Triazolopyrimidine Derivatives As Glycogen Synthase Kinase 3 Inhibitors

Abstract

This invention concerns compounds of formula N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof, their use, pharmaceutical compositions comprising them, processes for their preparation, and methods of their use.

1 . A method for treatment of a disease mediated through GSK3 comprising:
 administering a therapeutically effective amount of a compound of formula I   
     
       
         
         
             
             
         
       
       a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein 
       ring A represents phenyl; 
       R 1  represents hydrogen; aryl; formyl; C 1-6 alkylcarbonyl; C 1-6 alkyl; C 1-6 alkyloxycarbonyl; C 1-6 alkyl substituted with formyl, C 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylcarbonyloxy; or C 1-6 alkyloxyC 1-6 alkylcarbonyl optionally substituted with C 1-6 alkyloxycarbonyl; 
       X represents a direct bond; —(CH 2 ) n3 — or —(CH 2 ) n4 —X 1a —X 1b —;
 with n 3  representing an integer with value 1, 2, 3 or 4; 
 with n 4  representing an integer with value 1 or 2; 
 with X 1a  representing O, C(═O) or NR 5 ; and 
 with X 1b  representing a direct bond or C 1-2 alkyl; 
 
       R 2  represents C 3-7 cycloalkyl; phenyl; a 4, 5, 6- or 7-membered monocyclic heterocycle containing at least one heteroatom selected from O, S or N; benzoxazolyl or a radical of formula 
     
     
       
         
         
             
             
         
       
       
         wherein —B—C— represents a bivalent radical of formula
   —CH 2 —CH 2 —CH 2 —  (b-1); 
   —CH 2 —CH 2 —CH 2 —CH 2 —  (b-2); 
   —X 1 —CH 2 —CH 2 —(CH 2 ) n —  (b-3); 
   —X 1 —CH 2 —(CH 2 ) n —X 1 —  (b-4); 
   —X 1 —(CH 2 ) n′ —CH═CH—  (b-5); 
   —CH═N—X 1 —  (b-6); 
 
         with X 1  representing O or NR 5 ;
 n representing an integer with value 0, 1, 2 or 3; 
 n′ representing an integer with value 0 or 1; 
 
       
       wherein said R 2  substituent, where possible, may optionally be substituted with at least one substituent selected from halo; hydroxy; C 1-6 alkyl optionally substituted with at least one substituent selected from hydroxy, cyano, carboxyl, C 1-4 alkyloxy, C 1-4 alkyloxyC 1-4 alkyloxy, C 1-4 alkylcarbonyl, C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyloxy, NR 6 R 7 , —C(═O)—NR 6 R 7 , —NR 5 —C(═O)—NR 6 R 7 , —S(═O) n1 —R 8  or —NR 5 —S(═O) n1 —R 8 ; C 2-6 alkenyl or C 2-6 alkynyl, each optionally substituted with at least one substituent selected from hydroxy, cyano, carboxyl, C 1-4 alkyloxy, C 1-4 alkylcarbonyl, C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyloxy, NR 6 R 7 , —C(═O)—NR 6 R 7 , —NR 5 —C(═O)—NR 6 R 7 , —S(═O) n1 —R 8  or —NR 5 —S(═O) n1 —R 8 ; polyhaloC 1-6 alkyl optionally substituted with at least one substituent selected from hydroxy, cyano, carboxyl, C 1-4 alkyloxy, C 1-4 alkyloxyC 1-4 alkyloxy, C 1-4 alkylcarbonyl, C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyloxy, NR 6 R 7 , —C(═O)—NR 6 R 7 , —NR 5 —C(═O)—NR 6 R 7 , —S(═O) n1 —R 8  or —NR 5 —S(═O) n1 —R 8 ; C 1-6 alkyloxy optionally substituted with at least one substituent selected from hydroxy, cyano, carboxyl, C 1-4 alkyloxy, C 1-4 alkylcarbonyl, C 1-4 alkyl-oxycarbonyl, C 1-4 alkylcarbonyloxy, NR 6 R 7 , —C(═O)—NR 6 R 7 , —NR 5 —C(═O)—NR 6 R 7 , —S(═O) n1 —R 8  or —NR 5 —S(═O) n1 —R 8 ; polyhaloC 1-6 alkyloxy optionally substituted with at least one substituent selected from hydroxy, cyano, carboxyl, C 1-4 alkyloxy, C 1-4 alkyloxyC 1-4 alkyloxy, C 1-4 alkylcarbonyl, C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyloxy, NR 6 R 7 , —C(═O)—NR 6 R 7 , —NR 5 —C(═O)—NR 6 R 7 , —S(═O) n1 —R 8  or —NR 5 —S(═O) n1 —R 8 ; C 1-6 alkylthio; polyhaloC 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; C 1-6 alkylcarbonyl; polyhaloC 1-6 alkylcarbonyl; cyano; carboxyl; NR 6 R 7 ; C(═O)NR 6 R 7 ; —NR 5 —C(═O)—NR 6 R 7 ; —NR 5 —C(═O)—R 5 ; —S(═O) n1 —R 8 ; —NR 5 —S(═O) n1 —R 8 ; —S—CN; —NR 5 —CN; aryloxy; arylthio; arylcarbonyl; arylC 1-4 alkyl; arylC 1-4 alkyloxy; a 5- or 6-membered monocyclic heterocycle containing at least one heteroatom selected from O, S or N and said 5- or 6-membered monocyclic heterocycle optionally being substituted with at least one substituent selected from R 9 ; or 
     
