CONDENSED [1,4] DIAZEPINE COMPOUNDS AS AUTOTAXIN (ATX) AND LYSOPHOSPHATIDIC ACID (LPA) PRODUCTION INHIBITORS
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Abstract
Compounds of formula (I)
wherein R1, R2, A1 and A2 are as described herein, compositions including the compounds and methods of using the compounds as autotaxin inhibitors.
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Citations
26 Claims
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1. A Compound of formula (I)
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26)
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2. A compound according to claim 1, wherein
R1 is alkyl, haloalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenyl alkyl, substituted phenoxyalkyl, substituted phenylalkoxy, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridinyl, substituted pyridinyl alkyl, substituted pyridinyl alkenyl, substituted pyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl or substituted benzofuran-2-yl, wherein substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenyl alkyl, substituted phenoxyalkyl, substituted phenylalkoxy, substituted phenyl cycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinyl alkenyl, substituted pyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl and substituted benzofuran-2-yl are substituted with R3, R4 and R5; -
A1 is —
N—
or —
CR7—
;A2 is —
N—
or —
CR8— and
at least one of A1 and A2 is —
N—
;R2 is selected from the ring systems A, B, C, D, E, F, G, H, I, K and L. R3, R4 and R5 are independently selected from H, alkyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, cycloalkyl, cycloalkyl alkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkoxyalkyl, cycloalkyl alkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, halogen, hydroxy, cyano, alkylsulfanyl, haloalkyl sulfanyl, cycloalkyl sulfanyl, alkyl sulfinyl, haloalkyl sulfinyl, cycloalkylsulfinyl, alkyl sulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, alkylcarbonylamino, substituted aminosulfonyl, substituted amino and substituted aminoalkyl, wherein substituted aminosulfonyl, substituted amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and cycloalkylcarbonyl, and wherein substituted phenyl and substituted pyridinyl are optionally substituted with one to three substituents independently selected from alkyl, halogen, haloalkyl, alkoxy and haloalkoxy; R6 is H, alkyl, haloalkyl or cycloalkyl; R7 and R8 are independently selected from H, alkyl, haloalkyl or cycloalkyl; or a pharmaceutically acceptable salt thereof.
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3. The compound of claim 1, wherein R1 is substituted phenylalkyl, substituted phenoxyalkyl or substituted phenylalkoxy, wherein substituted phenylalkyl, substituted phenoxyalkyl and substituted phenylalkoxy are substituted with R3, R4 and R5;
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4. The compound of claim 1, wherein R1 is substituted phenoxyalkyl or substituted phenylalkoxy, wherein substituted phenoxyalkyl and substituted phenylalkoxy are substituted with R3, R4 and R5;
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5. The compound of claim 1, wherein R1 is phenylalkoxy substituted with R3, R4 and R5;
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6. The compound of claim 1, wherein R2 is selected from the ring systems A and E.
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7. The compound of claim 1, wherein R2 is the ring system A.
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8. The compound of claim 1, wherein A1 is —
- N— and
A2 is —
N—
or —
CR8—
.
- N— and
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9. The compound of claim 1, wherein R3, R4 and R5 are independently selected from H, alkyl, cycloalkyl, heterocycloalkylalkoxy, haloalkoxy, halogen, cyano and alkylcarbonylamino.
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10. The compound of claim 1, wherein R3, R4 and R5 are independently selected from H, alkyl, cycloalkyl, haloalkoxy, halogen, cyano and alkylcarbonylamino.
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11. The compound of claim 1, wherein R3 is heterocycloalkylalkoxy, haloalkoxy or cyano.
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12. The compound of claim 1, wherein R3 is haloalkoxy or cyano.
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13. The compound of claim 1, wherein R4 is H, alkyl, cycloalkyl or halogen.
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14. The compound of claim 1, wherein R4 is H, alkyl or halogen.
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15. The compound of claim 1, wherein R5 is H.
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16. The compound of claim 1, wherein R7 is H.
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17. The compound of claim 1, wherein R8 is H.
