Fused Bicyclic Heteroaromatic Derivatives as Kinase Inhibitors

Abstract

A series of fused bicyclic heteroaromatic derivatives of formula (IA) or (IB), as defined herein, being selective inhibitors of phosphatidylinositol-4-kinase IIIβ (PI4KIIIβ) activity, are beneficial in the treatment and/or prevention of various human ailments, including inflammatory, autoimmune and oncological disorders; viral diseases and malaria; and organ and cell transplant rejection.

1 . A compound of formula (IB) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein 
         X represents N or CH; 
         T represents C—R 2 ; 
         U represents N—R 4 ; 
         Q represents a group of formula (Qa), (Qb), (Qc), (Qd) or (Qe): 
       
       
         
           
           
               
               
           
         
         in which the asterisk (*) represents the point of attachment to the remainder of the molecule; 
         V represents —CH 2 —, —C(CH 3 ) 2 —, —CH 2 CH 2 — or —CH 2 CH 2 CH 2 —; 
         W represents the residue of a C 3-7  cycloalkyl group; 
         Y represents a covalent bond, or a linker group selected from —C(O)—, —S(O)—, —S(O) 2 —, —C(O)O—, —C(O)N(R 5 )—, —C(O)C(O)— and —S(O) 2 N(R 5 )—, or a linker group of formula (Ya): 
       
       
         
           
           
               
               
           
         
         in which the asterisk (*) represents the point of attachment to the remainder of the molecule; 
         Z represents hydrogen; or Z represents C 1-6  alkyl, C 2-6  alkenyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl(C 1-6 )alkyl, C 3-7  heterocycloalkyl, C 3-7  heterocycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents; 
         A 1  represents hydrogen, cyano or trifluoromethyl; or A 1  represents C 1-6  alkyl, optionally substituted by one or more substituents independently selected from fluoro, —OR a , trifluoromethoxy, -—NR b R c , CO 2 R d  and —CONR b R c ; or A 1  represents C 3-7  cycloalkyl; 
         A 2  represents hydrogen or C 1-6  alkyl; 
         R 1  and R 2  independently represent hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, —OR a , —SR a , —SOR a , —SO 2 R a , —NR b R c , —CH 2 NR b R c , —NR c COR d , —CH 2 NR c COR d , —NR c CO 2 R d , —NHCONR b R c , —NR c SO 2 R e , —N(SO 2 R e ) 2 , —NHSO 2 NR b R c , —COR d , —CO 2 R d , —CONR b R c , —CON(OR a )R b  or —SO 2 NR b R c ; or C 1-6  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, C 3-7  heterocycloalkyl, C 3-7  heterocycloalkyl(C 1-6 )alkyl, C 3-7  heterocycloalkenyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents; 
         R 3  represents hydrogen, halogen or C 1-6  alkyl; 
         R 4  represents hydrogen; or R 4  represents C 1-6  alkyl, aryl, aryl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents; 
         R 5  represents hydrogen; or R 5  represents C 1-6  alkyl, optionally substituted by one or more substituents independently selected from —OR a  and —NR b R c ; 
         R a  represents hydrogen; or R a  represents C 1-6  alkyl, aryl, aryl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more sub stituents; 
         R b  and R c  independently represent hydrogen or trifluoromethyl; or C 1-6  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, C 3-7  heterocycloalkyl, C 3-7  heterocycloalkyl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents; or 
         R b  and R c , when taken together with the nitrogen atom to which they are both attached, represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents; 
         R d  represents hydrogen; or C 1-6  alkyl, C 3-7  cycloalkyl, aryl, C 3-7  heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more sub stituents; and 
         R e  represents C 1-6  alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more sub stituents. 
       
     
     
         2 . The compound as claimed in  claim 1  wherein R 1  represents —NR b R c . 
     
     
         3 . The compound as claimed in  claim 1  wherein Q represents a group of formula (Qa-1), (Qa-2) or (Qa-3): 
       
         
           
           
               
               
           
         
         in which the asterisk (*) represents the point of attachment to the remainder of the molecule. 
       
     
     
         4 . The compound as claimed in  claim 1  represented by formula (IIB-1), or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein 
         A 11  represents hydrogen, cyano, C 1-6  alkyl, —CH 2 OR a , —CH 2 CH 2 OR a , —CH 2 CO 2 R d , —CH 2 CONR b R c  or C 3-7  cycloalkyl; and 
         R 11  represents hydrogen or amino. 
       
     
     
         5 . The compound as claimed in  claim 1  represented by formula (IIB-2), or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
         A 11  represents hydrogen, cyano, C 1-6  alkyl, —CH 2 OR a , —CH 2 CH 2 OR a , —CH 2 CO 2 R d , —CH 2 CONR b R c  or C 3-7  cycloalkyl; and R 11  represents hydrogen or amino. 
       
     
     
         6 . The compound as claimed in  claim 4  wherein A 11  represents hydrogen or C 1-6  alkyl. 
     
     
         7 . The compound as claimed in  claim 6  wherein A 11  represents hydrogen, methyl or ethyl. 
     
     
         8 . The compound as claimed in  claim 4  wherein R 11  is —NH 2 . 
     
     
         9 . The compound as claimed in  claim 1  wherein X represents N. 
     
     
         10 . The compound as claimed in a  claim 1  wherein Z represents aryl or heteroaryl, either of which groups may be optionally substituted by one, two or three substituents independently selected from C 1-6  alkyl, trifluoromethyl, (C 3-7 )heterocycloalkyl, dihalo(C 3-7 )heterocycloalkyl, C 1-6  alkoxy, trifluoromethoxy and di(C 1-6 )alkylamino. 
     
     
         11 . The compound as claimed in  claim 10  wherein Z represents methoxyphenyl, dimethylaminophenyl, (methoxy)(methyl)phenyl, (isopropoxy)(methyl)phenyl, (methyl)(trifluoromethoxy)phenyl, (azetidinyl)(methyl)pyridinyl, (difluoroazetidinyl)-(methyl)pyridinyl, (methoxy)(trifluoromethyl)pyridinyl, dimethoxypyridinyl, (ethoxy)-(methyl)pyridinyl or (dimethylamino)(methyl)pyridinyl. 
     
     
         12 . The compound as claimed in  claim 1  wherein R 3  represents hydrogen or methyl. 
     
     
         13 . The compound of formula (IA) or (TB) as defined in  claim 1  as herein specifically disclosed in any one of the Examples. 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . A pharmaceutical composition comprising a compound of formula (IA) or (IB) as defined in  claim 1  or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable carrier. 
     
     
         17 . (canceled) 
     
     
         18 . A method for the treatment and/or prevention of an inflammatory, autoimmune or oncological disorder, a viral disease or malaria, or organ or cell transplant rejection, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (IA) or (IB) as defined in  claim 1  or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof.