Novel Compounds Having Selective Inhibiting Effect at GSK3

Abstract

Compounds of formula I wherein Z, X, Y, ring P, ring Q, R, R 3 , R 4 , n and m are as defined in the specification, as a free base or a pharmaceutically acceptable salt, solvate or solvate of a salt; processes for their preparation and new intermediates used therein, pharmaceutical formulations containing said compounds, and the use of said compounds in therapy.

1 . A compound having the formula I 
     
       
         
         
             
             
         
       
     
     wherein:
 Z is N; 
 Y is CONR 5 , NR 5 CO, SO 2 NR 5 , NR 5 SO 2 , CH 2 NR 5 , NR 5 CH 2 , NR 5 CONR 5 , C 1-6 alkylene, CH 2 CO, COCH 2 , CH═CH, OCH 2  or CH 2 O; 
 X is CH or N; 
 P is phenyl or a 5 or 6 membered heteroaromatic ring containing one or more heteroatoms independently selected from N, O or S and said phenyl ring or heteroaromatic ring may optionally be fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring containing one or more atoms selected from C, N, O or S; 
 Q is phenyl or a 5 or 6 membered heteroaromatic ring containing one or more nitrogen atoms and said phenyl ring or heteroaromatic ring may optionally be fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring containing one or more atoms selected from C, N, O or S; 
 R is C 1-6 alkylNR 10 R 11  or C 1-6 alkylazetidine which azetidine ring may be optionally substituted by A; 
 R 3  and R 4  are independently selected from halo, nitro, CHO, C 0-6 alkylCN, OC 1-6 alkylCN, C 0-6 alkylOR 6 , OC 1-6 alkylOR 6 , fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C 0-6  alkylNR 6 R 7 , OC 1-6  alkylNR 6 R 7 , OC 1-6 alkylOC 1-6 alkylNR 6 R 7 , NR 6 OR 7  C 0-6 alkylCO 2 R 6 , OC 1-6 alkylCO 2 R 6 , C 0-6 alkylCONR 6 R 7 , OC 1-6 alkylCONR 6 R 7 , OC 1-6 alkylNR 6 (CO)R 7 , C 0-6  alkylNR 6 (CO)R 7 , O(CO)NR 6 R 7 , NR 6 (CO)OR 7 , NR 6 (CO)NR 6 R 7 , O(CO)OR 6 , O(CO)R 6 , C 0-6 alkylCOR 6 , OC 1-6 alkylCOR 6 , NR 6 (CO)(CO)R 6 , NR 6 (CO)(CO)NR 6 R 7 , SR 6 , C 0-6 alkyl(SO 2 )NR 6 R 7 , OC 1-6 alkylNR 6 (SO 2 )R 7 , OC 0-6 alkyl(SO 2 )NR 6 R 7 , C 0-6 alkyl(SO)NR 6 R 7 , OC 1-6 alkyl(SO)NR 6 R 7 , SO 3 R 6 , C 0-6 alkylNR 6 (SO 2 )NR 6 R 7 , C 0-6 alkylNR 6 (SO)R 7 , OC 1-6 alkylNR 6 (SO)R 7 , OC 0-6  alkylSO 2 R 6 , C 0-6 alkylSO 2 R 6 , C 0-6 alkylSOR 6 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl and C 0-6 alkylheteroaryl, wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl and C 0-6 alkylheteroaryl may be optionally substituted by one or more A; 
 m is 0, 1, 2, 3 or 4; 
 n is 0, 1, 2, 3 or 4; 
 R 5  is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6  alkylaryl, C 0-6  alkylheteroaryl, C 1-6  alkylNR 6 R 7  or C 1-6  alkylCONR 6 R 7 ; 
 R 6  and R 7  are independently selected from hydrogen, C 1-6 alkyl, (CO)OR 8 , C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl and C 1-6  alkylNR 8 R 9 ; 
 R 6  and R 7  may together form a substituted 5 or 6 membered heterocyclic ring containing one or more heteroatoms independently selected from N, O or S, which heterocyclic ring may be optionally substituted by A; 
 R 8  and R 9  are independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl and C 0-6 alkylheteroaryl; 
 R 8  and R 9  may together form a 5 or 6 membered heterocyclic ring containing one or more heteroatoms independently selected from N, O or S, which heterocyclic ring may be optionally substituted by A; 
 R 10  is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl or C 1-6 alkylNR 8 R 9 ; 
 R 11  is C 0-6 alkylC 3-6 cycloalkyl; 
 A is halo, nitro, CHO, CN, OR 6 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C 0-6 alkylNR 6 R 7 , OC 1-6 alkylNR 6 R 7 , CO 2 R 8 , CONR 6 R 7 , NR 6 (CO)R 6 , O(CO)R 6 , COR 6 , SR 6 , (SO 2 )NR 6 R 7 , (SO)NR 6 R 7 , SO 3 R 6 , SO 2 R 6  or SOR 6 ; 
 
     as a free base or a pharmaceutically acceptable salt, solvate or solvate of salt thereof. 
   
   
       2 . A compound according to  claim 1 , wherein:
 Z is N;   Y is CONR 5 ;   X is N;   P is phenyl;   Q is a 6 membered aromatic heterocyclic ring containing one nitrogen atom;   R is C 1-6 alkylNR 10 R 11 ;   m is 0; n is 0;   R 5  is hydrogen;   R 10  is hydrogen or C 0-6 alkylC 3-6 cycloalkyl; C 0-6 alkylaryl, C 0-6 alkylheteroaryl or C 1-6  alkylNR 8 R 9 ; and   R 11  is C 0-6 alkylC 3-6 cycloalkyl.   
   
   
       3 - 6 . (canceled) 
   
   
       7 . A pharmaceutical formulation comprising as active ingredient a therapeutically effective amount of a compound according to  claim 1  or  2  in association with at least one pharmaceutically acceptable carrier or diluent. 
   
   
       8 - 20 . (canceled)