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18. The compound of claim 1, wherein
R1 is substituted phenylalkoxy substituted with R3, R4 and R5; -
A1 is —
N—
;A2 is —
N—
or —
CR8—
;R2 is the ring system A. R3 is haloalkoxy or cyano; R4 is H or halogen; R5 is H; R8 is H; or pharmaceutically acceptable salts.
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19. The compound of claim 1, selected from
Benzyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate; -
Benzyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydroimidazo[1,2-d][1,4]diazepine-7-carboxylate; [3-Fluoro-4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate; 2-Fluoro-4-(trifluoromethoxy)benzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; [4-(Trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate; 4-Cyanobenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; 4-Cyano-3-fluorobenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; 4-Cyano-2-fluorobenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; (4-Cyano-2-propan-2-ylphenyl)methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate; [4-Cyano-2-(2,2-dimethylpropanoylamino)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate; [4-(Trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepine-7-carboxylate; [4-Cyano-2-(2,2-dimethylpropanoylamino)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepine-7-carboxylate; [4-(Trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydroimidazo[1,2-d][1,4]diazepine-7-carboxylate; 1-[2-(1,4,6,7-Tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-6-yl]-3-[4-(trifluoromethoxy)phenyl]propan-1-one; 3-Cyclopropyl-4-(2-oxo-2-(2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-6(5H)-yl)ethoxy)benzonitrile; 3-Ethyl-4-(2-oxo-2-(2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-6(5H)-yl)ethoxy)benzonitrile; 3-tert-Butyl-4-[2-oxo-2-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-6-yl]ethoxy]benzonitrile; 3-[3-fluoro-4-(trifluoromethoxy)phenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-6-yl]propan-1-one; 3-(4-methoxyphenyl)-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-6-yl]propan-1-one; 1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepin-7-yl]-3-[4-(trifluoromethoxy)phenyl]propan-1-one; 3-[3-fluoro-4-(trifluoromethoxy)phenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepin-7-yl]propan-1-one; 3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-6-yl]propan-1-one; 3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepin-7-yl]propan-1-one; (6-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)(6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)methanone; (E)-3-[4-(difluoromethoxy)-3-fluorophenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-6-yl]prop-2-en-1-one; 3-[4-(difluoromethoxy)-3-fluorophenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-6-yl]propan-1-one; 4-methoxybenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; 4-fluorobenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; 3-fluorobenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; (3,4-difluorophenyl)methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate; 4-(difluoromethoxy)-3-fluorobenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; 3-fluoro-4-methoxybenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; 4-methoxy-2-methylbenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; 4-cyclopropylbenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; [2-fluoro-4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepine-7-carboxylate; [3-fluoro-4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepine-7-carboxylate; 3-chloro-4-(trifluoromethoxy)benzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; 2-methoxy-4-(trifluoromethoxy)benzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; 2-methyl-4-(trifluoromethoxy)benzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; 4-(2,2,2-trifluoroethoxy)benzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; [3-chloro-4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepine-7-carboxylate; [3-chloro-4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydroimidazo[1,2-d][1,4]diazepine-7-carboxylate; 3-fluoro-4-(trifluoromethoxy)benzyl 2-((3aR,7aR)-2-oxooctahydrooxazolo[5,4-c]pyridine-5-carbonyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepine-7(6H)-carboxylate; and pharmaceutically acceptable salts thereof.
