 mg, 289 mol) in N,N-dimethylformamide (2 mL) were added N-methylmorpholine (146 mg, 1.45 mmol), 1H-benzo[d][1,2,3]triazole-5-carboxylic acid (47.2 mg, 289 mol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluoro-phosphate (110 mg, 289 mol). In the meantime a second solution with (4-(trifluoromethoxy)phenyl)methanol (CAS-RN 1736-74-9; 55.6 mg, 289 mol,) and 1,1-carbonyldiimidazole (49.3 mg, 304 mol) in DMF (2 ml) was prepared. The two reaction mixtures were stirred at room temperature for 4 h, then combined and stirred for another 16 h, then partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel; gradient dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (38 mg, 26%). White solid, MS: 502.3 (M+H)+.

Example 2.001

(3aR,3bS,6aR,6bS)-5-(1H-Benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrole-2-carboxylic acid 3,5-dichloro-benzyl ester

[0323] ##STR00133##

[0324] The title compound was produced in analogy to example 2, replacing (4-(trifluoromethoxy)-phenyl)methanol by (3,5-dichlorophenyl)methanol (CAS-RN 60211-57-6). White solid, MS: 486.5 (M+H).sup.+.

Example 3

(1H-Benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4-fluoro-biphenyl-4-sulfonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-methanone

[0325] ##STR00134##

[0326] (3aS,3bR,6aS,6bR)-5-(4-Fluoro-biphenyl-4-sulfonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrole-2-carboxylic acid tert-butyl ester (intermediate 12; 26 mg, 55.0 mol) was combined with hydrochloric acid solution (5-6 M in 2-propanol; 1 mL) and stirred at room temperature for 18 h. After evaporation of volatile material the residue was taken up in N,N-dimethylformamide (1 mL), then N-methylmorpholine (27.8 mg, 275 mol), 1H-benzo[d][1,2,3]triazole-5-carboxylic acid (9.9 mg, 61 mol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluoro-phosphate (23 mg, 61 mol) were added. After 16 h the reaction mixture was partitioned between water sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (26 mg, 82%). Light yellow gum, MS: 516.6 (MH).sup..

Example 3.001

(1H-Benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(6-chloro-naphthalene-2-sulfonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-methanone

[0327] ##STR00135##

[0328] A solution of 6-chloro-naphthalene-2-sulfonyl chloride (CAS-RN 102153-63-9, 33.6 mg, 129 mol) in dichloromethane (1 mL) was added at room temperature to a solution of (3aS,3bS,6aR,6bR)-decahydro-cyclobuta[1,2-c;3,4-c]dipyrrole (intermediate 1; 11.9 mg, 86 mol) in dichloromethane (2 mL) and pyridine (33.9 mg, 34.7 l, 428 mol, Eq: 5), then after 4 h the reaction mixture was evaporated. The residue was taken up with N,N-dimethylformamide, then 1H-benzo[d]-[1,2,3]triazole-5-carboxylic acid (14.0 mg, 86 mol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluoro-phosphate (35.8 mg, 94 mol) and 4-methylmorpholine (43.3 mg, 428 mol) were added, then after 16 h the reaction mixture was partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (4 mg, 9%). Colourless gum, MS: 508.6 (M+H).sup.+.

Example 4

[(3aR,3bS,6aR,6bS)-5-(1H-Benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrol-2-yl]-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone

[0329] ##STR00136##

[0330] To a solution of (3aS,3bS,6aR,6bR)-decahydro-cyclobuta[1,2-c;3,4-c]dipyrrole (intermediate 1; 30 mg, 217 mol) and N-methylmorpholine (108 mg, 1.07 mmol) and N,N-dimethylformamide (3 mL) was added a solution of 6-(trifluoromethyl)-3,4-dihydroisoquinoline-2(1H)-carbonyl chloride (intermediate 7; 57 mg, 214 mol) in N,N-dimethylformamide DMF (1 ml) dropwise at room temperature, then after 1 h 1H-benzo[d][1,2,3]triazole-5-carboxylic acid (34.9 mg, 214 mol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluoro-phosphate (81.4 mg, 214 mol) were added. After another 16 h the reaction mixture was partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (24 mg, 22%). White solid, MS: 511.4 (M+H).sup.+.

INTERMEDIATES

Intermediate 1

(3aS,3bS,6aR,6bR)-Decahydro-cyclobuta[1,2-c;3,4-c]dipyrrole

Step 1: (3aS,3bS,6aR,6bR)-2,5-Dibenzyl-tetrahydro-cyclobuta[1,2-c:3,4-c]dipyrrole-1,3,4,6-tetraone

[0331] A solution of 1-benzyl-1H-pyrrole-2,5-dione (1.12 g, 5.98 mmol) in acetonitrile (60 ml) was purged with nitrogen for 10 min, then irradiated at 300 nm for 6 h to produce a white suspension. About 30 mL of acetonitrile was distilled off, then the product was collected by filtration (447 mg, 40%). Off-white solid, MS: 375.5 (M+H).sup.+, .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 7.35-7.25 (m, 10H), 4.63 (s, 4H), 3.45 (s, 4H).

Step 2: (3aS,3bS,6aR,6bR)-2,5-Dibenzyl-decahydro-cyclobuta[1,2-c:3,4-c]dipyrrole

[0332] To a suspension of lithium aluminum hydride (3.05 g, 80.3 mmol) in diethyl ether (120 mL) was added portionwise (3aS,3bS,6aR,6bR)-2,5-dibenzyl-tetrahydro-cyclobuta[1,2-c;3,4-c]dipyrrole-1,3,4,6-tetraone (7.52 g, 20.1 mmol) over 10 min at room temperature. The reaction mixture was stirred at room temperature for 4 h, then cooled down to 0 C. and quenched by slow addition of water (40 mL) and 2 M aq. sodium hydroxide solution. Water (500 mL) and ethyl acetate (500 mL) were added, then after filtration through diatomaceous earth the organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. The residue was triturated in methanol (40 mL) to produce the title compound (4.60 g, 72%). White solid, MS: 319.6 (M+H).sup.+, .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.4-7.2 (m, 10H), 3.65 (s, 4H), 2.82 (d, J=9.3, 4H), 2.39 (d, J=4.4, 4H), 2.05 (dd, J=9.3, 4.4, 4H).

Step 3: (3aS,3bS,6aR,6bR)-Decahydro-cyclobuta[1,2-c:3,4-c]dipyrrole

[0333] A solution of (3aS,3bS,6aR,6bR)-2,5-dibenzyl-decahydro-cyclobuta[1,2-c;3,4-c]dipyrrole (4.6 g, 14.4 mmol, Eq: 1.00) was stirred for 4 h at 50 C. under a hydrogen atmosphere (3 bar) in the presence of palladium (10% on activated charcoal, 2.08 g), then insoluble material was removed by filtration through diatomaceous earth. The filtrate was evaporated to produce the title compound (1.72 g, 86%). White solid, MS: 139.2 (M+H).sup.+, .sup.1H-NMR (300 MHz, CDCl.sub.3): 2.99 (d, J=11.4, 4H), 2.68 (dd, J=11.4, 4.4, 4H), 2.25-2.15 (m, 6H).

Intermediate 2

4-isopropoxy-7-(trifluoromethyl)quinoline-2-carboxylic acid

Step 1: Methyl 4-isopropoxy-7-(trifluoromethyl)quinoline-2-carboxylate

[0334] To a stirring suspension of methyl 4-hydroxy-7-(trifluoromethyl)quinoline-2-carboxylate (300 mg, 1.08 mmol) in acetonitrile (3 mL) were added potassium carbonate (449 mg, 3.25 mmol) and 2-iodopropane (570 mg, 3.25 mmol). The reaction mixture was stirred for 16 h at 80 C., then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; heptane-ethyl acetate gradient) produced the title compound (334 mg, 98%) as a white solid.

Step 2: 4-Isopropoxy-7-(trifluoromethyl)quinoline-2-carboxylic acid

[0335] A mixture of methyl 4-isopropoxy-7-(trifluoromethyl)quinoline-2-carboxylate (330 mg, 1.05 mmol), potassium hydroxide (209 mg, 3.16 mmol), ethanol (3.5 mL), and water (3.5 mL) was heated at 80 C. for 45 min, then most of the ethanol was distilled off. The remaining aqueous solution was acidified to pH 1 with 1 M hydrochloric acid solution. The precipitate was collected by filtration and dried to produce the title compound (304 mg, 96%). White solid MS: 299.9 (M+H).sup.+.

