Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors

Abstract

The present invention relates to novel heterocyclic compounds which are useful for inhibiting glycogen synthase kinase 3 (GSK-3), methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.

1 . A heterocyclic compound of the general formulae IA and IB 
       
         
           
           
               
               
           
         
         a stereoisomer, N-oxide, tautomer and/or physiologically tolerated acid addition salt thereof; and the compound of the general formulae IA and IB, wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope, 
         wherein 
         X 1 , X 2 , X 3  and X 4  are independently of each other selected from the group consisting of CR 1  and N; 
         each R 1  is independently selected from the group consisting of hydrogen, cyano, NR a R b , OH, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -halocycloalkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -haloalkenyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, formyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, COOH, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -haloalkoxycarbonyl, C 1 -C 6 -alkyl-NR a R b , CO—NR a R b , an aromatic radical Ar, which is selected from the group consisting of phenyl and a 5- or 6-membered N- or C-bound heteroaromatic radical comprising 1, 2 or 3 heteroatoms independently selected from O, S and N as ring members, wherein Ar is unsubstituted or carries one or two radicals R 7  and wherein Ar may also be bonded via a CH 2  group, and saturated or partially unsaturated 3-, 4-, 5-, 6- or 7-membered heterocyclic radical comprising 1, 2 or 3 heteroatoms selected from O, S and N as ring members, wherein the heterocyclic radical is unsubstituted or substituted by 1, 2, 3 or 4 radicals independently selected from halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy; 
         R 2  is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -haloalkenyl, OH or F; 
         R 3  and R 4 ; or R 4  and R 5 ; or R 5  and R 6  form together a bridging group —(CH 2 ) m —, wherein m is 3, 4 or 5, where 1, 2 or 3 of the CH 2  groups may be replaced by a group or a heteroatom selected from CO, O, S, SO, SO 2 , NR c  and NO, and where 1, 2 or 3 hydrogen atoms of the bridging group may be replaced by a radical R 8 ;
 where the radicals R 3 , R 4 , R 5  and R 6 , which are not part of the bridging group, are independently selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy and NR a R b ; 
 
         each R 7  is independently selected from the group consisting of halogen, OH, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, NR a R b , C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -haloalkoxycarbonyl, CO—NR a R b , a phenyl group and a saturated, partially unsaturated or aromatic 5- or 6-membered heterocyclic radical comprising 1, 2 or 3 heteroatoms selected from O, S and N as ring members, wherein phenyl and the hetero-cyclic radical are, independently of each other, unsubstituted or substituted by 1, 2, 3 or 4 radicals independently selected from halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy, or in the hetero-cyclic ring two geminally bound radicals may together form a group ═O; 
         each R 8  is independently selected from the group consisting of halogen, OH, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, NR a R b , C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -haloalkoxycarbonyl, CO—NR a R b , a phenyl group and a saturated, partially unsaturated or aromatic 3-, 4-, 5-, 6- or 7-membered heterocyclic radical comprising 1, 2 or 3 heteroatoms selected from O, S and N as ring members, wherein phenyl and the heterocyclic radical are, independently of each other, unsubstituted or substituted by 1, 2, 3 or 4 radicals independently selected from halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy; 
         R a  and R b  are independently of each other selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl and C 1 -C 6 -haloalkoxycarbonyl; or
 R a  and R b  form, together with the nitrogen atom to which they are bonded, a 3-, 4-, 5-, 6- or 7-membered saturated or unsaturated aromatic or non-aromatic N-heterocyclic ring, which may contain 1 further heteroatom or heteroatom-containing group selected from N, O, S, SO and SO 2  as a ring member, where the N-heterocyclic ring may carry 1 or 2 radicals selected from halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy; and 
 
         each R c  is independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl and C 1 -C 6 -haloalkoxycarbonyl. 
       
     
     
         2 . The heterocyclic compound of  claim 1 , wherein R 3  and R 4 ; or R 4  and R 5 ; or R 5  and R 6  form together a bridging group —(CH 2 ) m —, wherein m is 3, 4 or 5, where 1, 2 or 3 of the CH 2  groups may be replaced by a group or a heteroatom selected from CO, O, S, SO, SO 2 , NR c  and NO, and where 1, 2 or 3 hydrogen atoms of the bridging group may be replaced by a radical R 8 ;
 with the proviso that in case R 3  and R 4  form together a bridging group —(CH 2 ) m —, the CH 2  unit bound in the position of R 3  is not replaced by a NW group; 
 where the radicals R 3 , R 4 , R 5  and R 6 , which are not part of the bridging group, are independently selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy, and where R 4 , R 5  and R 6  may independently also be selected from NR a R b . 
 
     
     
         3 . The heterocyclic compound of  claim 1 , wherein R 3  and R 4 ; or R 4  and R 5 ; or R 5  and R 6  form together a bridging group —(CH 2 ) m —, wherein m is 3, 4 or 5, where 1 or 2 of the CH 2  groups may be replaced by a group or a heteroatom selected from CO, 0 and NW, and where 1 or 2 or 3 hydrogen atoms of the bridging group may be replaced by a radical R 8 . 
     
     
         4 . The heterocyclic compound of  claim 1 , where m is 3 or 4. 
     
     
         5 . The heterocyclic compound of  claim 3 , where the bridging group is selected from —CH 2 CH 2 CH 2 —, —OCH 2 CH 2 —, —CH 2 CH 2 O—, —CH 2 OCH 2 —, —NR c CH 2 CH 2 —, —CH 2 CH 2 NR c —, —CH 2 NR c CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —OCH 2 CH 2 CH 2 —, —CH 2 OCH 2 CH 2 —, —CH 2 CH 2 OCH 2 —, —CH 2 CH 2 CH 2 O—, —NR c CH 2 CH 2 CH 2 —, —CH 2 NR c CH 2 CH 2 —, —CH 2 CH 2 NR c CH 2 —, —CH 2 CH 2 CH 2 NR c —, —C(═O)CH 2 CH 2 CH 2 —, —CH 2 C(═O)CH 2 CH 2 —, —CH 2 CH 2 C(═O)CH 2 — and —CH 2 CH 2 CH 2 C(═O)—, where the hydrogen atoms of the above groups may be replaced by 1 or 2 radicals R 8 . 
     
     
         6 . The heterocyclic compound of  claim 5 , where the bridging group is selected from —CH 2 CH 2 CH 2 —, —OCH 2 CH 2 —, —CH 2 CH 2 O—, —CH 2 OCH 2 —, —CH 2 NR c CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —OCH 2 CH 2 CH 2 —, —CH 2 OCH 2 CH 2 —, —CH 2 CH 2 OCH 2 —, —CH 2 CH 2 CH 2 O—, —CH 2 NR c CH 2 CH 2 —, —CH 2 CH 2 NR c CH 2 —, —C(═O)CH 2 CH 2 CH 2 —, —CH 2 C(═O)CH 2 CH 2 —, —CH 2 CH 2 C(═O)CH 2 — and —CH 2 CH 2 CH 2 C(═O)—, where the hydrogen atoms of the above groups may be replaced by 1 or 2 radicals R 8 . 
     
     
         7 . The heterocyclic compound of  claim 6 , where the bridging group is selected from —CH 2 CH 2 CH 2 —, —CH 2 NR c CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CH 2 NR c CH 2 CH 2 —, —CH 2 CH 2 NR c CH 2 —, —C(═O)CH 2 CH 2 CH 2 —, —CH 2 C(═O)CH 2 CH 2 —, —CH 2 CH 2 C(═O)CH 2 — and —CH 2 CH 2 CH 2 C(═O)—, where the hydrogen atoms of the above groups may be replaced by 1 or 2 radicals R 8 . 
     
     
         8 . The heterocyclic compound of  claim 1 , where the radicals R 3 , R 4 , R 5  and R 6 , which are not part of the bridging group, are hydrogen. 
     
     
         9 . The heterocyclic compounds of  claim 1 , where R 3  and R 4 ; or R 4  and R 5  form together a bridging group. 
     
     
         10 . The heterocyclic compounds of  claim 9 , where R 3  and R 4  form together a bridging group. 
     
     
         11 . The heterocyclic compound of  claim 1 , where each R 8  is independently selected from the group consisting of halogen, OH, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, NR a R b , C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl and C 1 -C 6 -haloalkoxycarbonyl. 
     
     
         12 . The heterocyclic compound of  claim 11 , where each R 8  is independently selected from the group consisting of OH, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy. 
     
     
         13 . The heterocyclic compound of  claim 1 , where R′ is hydrogen or C 1 -C 6 -alkoxycarbonyl. 
     
     
         14 . The heterocyclic compound of  claim 1 , where all of X 1 , X 2 , X 3  and X 4  are CR 1  or one of X 2 , X 3  and X 4  is N and the others are CR 1 . 
     
     
         15 . The heterocyclic compound of  claim 14 , where all of X 1 , X 2 , X 3  and X 4  are CR 1 . 
     
     
         16 . The heterocyclic compound of  claim 15 , where X 1 , X 2  and X 4  are CH and X 3  is CR 1 . 
     
     
         17 . The heterocyclic compound of  claim 16 , where X 3  is CR 1 , wherein R 1  is H, CN or COOH, preferably CN. 
     
     
         18 . The heterocyclic compound of  claim 1 , where R 2  is hydrogen. 
     
     
         19 . The heterocyclic compound of  claim 1 , where R 2  is C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 2 -C 4 -alkenyl or fluorine. 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . A pharmaceutical composition comprising at least one heterocyclic compound as defined in  claim 1 , a stereoisomer, N-oxide, tautomer and/or physiologically tolerated acid addition salt thereof or comprising at least one heterocyclic compound as defined in any of the preceding claims wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope, and at least one physiologically acceptable carrier and/or auxiliary substance. 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . (canceled)