Condensed [1,4] diazepine compounds as autotaxin (atx) and lysophosphatidic acid (lpa) production inhibitors

Abstract

Compounds of formula (I) wherein R 1 , R 2 , A 1 and A 2 are as described herein, compositions including the compounds and methods of using the compounds as autotaxin inhibitors.

1 . Compounds of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is alkyl, haloalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylalkoxy, 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 or substituted benzofuran-2-yl, wherein substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylalkoxy, 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 R 3 , R 4  and R 5 ; 
         A 1  is —N— or —CR 7 —; 
         A 2  is —N— or —CR 8 — and at least one of A 1  and A 2  is —N—; 
         R 2  is selected from the ring systems A, B, C, D, E, F, G, H, I, K and L, 
       
       
         
           
           
               
               
           
         
         R 3 , R 4  and R 5  are independently selected from H, alkyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, heterocycloalkylalkoxy, phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, halogen, hydroxy, cyano, alkylsulfanyl, haloalkylsulfanyl, cycloalkylsulfanyl, alkylsulfinyl, haloalkylsulfinyl, cycloalkylsulfinyl, alkylsulfonyl, 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; 
         R 6  is H, alkyl, haloalkyl or cycloalkyl; 
         R and R 8  are independently selected from H, alkyl, haloalkyl or cycloalkyl; 
         or pharmaceutically acceptable salts. 
       
     
     
         2 . A compound according to  claim 1 , wherein
 R 1  is alkyl, haloalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylalkoxy, 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 or substituted benzofuran-2-yl, wherein substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylalkoxy, 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 R 3 , R 4  and R 5 ;   A 1  is —N— or —CR—;   A 2  is —N— or —CR 8 — and at least one of A 1  and A 2  is —N—;   R 2  is selected from the ring systems A, B, C, D, E, F, G, H, I, K and L.   R 3 , R 4  and R 5  are independently selected from H, alkyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, halogen, hydroxy, cyano, alkylsulfanyl, haloalkylsulfanyl, cycloalkylsulfanyl, alkylsulfinyl, haloalkylsulfinyl, cycloalkylsulfinyl, alkylsulfonyl, 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;   R 6  is H, alkyl, haloalkyl or cycloalkyl;   R 7  and R 8  are independently selected from H, alkyl, haloalkyl or cycloalkyl;   or pharmaceutically acceptable salts.   
     
     
         3 . A compound according to  claim 1  or  2 , wherein R 1  is substituted phenylalkyl, substituted phenoxyalkyl or substituted phenylalkoxy, wherein substituted phenylalkyl, substituted phenoxyalkyl and substituted phenylalkoxy are substituted with R 3 , R 4  and R 5 ; 
     
     
         4 . A compound according to any one of  claims 1  to  3 , wherein R 1  is substituted phenoxyalkyl or substituted phenylalkoxy, wherein substituted phenoxyalkyl and substituted phenylalkoxy are substituted with R 3 , R 4  and R 5 ; 
     
     
         5 . A compound according to any one of  claims 1  to  4 , wherein R 1  is phenylalkoxy substituted with R 3 , R 4  and R 5 ; 
     
     
         6 . A compound according to any one of  claims 1  to  5 , wherein R 2  is selected from the ring systems A and 0. 
     
     
         7 . A compound according to any one of  claims 1  to  6 , wherein R 2  is the ring system A. 
     
     
         8 . A compound according to any one of  claims 1  to  7 , wherein A 1  is —N— and A 2  is —N— or —CR 8 —. 
     
     
         9 . A compound according to any one of  claims 1  to  8 , wherein R 3 , R 4  and R 5  are independently selected from H, alkyl, cycloalkyl, heterocycloalkylalkoxy, haloalkoxy, halogen, cyano and alkylcarbonylamino. 
     
     
         10 . A compound according to any one of  claims 1  to  9 , wherein R 3 , R 4  and R 5  are independently selected from H, alkyl, cycloalkyl, haloalkoxy, halogen, cyano and alkylcarbonylamino. 
     
     
         11 . A compound according to any one of  claims 1  to  10 , wherein R 3  is heterocycloalkylalkoxy, haloalkoxy or cyano. 
     
     
         12 . A compound according to any one of  claims 1  to  11 , wherein R 3  is haloalkoxy or cyano. 
     
     
         13 . A compound according to any one of  claims 1  to  12 , wherein R 4  is H, alkyl, cycloalkyl or halogen. 
     
     
         14 . A compound according to any one of  claims 1  to  13 , wherein R 4  is H, alkyl or halogen. 
     
     
         15 . A compound according to any one of  claims 1  to  14 , wherein R 5  is H. 
     
     
         16 . A compound according to any one of  claims 1  to  15 , wherein R 7  is H. 
     
     
         17 . A compound according to any one of  claims 1  to  16 , wherein R 8  is H. 
     
     
         18 . A compound according to any one of  claims 1  to  17 , wherein R 1  is substituted phenylalkoxy substituted with R 3 , R 4  and R 5 ;
 A 1  is —N—; 
 A 2  is —N— or —CR—; 
 R 2  is the ring system A. 
 R 3  is haloalkoxy or cyano; 
 R 4  is H or halogen; 
 R 5  is H; 
 R 8  is H; 
 or pharmaceutically acceptable salts. 
 
     
     
         19 . A compound according to any one of  claims 1  to  18 , 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-pyrazzol[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 [,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 [,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 [,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][,4]diazepine-7(6H)-carboxylate; 
 and pharmaceutically acceptable salts thereof. 
 
     
     
         20 . A compound according to any one of  claims 1  to  19 , 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. 
 
     
     
         21 . A compound according to any one of  claims 1  to  19 , 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. 
 
     
     
         22 . A compound according to any one of  claims 1  to  20 , 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. 
 
     
     
         23 . A process to prepare a compound according to any one of  claims 1  to  22  comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III), wherein R 1  is phenylalkoxy substituted with R 3 , R 4  and R 5 , R A  is phenylalkyl substituted with R 3 , R 4  and R 5  and R 2 , R 3 , R 4 , R 5  A 1  and A 2  are as defined in any one of  claim 1  to  18 . 
       
         
           
           
               
               
           
         
       
     
     
         24 . A process to prepare a compound according to any one of  claims 1  to  22  comprising the reaction of a compound of formula (II) in the presence of a compound of formula (IV), wherein R 1  is alkyl, haloalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, 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 or substituted benzofuran-2-yl, wherein substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, 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 R 3 , R 4  and R 5  and R 2 , R 3 , R 4 , R 5  A 1  and A 2  are as defined in any one of  claim 1  to  18 . 
       
         
           
           
               
               
           
         
       
     
     
         25 . A compound according to any one of  claims 1  to  22  for use as therapeutically active substance. 
     
     
         26 . A pharmaceutical composition comprising a compound according to any one of  claims 1  to  22  and a therapeutically inert carrier. 
     
     
         27 . The use of a compound according to any one of  claims 1  to  22  for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection. 
     
     
         28 . A compound according to any one of  claims 1  to  22  for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection. 
     
     
         29 . The use of a compound according to any one of  claims 1  to  22  for the preparation of a medicament for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection. 
     
     
         30 . 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 according to any one of  claims 1  to  22 . 
     
     
         31 . A compound according to any one of  claims 1  to  22 , when manufactured according to a process of  claim 23  or  24 . 
     
     
         32 . The invention as hereinbefore described.