[0336] The following intermediates were produced in analogy to intermediate 2, replacing methyl 4-hydroxy-7-(trifluoromethyl)quinoline-2-carboxylate and 2-iodopropane by the appropriate starting material and alkylating agent, respectively.

TABLE-US-00003 No. Systematic name Starting material alkylating agent MS, m/e 2.1 1-ethyl-4-(2,2,2- methyl 1-ethyl-4-hydroxy- 2,2,2- 288.4 trifluoroethoxy)-1H- 1H-indole-6-carboxylate trifluoroethyl indole-6-carboxylic acid (CAS-RN 934617-51-3) trifluoromethane- sulfonate 2.2 4-ethoxy-6- methyl 4-hydroxy-6- iodoethane 286.5 (trifluoromethyl)quinoline- (trifluoromethyl)quinoline-2- 2-carboxylic acid carboxylate (CAS-RN 1422284-64-7) 2.3 4-(2-methoxyethoxy)-7- methyl 4-hydroxy-7- 1-bromo-2- 316.5 (trifluoromethyl)quinoline- (trifluoromethyl)quinoline-2- methoxyethane (M + H).sup.+ 2-carboxylic acid carboxylate (CAS-RN 1072944-69-4) 2.4 4-isopropoxy-5,6,7,8- methyl 4-hydroxy-5,6,7,8- 2-iodopropane 233.3 tetrahydronaphthalene-2- tetrahydronaphthalene-2- (M H).sup. carboxylic acid carboxylate (CAS-RN 184107-09-3) 2.5 7-chloro-4- methyl 7-chloro-4- iodoethane 252.5 ethoxyquinoline-2- hydroxyquinoline-2- (M + H).sup.+ carboxylic acid carboxylate 2.6 1-ethyl-4-propan-2- methyl 1-ethyl-4-hydroxy- 2-iodopropane 248.6 yloxyindole-6-carboxylic 1H-indole-6-carboxylate (M + H).sup.+ acid (CAS-RN 934617-51-3) 2.8 4-ethoxy-7- methyl 4-hydroxy-7- iodoethane 248.2 methoxyquinoline-2- methoxyquinoline-2- (M + H).sup.+ carboxylic acid carboxylate (CAS-RN 259214-73-8) 2.9 4-ethoxy-1-(2,2,2- methyl 4-ethoxy- 2,2,2-trifluoro- 288.5 trifluoroethyl)- 1H-indole- ethyl trifluoro- (M + H).sup.+ 1H-indole- 6-carboxylate methanesulfonate 6-carboxylic acid (CAS-RN 372099-86-0)

Intermediate 3

5-Chloro-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridine-3-carboxylic acid

[0337] Lithium hydroxide monohydrate (102 mg, 2.4 mmol) was added to a solution of methyl 5-chloro-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridine-3-carboxylate (328 mg, 1.22 mmol) in tetrahydrofuran (1 mL) and water (1 mL), then after 16 h the reaction mixture was partially evaporated in order to remove most of the tetrahydrofuran. The remaining aqueous solution was acidified to pH 1 with 1M aq. hydrochloric acid solution. The precipitate was collected by filtration and dried to afford the title compound (289 mg, 93%). White solid, MS: 254.2 (MH).sup..

[0338] The following intermediates were prepared in analogy to intermediate 3, replacing methyl 5-chloro-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridine-3-carboxylate by the appropriate starting material.