     
       
         
         
             
             
         
       
       
         with n2 representing an integer with value 0, 1, 2, 3 or 4; 
         with X 2  representing O, NR 5  or a direct bond; 
         with X 3  representing O, CH 2 , CHOH, CH—N(R 5 ) 2 , NR 5  or 
         N—C(═O)—C 1-4 alkyl; 
       
       R 3  represents halo; hydroxy; C 1-6 alkyl optionally substituted with at least one substituent selected from hydroxy, cyano, carboxyl, C 1-4 alkyloxy, C 1-4 alkyloxyC 1-4 alkyloxy, C 1-4 alkylcarbonyl, C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyloxy, NR 6b R 7b , —C(═O)—NR 6b R 7b , —NR 5 —C(═O)—NR 6b R 7b , —S(═O) n1 —R 8a  or —NR 5 —S(═O) n1 —R 8a ; C 2-6 alkenyl or C 2-6 alkynyl, each optionally substituted with at least one substituent selected from hydroxy, cyano, carboxyl, C 1-4 alkyloxy, C 1-4 alkylcarbonyl, C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyloxy, NR 6b R 7b , —C(═O)—NR 6b R 7b , —NR 5 —C(═O)—NR 6b R 7b , —S(═O) n1 —R 8a  or —NR 5 —S(═O) n1 —R 8a ; polyhaloC 1-6 alkyl optionally substituted with at least one substituent selected from hydroxy, cyano, carboxyl, C 1-4 alkyloxy, C 1-4 alkyloxy-C 1-4 alkyloxy, C 1-4 alkylcarbonyl, C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyloxy, NR 6b R 7b , —C(═O)—NR 6b R 7b , —NR 5 —C(═O)—NR 6b R 7b , —S(═O) n1 —R 8a  or —NR 5 —S(═O) n1 —R 8a ; C 1-6 alkyloxy optionally substituted with one substituent selected from hydroxy, cyano, carboxyl, C 1-4 alkyloxy, C 1-4 alkylcarbonyl, C 1-4 alkyloxy-carbonyl, C 1-4 alkylcarbonyloxy, NR 6b R 7b , —C(═O)—NR 6b R 7b , —NR 5 —C(═O)—NR 6b R 7b , —S(═O) n1 —R 8a  or —NR 5 —S(═O) n1 —R 8a ; polyhaloC 1-6 alkyloxy optionally substituted with at least one substituent selected from hydroxy, cyano, carboxyl, C 1-4 alkyloxy, C 1-4 alkyloxyC 1-4 alkyloxy, C 1-4 alkylcarbonyl, C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyloxy, NR 6b R 7b , —C(═O)—NR 6b R 7b , —NR 5 —C(═O)—NR 6b R 7b , —S(═O) n1 —R 8a  or —NR 5 —S(═O) n1 —R 8a ; C 1-6 alkylthio; polyhaloC 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; C 1-6 alkylcarbonyl; polyhaloC 1-6 alkylcarbonyl; cyano; carboxyl; aryloxy; arylthio; arylcarbonyl; NR 6b R 7b ; C(═O)—NR 6b R 7b ; —NR 5 —C(═O)—NR 6b R 7b ; —NR 5 —C(═O)—R 5 ; —S(═O) n1 —R 8a ; —NR 5 —S(═O) n1 —R 8a ; —S—CN; or —NR 5 —CN; 
       R 4  represents hydrogen; halo; hydroxy; C 1-4 alkyl optionally substituted with at least one substituent selected from hydroxy, cyano, carboxyl, C 1-4 alkyloxy, C 1-4 alkylcarbonyl, C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyloxy, NR 10 R 11 , —C(═O)—NR 10 R 11 , —NR 5 —C(═O)—NR 10 R 11 , —S(═O) n1 —R 12  or —NR 5 —S(═O) n1 —R 12 ; C 2-4 alkenyl or C 2-4 alkynyl, each optionally substituted with at least one substituent selected from hydroxy, cyano, carboxyl, C 1-4 alkyloxy, C 1-4 alkylcarbonyl, C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyloxy, NR 10 R 11 , —C(═O)—NR 10 R 11 , —NR 5 —C(═O)—NR 10 R 11 , —S(═O) n1 —R 12  or —NR 5 —S(═O) n1 —R 12 ; polyhaloC 1-3 alkyl; C 1-4 alkyloxy optionally substituted with carboxyl; polyhaloC 1-3 alkyloxy; C 1-4 alkylthio; polyhaloC 1-3 alkylthio; C 1-4 alkyloxycarbonyl; C 1-4 alkylcarbonyloxy; C 1-4 alkylcarbonyl; polyhaloC 1-4 alkylcarbonyl; nitro; cyano; carboxyl; NR 10 R 11 ; C(═O)NR 10 R 11 ; —NR 5 —C(═O)—NR 10 R 11 ; —NR 5 —C(═O)—R 5 ; —S(═O) n1 —R 12 ; —NR 5 —S(═O) n1 —R 12 ; —S—CN; or —NR 5 —CN; 
       R 5  represents hydrogen; C 1-4 alkyl or C 2-4 alkenyl; 
       R 6  and R 7  each independently represent hydrogen; cyano; C 1-6 alkylcarbonyl optionally substituted with C 1-4 alkyloxy or carboxyl; C 1-6 alkyloxycarbonyl; C 3-7 cycloalkylcarbonyl; adamantanylcarbonyl; C 1-4 alkyloxyC 1-4 alkyl; C 1-4 alkyl substituted with C 1-4 alkyl-NR 5 —; C 1-6 alkyl optionally substituted with at least one substituent selected from halo, hydroxy, cyano, carboxyl, C 1-4 alkyloxy, polyhaloC 1-4 alkyl, C 1-4 alkyloxyC 1-4 alkyloxy, NR 6a R 7a , C(═O)NR 6a R 7a  or 
     
     
       
         
         
             
             
         
       
