NEW OCTAHYDRO-PYRROLO[3,4-c]-PYRROLE DERIVATIVES AND ANALOGS THEREOF AS AUTOTAXIN INHIBITORS

Abstract

The invention provides novel compounds having the general formula (I) wherein R 1 , Y, A, W, R 2 , m, n, p and q are as described herein, compositions including the compounds and methods of using the compounds.

1 . A Compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted naphthyl, substituted naphthylalkyl, substituted naphthyloxyalkyl, substituted naphthylalkenyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl, substituted indolyl, substituted quinolyl, substituted isoquinolyl, 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 naphthyl, substituted naphthylalkyl, substituted naphthyloxyalkyl, substituted naphthylalkenyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl, substituted indolyl, substituted quinolyl, substituted isoquinolyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl and substituted benzofuran-2-yl are substituted with R 7 , R 8  and R 9 ; 
 R 2  is substituted phenyl, substituted pyridinyl, substituted pyrrolyl, oxodihydropyridinyl or substituted thiophenyl, wherein substituted phenyl, substituted pyridinyl, substituted pyrrolyl and substituted thiophenyl are substituted with R 10 , R 11  and R 12 ; 
 Y is —OC(O)—, —NR 5 C(O)—, —C(O)—, —S(O) 2 —, 
 
       
         
           
           
               
               
           
         
         A is —N— or CH—; 
         W is —O—, —S—, —NR 6 —, —C(O)—, —S(O) 2 —, or —CR 3 R 4 —; 
         R 3  and R 4  are independently selected from H, halogen, alkyl and cycloalkyl; 
         R 5  and R 6  are independently selected from H, alkyl and cycloalkyl; 
         R 7 , R 8  and R 9  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, 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, wherein at least one of R 7 , R 8  and R 9  is not H; 
         R 10  is substituted aminosulfonyl, alkoxycarbonyl, alkylcarbonylamino, alkylsulfonylamino, substituted amino, carboxy, cyano, hydroxy or tetrazolyl, wherein substituted amino is substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl and alkoxyalkyl; 
         R 11  and R 12  are independently selected from H, alkyl, cycloalkyl, alkoxy, halogen and haloalkyl; 
         m, n, p and q are independently selected from 1 or 2; 
       
       or pharmaceutically acceptable salts. 
     
     
         2 . The compound according to  claim 1 , wherein R 1  is substituted phenyl, substituted phenylalkyl, substituted phenylalkenyl, substituted naphthyl, substituted indolyl, substituted quinolyl, or substituted isoquinolyl, wherein substituted phenyl, substituted phenylalkyl, substituted phenylalkenyl, substituted naphthyl, substituted indolyl, substituted quinolyl and substituted isoquinolyl are substituted with R 7 , R 8  and R 9 . 
     
     
         3 . The compound according to  claim 1 , wherein R 1  is phenylalkyl substituted with R 7 , R 8  and R 9 . 
     
     
         4 . The compound according to  claim 1 , wherein R 1  is 3,5-dichlorobenzyl, 4-trifluoromethoxybenzyl or 4-trifluoromethoxyphenylethyl. 
     
     
         5 . The compound according to  claim 1 , wherein R 2  is substituted phenyl or substituted pyridinyl, wherein substituted phenyl and substituted pyridinyl are substituted with R 10 , R 11  and R 12 . 
     
     
         6 . The compound according to  claim 1 , wherein R 2  is phenyl substituted phenyl with R 10 , R 11  and R 12 . 
     
     
         7 . The compound according to  claim 1 , wherein R 2  is 4-aminosulfonylphenyl, 3-fluoro-4-aminosulfonylphenyl, 3-aminosulfonylpyridin-6-yl or 2-aminosulfonylpyridin-5-yl. 
     
     
         8 . The compound according to  claim 1 , wherein Y is —OC(O)— or —C(O)—. 
     
     
         9 . The compound according to  claim 1 , wherein A is —N—. 
     
     
         10 . The compound according to  claim 1 , wherein W is —C(O)— or —S(O) 2 —. 
     
     
         11 . The compound according to  claim 1 , wherein W is —C(O)—. 
     
     
         12 . The compound according to  claim 1 , wherein R 7 , R 8  and R 9  are independently selected from H, alkoxy, haloalkoxy, halogen, alkylsulfonyl and phenyl substituted with one halogen, and wherein at least one of R 7 , R 8  and R 9  is not H. 
     
     
         13 . The compound according to  claim 1 , wherein R 7  is alkoxy, haloalkoxy, halogen or phenyl substituted with one halogen. 
     
     
         14 . The compound according to  claim 1 , wherein R 7  is haloalkoxy or halogen. 
     
     
         15 . The compound according to  claim 1 , wherein R 8  is H, halogen or alkylsulfonyl. 
     
     
         16 . The compound according to  claim 1 , wherein R 8  is H or halogen. 
     
     
         17 . The compound according to  claim 1 , wherein R 9  is H. 
     
     
         18 . The compound according to  claim 1 , wherein R 10  is aminosulfonyl. 
     
     
         19 . The compound according to  claim 1 , wherein R 11  and R 12  are independently selected from H, alkyl and halogen. 
     
     
         20 . The compound according to  claim 1 , wherein R 11  and R 12  are independently selected from H and halogen. 
     
     
         21 . The compound according to  claim 1 , wherein m and n are 1. 
     
     
         22 . The compound according to  claim 1 , wherein m, n, p and q are 1. 
     
     
         23 . The compound according to  claim 1  of formula (Ia). 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound according to  claim 1 , selected from
 (3aR,6aS)-3,5-dichlorobenzyl 5-(4-(N-methylsulfamoyl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;   (3aR,6aS)-3,5-dichlorobenzyl 5-(5-hydroxypicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;   (3aR,6aS)-3,5-dichlorobenzyl 5-(4-hydroxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;   trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5 (6H)-carboxylate;   (3aR,6aS)-3,5-dichlorobenzyl 5-(5-sulfamoylthiophene-2-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;   (3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;   (3aR,6aS)-3,5-dichlorobenzyl 5-(4-aminobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;   (3aR,6aS)-3,5-dichlorobenzyl 5-(5-aminopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;   (3aR,6aS)-3,5-dichlorobenzyl 5-(4-cyanobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;   (3aR,6aS)-3,5-dichlorobenzyl 5-(4-(methoxycarbonyl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;   4-{(3aS,8aR)-6-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-octahydro-pyrrolo[3,4-d]azepine-2-carbonyl}-benzenesulfonamide;   (3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;   (3aS,6aS)-5-(6-oxo-1,6-dihydro-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;   (3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;   (3aS,6aS)-5-(1-methyl-4-sulfamoyl-1H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;   (3aS,6aS)-5-(1-methyl-5-sulfamoyl-1H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;   (3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;   (3aS,6aS)-5-(5-hydroxy-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;   (3aS,6aS)-5-(4-hydroxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;   (3aR,6aS)-3,5-dichlorobenzyl 5-(4-acetamidobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;   (3aR,6aS)-3,5-dichlorobenzyl 5-(5-acetamidopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;   (3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylphenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;   (3aR,6aS)-3,5-dichlorobenzyl 5-(4-(1H-tetrazol-5-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;   4-((3aR,6aS)-5-((3,5-dichlorobenzyloxy)carbonyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzoic acid;   (3aR,6aS)-3,5-dichlorobenzyl 5-(5-(methylsulfonamido)picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;   (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-chloro-5-methanesulfonyl-benzyl ester;   (3aR,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 2-fluoro-4-trifluoromethoxy-benzyl ester;   (3aR,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;   (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;   4-{(3 aR,6aR)-5-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;   4-{(3 aR,6aR)-5-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;   4-[(3aR,6aS)-5-(4-isopropoxy-naphthalene-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;   4-{(3 aR,6aS)-5-[1-(2,2,2-trifluoro-ethoxy)-isoquinoline-3-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;   4-[(3 aR,6aS)-5-(1-Methyl-5-trifluoromethoxy-1H-indole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;   4-[(3 aR,6aS)-5-(4-Isopropoxy-quinoline-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;   4-[(3 aS,6aR)-5-(4′-chloro-biphenyl-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;   4-{(3 aS,6aR)-5-[3-(2-fluoro-4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;   4-{(3 aS,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;   4-((3aR,6aR)-5-(3-(2-fluoro-4-(trifluoromethoxy)phenyl)propanoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide;   (+)-trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5 (6H)-carboxylate;   (−)-trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate;   (3aS,6aS)-5-(2-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;   5-{(3aR,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-pyridine-2-sulfonic acid amide;   5-((3aS,6aS)-5-(4-ethoxyquinoline-2-carbonyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)pyridine-2-sulfonamide;   (3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester;   (3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester;   (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzylester;   (3aS,6aS)-5-(2-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester;   (3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester;   and pharmaceutically acceptable salts thereof.   
     
     
         25 . A compound according to  claim 1 , selected from
 (3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;   (3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;   (3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;   (3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;   (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;   4-{(3aR,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;   (3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester;   and pharmaceutically acceptable salts thereof.   
     
     
         26 . A process to prepare a compound according to  claim 1  comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III), wherein R 1 , R 2 , A, W, m, n, p and q are as defined above, Y is —OC(O)—. 
       
         
           
           
               
               
           
         
       
     
     
         27 . (canceled) 
     
     
         28 . A pharmaceutical composition comprising a compound according to  claim 1  and a therapeutically inert carrier. 
     
     
         29 - 31 . (canceled) 
     
     
         32 . 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  claim 1 . 
     
     
         33 - 34 . (canceled)