TABLE-US-00004 No. Systematic name Starting material MS, m/e 3.1 4-ethoxy-1-ethyl- methyl 4-ethoxy-1- 234.5 1H-indole-6- ethyl-1H-indole- (M + H).sup.+ carboxylic 6-carboxylate acid (CAS-RN 372099-98-4) 3.2 5-(4-chlorophenyl)- methyl 5- 248.1 6-oxo-1,6- (4-chlorophenyl)-6- (M H).sup. dihydropyridine- hydroxypicolinate 2-carboxylic acid 3.3 4-isopropoxy- methyl 4-isopropoxy- 218.3 1H-indole- 1H-indole-6- (M H).sup. 6-carboxylic carboxylate acid (intermediate 9, step 1)

Intermediate 4

5-Cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid

[0339] 5-Cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinonitrile (250 mg, 1.03 mmol) was combined with 25% aq. hydrochloric acid solution (5 mL) and heated at 110 C. for 3 h. After cooling the reaction mixture was evaporated to dryness. The residue was suspended in water (5 mL) basified with 6 M aq. sodium hydroxide solution, then the resulting solution was acidified to pH 1. The precipitate was collected by filtration and dried to produce the title compound (159 mg, 59%). White solid, MS: 262.2 (M+H).sup.+.

Intermediate 5

5-(Methylsulfonyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid

Step 1: Methyl 5-(methylsulfonyl)-6-(2,2,2-trifluoroethoxy)nicotinate

[0340] A mixture of L-proline (88 mg, 0.76 mmol, Eq: 0.8) and sodium hydroxide (31 mg, 0.76 mmol) and dimethyl sulfoxide (5 mL), was stirred at room temperature for 30 min, then methyl 5-bromo-6-(2,2,2-trifluoroethoxy)nicotinate (300 mg, 955 mol), sodium methanesulfinate (804 mg, 7.64 mmol) and copper(I) iodide (146 mg, 764 mol) were added, and the reaction mixture was heated at 80 C. for 16 h, then partitioned between 1 M aq. hydrochloric acid solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. The residue was purified by chromatography (silica gel; heptane-ethyl acetate gradient produced the title compound (80 mg, 27%). White solid, MS:314 (M+H).sup.+.

Step 2: 5-(Methylsulfonyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid

[0341] The title compound was produced in analogy to intermediate 2, step 2 from methyl 5-(methylsulfonyl)-6-(2,2,2-trifluoroethoxy)nicotinate. White solid, MS: 298.1 (MH).sup..

Intermediate 6

1-(3-Methoxy-propyl)-1,2,3,4-tetrahydro-quinoline-3-carboxylic acid

[0342] A mixture of methyl 1,2,3,4-tetrahydroquinoline-3-carboxylate (CAS-RN 177202-62-9; 300 mg, 1.57 mmol) 1-bromo-3-methoxypropane (735 mg, 4.71 mmol) and sodium hydrogencarbonate (659 mg, 7.84 mmol) in ethanol (3 mL) was heated at reflux. After 18 h the reaction mixture was evaporated and the residue chromatographed (silica gel; heptane-ethyl acetate gradient) to produce a mixture of 1-(3-methoxy-propyl)-1,2,3,4-tetrahydro-quinoline-3-carboxylic acid methyl ester and 1-(3-methoxy-propyl)-1,2,3,4-tetrahydro-quinoline-3-carboxylic acid ethyl ester (251 mg). This material was combined with ethanol (2.5 mL), water (2.5 mL) and potassium hydroxide (264 mg, 4.71 mmol) and heated at 80 C. for 45 min, then the reaction mixture was partially evaporated in order to remove most of the ethanol. The remaining aqueous solution was partitioned between ethyl acetate and 1 M aq. hydrochloric acid solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to produce the title compound (190 mg, 49%). Light yellow oil, MS: 248.5 (MH).sup..

Intermediate 7

6-(Trifluoromethyl)-3,4-dihydroisoquinoline-2(1H)-carbonyl chloride

[0343] To a white suspension of 6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (CAS-RN 215798-14-4; 500 mg, 2.04 mmol) and pyridine (339 mg, 4.29 mmol) in dichloromethane (5 mL) was added dropwise a solution of triphosgene (273 mg, 918 mol,) in dichloromethane (5 mL) at 0 C. After 30 min the ice bath was removed, then after 16 h the reaction mixture was partitioned between 1 M aq. hydrochloric acid solution and dichloromethane. The organic layer was washed with brined, dried over magnesium sulfate, filtered, and evaporated to produce the title compound (546 mg, quant.) as a yellow oil.

Intermediate 8

4-Ethoxy-5,6,7,8-tetrahydroquinoline-2-carboxylic acid

Step 1: Methyl 4-hydroxy-5,6,7,8-tetrahydroquinoline-2-carboxylate

[0344] A solution of methyl 4-hydroxyquinoline-2-carboxylate (CAS-RN 5965-59-3; 1.0 g, 4.92 mmol) in 37% aq. hydrochloric acid solution (36 mL) was stirred at room temperature under an atmosphere of hydrogen (4 bar) in the presence of platinum(IV) oxide (124 mg). After 72 h insoluble material was removed by filtration through diatomaceous earth, and the filtrate was evaporated to produce the title compound (1.06 g, 69%). White solid, MS: 208.3 (M+H).sup.+.

Step 2: Methyl 4-ethoxy-5,6,7,8-tetrahydroquinoline-2-carboxylate

[0345] The title compound was produced in analogy to intermediate 2, step 1 from methyl 4-hydroxy-5,6,7,8-tetrahydroquinoline-2-carboxylate. White solid, MS: 236.3 (M+H).sup.+.

Step 3: 4-Ethoxy-5,6,7,8-tetrahydroquinoline-2-carboxylic acid

[0346] A mixture of methyl 4-ethoxy-5,6,7,8-tetrahydroquinoline-2-carboxylate (156 mg, 663 mol, Eq: 1.00) in ethanol (2 mL) and water (2 mL) was heated at reflux for 2 h, then most of the ethanol was distilled off and the remaining aqueous solution was acidified to pH 1, then evaporated to dryness. The residue was suspended in dichloromethane, then insoluble material was removed by filtration. The filtrate was evaporated to produce the title compound (172 mg, quant.). White solid, MS: 222.3 (M+H).sup.+.

Intermediate 9

4-Isopropoxy-1-methyl-1H-indole-6-carboxylic acid

Step 1: Methyl 4-isopropoxy-1H-indole-6-carboxylate

[0347] Potassium carbonate (651 mg, 4.71 mmol) and 2-iodopropane (275 mg, 1.57 mmol) were added to a solution of methyl 4-hydroxy-1H-indole-6-carboxylate (CAS-RN 77140-48-8; 300 mg, 1.57 mmol) in N,N-dimethylformamide (9 mL) at 0 C. The reaction mixture was stirred for 16 h at 0 C., then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to give a light brown oil.

[0348] Chromatography (silica gel; heptane-ethyl acetate gradient) produced the title compound (280 mg, 77%). White solid, MS: 232.2 (MH).sup..

Step 2: Methyl 4-isopropoxy-1-methyl-1H-indole-6-carboxylate

[0349] Potassium carbonate (296 mg, 2.14 mmol) and iodomethane (183 mg, 1.29 mmol) were added to a solution of methyl 4-isopropoxy-1H-indole-6-carboxylate (100 mg, 429 mol) in acetone (2.5 mL). The reaction mixture was heated at reflux for 16 h, then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to give a light brown oil. Chromatography (silica gel; heptane-ethyl acetate gradient) produced the title compound (102 mg, 96%). Colourless oil, MS: 248.2 (MH).sup..

Step 3: 4-Isopropoxy-1-methyl-1H-indole-6-carboxylic acid

[0350] The title compound was produced in analogy to intermediate 2, step 2 from methyl 4-isopropoxy-1-methyl-1H-indole-6-carboxylate. Off-white solid, MS: 232.2 (MH).sup..

Intermediate 10

4-Fluoro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid

Step 1: 5-Bromo-4-fluoro-1H-benzo[d][1,2,3]triazole

[0351] To a light brown suspension of 4-bromo-3-fluorobenzene-1,2-diamine (1.50 g, 7.32 mmol) in water (15 mL) and acetic acid (5 mL) was added a solution of sodium nitrite (555 mg, 8.05 mmol) in water (1.5 mL) dropwise at 0 C. After 1 h at 0 C. the reaction mixture was heated to 85 C. for 1 h. After cooling the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to produce the title compound (1.53 g, 97%). Brown solid, MS: 214.1 (MH).sup..