        with X 4  representing O, CH 2 , CHOH, CH—N(R 5 ) 2 , NR 5  or N—C(═O)—C 1-4 alkyl; 
       R 6a  and R 7a  each independently represent hydrogen; C 1-4 alkyl; C 1-4 alkylcarbonyl or a 5- or 6-membered monocyclic heterocycle containing at least one heteroatom selected from O, S or N; 
       R 6b  and R 7b  each independently represent hydrogen; cyano; C 1-6 alkylcarbonyl optionally substituted with C 1-4 alkyloxy or carboxyl; C 1-6 alkyloxycarbonyl; C 3-7 cycloalkylcarbonyl; adamantanylcarbonyl; C 1-4 alkyloxyC 1-4 alkyl; C 1-4 alkyl substituted with C 1-4 alkyl-NR 5 —; C 1-6 alkyl optionally substituted with at least one substituent selected from halo, hydroxy, cyano, carboxyl, C 1-4 alkyloxy, polyhaloC 1-4 alkyl, C 1-4 alkyloxyC 1-4 alkyloxy, NR 6c R 7c  or C(═O)NR 6c R 7c ; 
       R 6c  and R 7c  each independently represent hydrogen; C 1-4 alkyl or C 1-4 alkylcarbonyl; 
       R 8  represents C 1-4 alkyl optionally substituted with hydroxy; polyhaloC 1-4 alkyl or NR 6 R 7 ; 
       R 8a  represents C 1-4 alkyl optionally substituted with hydroxy; polyhaloC 1-4 alkyl or NR 6b R 7b ; 
       R 9  represents halo; hydroxy; C 1-6 alkyl optionally substituted with at least one substituent selected from hydroxy, cyano, carboxyl, C 1-4 alkyloxy, C 1-4 alkylcarbonyl, C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyloxy, NR 6 R 7 , —C(═O)—NR 6 R 7 , —NR 5 —C(═O)—NR 6 R 7 , —S(═O) n1 —R 8  or —NR 5 —S(═O) n1 —R 8 ; C 2-6 alkenyl or C 2-6 alkynyl, each optionally substituted with at least one substituent selected from hydroxy, cyano, carboxyl, C 1-4 alkyloxy, C 1-4 alkylcarbonyl, C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyloxy, NR 6 R 7 , —C(═O)—NR 6 R 7 , —NR 5 —C(═O)—NR 6 R 7 , —S(═O) n1 —R 8  or —NR 5 —S(═O) n1 —R 8 ; polyhaloC 1-6 alkyl; C 1-6 alkyloxy optionally substituted with carboxyl; polyhaloC 1-6 alkyloxy; C 1-6 alkylthio; polyhaloC 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; C 1-6 alkylcarbonyl; cyano; carboxyl; NR 6 R 7 ; C(═O)NR 6 R 7 ; —NR 5 —C(═O)—NR 6 R 7 ; —NR 5 —C(═O)—R 5 ; —S(═O) n1 —R 8 ; —NR 5 —S(═O) n1 —R 8 ; —S—CN; or —NR 5 —CN; 
       R 10  and R 11  each independently represent hydrogen; C 1-6 alkyl; cyano; C 1-6 alkylcarbonyl; C 1-4 alkyloxyC 1-4 alkyl; or C 1-4 alkyl substituted with C 1-4 alkyl-NR 5 —; 
       R 12  represents C 1-4 alkyl or NR 10 R 11 ; 
       n1 represents an integer with value 1 or 2; 
       aryl represents phenyl or phenyl substituted with at least one substituent selected from halo, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, cyano, nitro, polyhaloC 1-6 alkyl or polyhaloC 1-6 alkyloxy; 
       to a patient in need of treatment for a disease mediated through GSK3. 
     
   
   
       2 . The method for the treatment of a disease mediated through GSK3 of  claim 1  wherein the disease is selected from the group consisting of bipolar disorder, type-2 diabetes, Alzheimer's disease, leukopenia, FTDP-17 (Fronto-temporal dementia associated with Parkinson's disease), cortico-basal degeneration, progressive supranuclear palsy, multiple system atrophy, Pick's disease, Niemann Pick's disease type C, Dementia Pugilistica, dementia with tangles only, dementia with tangles and calcification, Downs syndrome, myotonic dystrophy, Parkinsonism-dementia complex of Guam, AIDS-related dementia, Postencephalic Parkinsonism, prion diseases with tangles, subacute sclerosing panencephalitis, frontal lobe degeneration, argyrophilic grains disease, subacute sclerotizing panencephalitis, GSK3-mediated inflammatory diseases, depression, dermatological disorders, neuroprotection, schizophrenia, and pain. 
   
   
       3 . The method for the treatment of a disease mediated through GSK3 of  claim 1  wherein the disease is selected from the group consisting of Alzheimer's disease; type 2 diabetes; GSK3-mediated inflammatory diseases; bipolar disorder; depression; and pain.