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20. A compound according to claim 1, selected from
Benzyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate; -
Benzyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydroimidazo[1,2-d][1,4]diazepine-7-carboxylate; [3-Fluoro-4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate; 2-Fluoro-4-(trifluoromethoxy)benzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; [4-(Trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate; 4-Cyanobenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; 4-Cyano-3-fluorobenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; 4-Cyano-2-fluorobenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; (4-Cyano-2-propan-2-ylphenyl)methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate; [4-Cyano-2-(2,2-dimethylpropanoylamino)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate; [4-(Trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepine-7-carboxylate; [4-Cyano-2-(2,2-dimethylpropanoylamino)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepine-7-carboxylate; [4-(Trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydroimidazo[1,2-d][1,4]diazepine-7-carboxylate; 1-[2-(1,4,6,7-Tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-6-yl]-3-[4-(trifluoromethoxy)phenyl]propan-1-one; 3-Cyclopropyl-4-(2-oxo-2-(2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-6(5H)-yl)ethoxy)benzonitrile; 3-Ethyl-4-(2-oxo-2-(2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-6(5H)-yl)ethoxy)benzonitrile; 3-tert-Butyl-4-[2-oxo-2-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-6-yl]ethoxy]benzonitrile; and pharmaceutically acceptable salts thereof.
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21. The compound of claim 1, selected from
(6-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)(6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)methanone; -
(E)-3-[4-(difluoromethoxy)-3-fluorophenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-6-yl]prop-2-en-1-one; 4-(difluoromethoxy)-3-fluorobenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; [3-fluoro-4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepine-7-carboxylate; 3-chloro-4-(trifluoromethoxy)benzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; 2-methyl-4-(trifluoromethoxy)benzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; [3-chloro-4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepine-7-carboxylate; [3-chloro-4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydroimidazo[1,2-d][1,4]diazepine-7-carboxylate; and pharmaceutically acceptable salts thereof.
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22. The compound of claim 1, selected from
3-Fluoro-4-(Trifluoromethoxy)benzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate; -
[4-(Trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate; [4-(Trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepine-7-carboxylate; [4-(Trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydroimidazo[1,2-d][1,4]diazepine-7-carboxylate; 3-tert-Butyl-4-[2-oxo-2-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-6-yl]ethoxy]benzonitrile; and pharmaceutically acceptable salts thereof.
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23. A process to prepare a compound of claim 1, comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III), wherein R1 is phenylalkoxy substituted with R3, R4 and R5, RA is phenylalkyl substituted with R3, R4 and R5 and R2, R3, R4, R5 A1 and A2 are as defined in any one of claims 1 to 18.
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24. A process to prepare a compound of claim 1, comprising the reaction of a compound of formula (II) in the presence of a compound of formula (IV), wherein R1 is alkyl, haloalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenyl alkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl, substituted thiophenyl, substituted thiophenyl alkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl or substituted benzofuran-2-yl, wherein substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenyl alkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl and substituted benzofuran-2-yl are substituted with R3, R4 and R5 and R2, R3, R4, R5 A1 and A2 are as defined in any one of claims 1 to 18.
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25. A pharmaceutical composition comprising a compound of claim 1 and a therapeutically inert carrier.
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26. A method for the treatment or prophylaxis a renal condition selected from the group consisting of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection, which method comprises administering an effective amount of a compound of claim 1.
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2. A compound according to claim 1, wherein
Specification
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Current AssigneeHoffmann-La Roche Incorporated (Roche Holding AG)
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Original AssigneeHoffmann-La Roche Incorporated (Roche Holding AG)
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InventorsHunziker, Daniel, Hert, Jerome, Kuehne, Holger, Mattei, Patrizio, Rudolph, Markus
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current1/1
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CPC Class CodesA61P 1/16 for liver or gallbladder di...A61P 11/00 Drugs for disorders of the ...A61P 13/00 Drugs for disorders of the ...A61P 13/12 of the kidneysA61P 25/00 Drugs for disorders of the ...A61P 27/00 Drugs for disorders of the ...A61P 29/00 Non-central analgesic, anti...A61P 3/00 Drugs for disorders of the ...A61P 35/00 Antineoplastic agentsA61P 37/00 Drugs for immunological or ...A61P 37/06 Immunosuppressants, e.g. dr...A61P 37/08 Antiallergic agents antiast...A61P 43/00 Drugs for specific purposes...A61P 5/00 Drugs for disorders of the ...A61P 9/00 Drugs for disorders of the ...C07D 487/04 Ortho-condensed systemsC07D 519/00 Heterocyclic compounds cont...