Step 2: Methyl 4-fluoro-1H-benzo[d][1,2,3]triazole-5-carboxylate

[0352] A solution of 5-bromo-4-fluoro-1H-benzo[d][1,2,3]triazole (415 mg, 1.92 mmol), 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (63.4 mg, 76.8 mol), and triethylamine (253 mg, 2.50 mmol) in methanol (5 mL) was stirred for 18 h under a hydrogen atmosphere (70 bar) at 110 C. After cooling the reaction mixture was evaporated and the residue was purified by chromatography (silica gel; gradient dichloromethane to dichloromethane/methanol 95:5) to produce the title compound (127 mg, 31%). Red solid, MS: 194.2 (MH).sup..

Step 3: 4-Fluoro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid

[0353] The title compound was produced in analogy to intermediate 3 from methyl 4-fluoro-1H-benzo[d][1,2,3]triazole-5-carboxylate. Brown solid, MS: 180.2 (MH).sup..

Intermediate 11

(+)-(R)-4,5,6,7-Tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid

[0354] Racemic 4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid (CAS-RN 33062-47-4; 1.10 g, 6.58 mmol) was separated by preparative HPLC using a Chiralpak AD column as the stationary phase and heptane/ethanol 3:2 as the mobile phase. This produced the faster eluting (+)-(R)-enantiomer (452 mg, 41%), followed by the slower eluting ()-(S)-enantiomer (381 mg, 35%). White solid, MS: 166.2 (MH).sup..

Intermediate 12

(3aS,3bR,6aS,6bR)-5-(4-Fluoro-biphenyl-4-sulfonyl)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrole-2-carboxylic acid tert-butyl ester

[0355] A solution of 4-fluorobiphenyl-4-sulfonyl chloride (CAS-RN 116748-66-4; 42.9 mg, 158 mol) in dichloromethane (1 mL) was added at room temperature to a solution of (3aR,3bS,6aR,6bS)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrole-2-carboxylic acid tert-butyl ester hydrochloride (intermediate 13; 29 mg, 106 mol) and pyridine (25.0 mg, 317 mol) in dichloromethane (1 mL). After 2 h the reaction mixture was concentrated under vacuum, and the residue was purified by chromatography (silica gel; heptane-ethyl acetate gradient) to produce the title compound (30 mg, 60%). White solid, MS: 394.6 (M+Me.sub.3COCO+Na).sup.+.

Intermediate 13

(3aR,3bS,6aR,6bS)-Octahydro-cyclobuta[1,2-c;3,4-c]dipyrrole-2-carboxylic acid tert-butyl ester hydrochloride

Step 1: (3aS,3bS,6aR,6bR)-Octahydro-cyclobuta[1,2-c:3,4-c]dipyrrole-2,5-dicarboxylic acid di-tert-butyl ester

[0356] To a solution of (3aS,3bS,6aR,6bR)-decahydro-cyclobuta[1,2-c;3,4-c]dipyrrole (intermediate 1; 100 mg, 724 mol) in chloroform (3 ml) was added dropwise a solution of di-tert-butyl dicarbonate (474 mg, 2.17 mmol) in chloroform (3 ml). After 2 h the reaction mixture was evaporated and the residue was chromatographed (silica gel; heptane-ethyl acetate gradient) to produce the title compound (222 mg, 91%). White solid, MS: 338.6 (M+H).sup.+.

Step 2: (3aR,3bS,6aR,6bS)-Octahydro-cyclobuta[1,2-c:3,4-c]dipyrrole-2-carboxylic acid tert-butyl ester hydrochloride

[0357] Hydrogen chloride solution (5-6 M in 2-propanol, 90 L, 0.45 mmol) was added at 0 C. to a solution of (3aS,3bS,6aR,6bR)-octahydro-cyclobuta[1,2-c;3,4-c]dipyrrole-2,5-dicarboxylic acid di-tert-butyl ester (76 mg, 225 mol) in ethyl acetate (2 mL). The reaction mixture was stirred at room temperature for 3 days, then the precipitate was collected by filtration and dried to afford the title compound (33 mg, 48%). White solid, MS: 239.6 (M+H).sup.+.

Example A

[0358] A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:

TABLE-US-00005 Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

Example B

[0359] A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:

TABLE-US-00006 Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg