Diazaspirocycloalkane and azaspirocycloalkane

Abstract

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

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is alkyl, haloalkyl, cycloalkyl, 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 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 8 , R 9  and R 10 , wherein in case R 1  is alkyl and Y is —C(O)—, then R 3  is selected from the groups S, T, U, V, X, Z, AA, AB, AC, AD, AE, AF, AG, AH, AI, AJ, AK and AL; 
         R 2  is —(CR 4 R 5 ) n —R 3 , —C(O)—R 3 , —S(O) 2 —R 3  or —C(O)—NR 6 R 3 ; 
         Y is —OC(O)—, —NR 14 C(O)—, —C(O)—, —S(O) 2 —, 
       
       
         
           
           
               
               
           
         
          wherein in case R 1  is substituted phenylalkenyl, substituted pyridinylalkenyl or substituted thiophenylalkenyl, then Y is not —OC(O)—; 
         W is selected from one of the following ring systems: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
          wherein in case W is one of the ring systems M or N, then R 3  is selected from the groups S, T, U, V, X, Z, AA, AB, AC, AD, AE, AF, AG, AH, AI, AJ, AK and AL and wherein in case W is the ring system O, then R 2  is —C(O)—NR 6 R 3 ; 
         R 3  is selected from S, T, V, W, X, Y, Z, AA, AB, AC, AD, AE, AG, AH, AI, AJ, AK and AL from the following groups 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or R 3  is substituted phenyl, substituted pyridinyl or substituted thiophenyl, wherein substituted phenyl, substituted pyridinyl and substituted thiophenyl are substituted with R 11 , R 12  and R 13 ; 
         R 4  and R 5  are independently selected from H, halogen, alkyl and cycloalkyl; 
         R 6 , R 7  and R 14  are independently selected from H, alkyl and cycloalkyl; 
         R 8 , R 9 , R 10 , R 11 , R 12 , and R 13  are independently selected from H, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, halogen, hydroxy, cyano, alkylsulfonyl, 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 hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and cycloalkylcarbonyl; 
         n is zero, 1, 2 or 3; 
         or pharmaceutically acceptable salts. 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  is substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridinylalkyl, substituted thiophenylalkyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl or substituted benzofuran-2-yl, wherein substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted pyridinylalkyl, substituted thiophenylalkyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl and substituted benzofuran-2-yl are substituted with R 8 , R 9  and R 10 . 
     
     
         3 . The compound of  claim 1 , wherein R 1  is substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl or substituted phenylalkenyl, wherein substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl and substituted phenylalkenyl are substituted with R 8 , R 9  and R 10 . 
     
     
         4 . The compound of  claim 1 , wherein R 1  is phenylalkyl substituted with R 8 , R 9  and Rth. 
     
     
         5 . The compound of  claim 1 , wherein R 2  is —C(O)—R 3 . 
     
     
         6 . The compound of  claim 1 , wherein Y is —OC(O)— or —C(O)—, wherein in case R 1  is substituted phenylalkenyl, substituted pyridinylalkenyl or substituted thiophenylalkenyl, then Y is not —OC(O)—. 
     
     
         7 . The compound of  claim 1 , wherein Y is —OC(O)— and R 1  is not substituted phenylalkenyl, substituted pyridinylalkenyl or substituted thiophenylalkenyl. 
     
     
         8 . The compound of  claim 1 , wherein W is selected from one of the ring systems A, C, D, H, I, J, L, M, N, O, Q and R. 
     
     
         9 . The compound of  claim 1 , wherein W is the ring system A. 
     
     
         10 . The compound of  claim 1 , wherein R 3  is substituted phenyl, substituted pyridinyl or substituted thiophenyl, wherein substituted phenyl, substituted pyridinyl and substituted thiophenyl are substituted with R 11 , R 12  and R 13 . 
     
     
         11 . The compound of  claim 1 , wherein R 8  is haloalkoxy, halogen or alkylsulfonyl. 
     
     
         12 . The compound of  claim 1 , wherein R 9  is alkyl, haloalkyl or halogen. 
     
     
         13 . The compound of  claim 1 , wherein R 10  is H. 
     
     
         14 . A process to prepare a compound of  claim 1  comprising
 a) the reaction of a compound of formula (II) in the presence of a compound of formula (III); 
 
       
         
           
           
               
               
           
         
         or 
         b) the reaction of a compound of formula (IV) in the presence of a compound of formula (V); 
       
       
         
           
           
               
               
           
         
          wherein in step a) R 1 , R 2  and W are as defined in  claim 1 , Y is —C(O)— and compounds of formula (I) are of formula (In), and wherein in step b) R 1  and Y are as defined in claim, W is A, B, C, D, E, F, G, H, I, J, K, L, M, N, P or Q and R 2  is —C(O)—R 3 . 
       
     
     
         15 . A pharmaceutical composition comprising a compound of  claim 1  and a therapeutically inert carrier. 
     
     
         16 . 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 .