CASEIN KINASE 1delta (CK 1delta) INHIBITORS AND THEIR USE IN THE TREATMENT OF NEURODE-GENERATIVE DISEASES SUCH AS TAUOPATHIES

Abstract

The invention relates to pharmaceutical compositions comprising casein kinase 1 delta (CK1δ) and to the use of said inhibitors in the treatment of neurodegenerative disorders such as Alzheimer's disease.

1 . A pharmaceutical composition comprising a compound of formula (IC) or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein 
         “Het C” represents a 6 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S, wherein said ring system is optionally fused to one or more (e.g. 1-3) further rings to form a polycyclic ring system comprising up to 4 rings; 
         X c  and Y c  independently represent a bond, —C(R 7c )(R 8c )-, (CH 2 ) 2 , —O—, —S—, -CH 2 —O—, —(CH 2 ) 2 —O—, NR 6c , —N(R 6c )—C(R 7c )(R 8c )-, —N(R 6c )—(CH 2 ) 2 -, —N(R 6c )—(CH 2 ) 3 -, -CH 2 —N(R 6c )—(CH 2 ) 2 - , —N(R 6c )—CO—, -CH 2 —NH—CO—(CH 2 ) 2 -, —N(R 6c )—CO—CH 2 -, —CO—N(R 6c )—CH 2 -, =N—, —C(H)(CN)-, —C(=N—NH—COC 1-6  alkyl)-, -CH=C(R 6c )—CO—, =CH-, —N=CH-, —N=C(Me)-, —C(R 6c )=CH-, -NH—CO—C(=CH-heteroaryl)-, —C=C(Me) 2 -, -CH=CH—CO—N(R 6c )-, -CH=C(R 6c )—NH—CO—, - CH=C(R 6c )—CO—O—CH 2 -, —CS—S—CH 2 -, -NH—CS—NH-, -NH—CS—NH—CH 2 -, -NH—CS—NH—(CH 2 ) 2 - , -CH 2 -N(CSNH 2 )-CH 2 -, —S—CH 2 -, —S—(CH 2 ) 2 —O—, SO 2 , -NH—SO 2 -, -CH 2 —NH—SO 2 -, CO, -CH 2 —CO—, -(CH 2 ) 2 —CO—, —O—CH 2 —COO-, -(CH 2 ) 2 —CO—, COO, -COO—C(R 6c )(R 7c )CO—, -CH=C(R 5c )—CONH—CH 2 -, —CO—CH 2 —N(R 6c )—COO-, —CO—CH 2 —C(R 6c )—CH 2 —CO—, —CO—CH 2 —N(R 6c )—CH 2 -, —CO—NH—N=C(R 7c )-, —S—CH 2 —CO—, —S—CH 2 —CO—N(R 6c )-, —S—CH 2 —CO—N(R 6c )—CH 2 -, —SO 2 —N(R 6c )—C(R 7c )(R 8c )—CONH-, —SO 2 —N(R 6c )—CH(—CH 2 -aryl)—CONH—CH 2 -, -CH(—S—C 1-6  alkyl)—C(Me)(OH)-, -CH 2 —C(R 6c )(OH)-, —C(OH)(CH(Me)(C 3-8  cycloalkyl))—CH 2 -, —C(OH)(R 6c )—CH 2 -, -CH(Me)—NH—CO—CH 2 -, —CO—N(R 6c )—CH 2 -, —CO—N(R 6c )—CH 2 —CH 2 -, —CO—N(R 6c )—CH 2 —CH 2 —CO—NH—CH 2 -, —CO—NH—C(—CONH 2 )=CH-, —CO—NH—CH(—CONH 2 )—CH 2 -, -CH 2 —C(H)(Me)—CH 2 —S—, —O—CH 2 —CO—NH-, -CH 2 —N(R 6c )—CO—CH 2 —O—, —N(R 6c )—CO—CH 2 —O—, —C(H)(—CH 2 -aryl)-, —C(H)(—CH 2 -heteroaryl)-, —C(NH-aryl)=N—N=CH-, —C(NH-aryl)=N—N=CH-, -NH—N=C(-aryl)-, —NH—N=C(-aryl)—CO—, -NH—C(=N—CO—C 1-6  alkyl)—NH—(CH 2 ) 2 -, —C(—NH-aryl)=N—N=CH-, -NH—C(—NH-aryl)=N—CONH-, —C(=CH-aryl—CONH—CH 2 -, -CH=C(R 6c )—CONH-, -CH(—CH 2 -aryl)—NH—CO— or -CH(OH)-, wherein said aryl or heteroaryl groups of X c  and Y c  may be optionally substituted by one or more halogen, C 1-6  alkyl, C 1-6  alkoxy, NO 2  or hydroxyl groups; 
         R 5c  represents hydrogen, C 1-6  alkyl or cyano; 
         R 6c  represents hydrogen, C 1-6  alkyl, C 1-6  alkoxy, cyano, C 3-8  cycloalkyl, -CH 2 —C 3-8  cycloalkyl, aryl, heteroaryl, —C 1-6  alkylene-aryl, —CO-aryl, —CO-heteroaryl or —C(R 7c )(R 8c )- heteroaryl, wherein said aryl groups of R 6c  may be optionally substituted by one or more halogen or C 1-6  alkoxy groups; 
         R 7c  and R 8c  independently represent hydrogen or C 1-6  alkyl; 
         R 1c  and R 2c  independently represent aryl, C 3-8  cycloalkyl, monocyclic or bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring system, wherein R 1c  and R 2c  may be substituted by one or more (e.g. 1, 2 or 3) R 4c  groups; 
         R 4c  represents halogen, C 1-6  alkyl, C 1-6  alkenyl, C 1-6  alkynyl, C 3-8  cycloalkyl, haloC 1-6  alkyl, hydroxyl, C 1-6  alkoxy, —O—C 1-6  alkenyl, haloC 1-6  alkoxy, -COOH, —CO—C 1-6  alkyl, -COO—C 1-6  alkyl, -CONH 2 , -CH 2 —CONH 2 , -NH—C 1-6  alkyl, -NH—C 2-6  alkenyl, -NH—CO—C 1-6  alkyl, —CO—NH—C 1-6  alkyl, —O—CH 2 —CO—NH—C 1-6  alkyl, -CH 2 —CH 2 —CO—NH—C 1-6  alkyl, —S—C 1-6  alkyl, —SO—C 1-6  alkyl, —SO 2 —C 1-6  alkyl, —SO 2 —NH—C 1-6  alkyl, —S—CH 2 —CO—C 2-6  alkenyl, —SO 2 —OH, amino, cyano, NO 2 , =O, —CO—NH—(OH 2 ) 2 )—OMe, -NH—C 3-8  cycloalkyl, —CO-heterocyclyl, —CO- heteroaryl, -COO—(CH 2 ) 2 -heterocyclyl, -OCH 2 -aryl, -OCH 2 -heteroaryl, -CH 2 —O—CO-aryl, —O-aryl, -NH—CO-heteroaryl, -NH—CO—CH 2 -aryl, aryl or heteroaryl groups, wherein said aryl, heterocyclyl or heteroaryl groups of R 4c  may be optionally substituted by one or more halogen, C 1-6  alkyl, C 1-6  alkoxy, =S or hydroxyl groups and wherein said C 1-6  alkyl or C 2-6  alkenyl groups of R 4c  may be optionally substituted by one or more hydroxyl, amino, cyano, C 1-6  alkoxy, CONH 2  or -COO—C 1-6  alkyl groups; 
         p represents an integer from 0 to 3; 
         R 3c  represents halogen, haloC 1-6  alkyl, C 1-6  alkyl, hydroxyl, C 1-6  alkoxy, —S—C 1-6  alkyl, -CH 2 —S—C 1-6  alkyl, —S—C 2-6  alkynyl, amino, cyano, NO 2 , =O, =S, —SO 2 —C 1-6  alkyl, -CONH 2 , —CO—C 1-6  alkyl, -COO—C 1-6  alkyl, -NH—C 1-6  alkyl, -NH—CO—C 1-6  alkyl, -NH—CO—CH=CH—CH 2 —N(Me) 2 , C 1-6  alkyl, —CO—NH—C 1-6  alkyl, —CO—NH—CH(Me)—COOH, —S—CH 2 —CO—N(Et) 2 , -NH—(CH 2 ) 2 —OH, -NH—(OH 2 ) 3 —OH, -NH—CH(Et)—CH 2 —OH, —CO—NH—(OH 2 ) 3 —OH, -CH(CH 2 OH) 2  or —S—CH 2 —CO—NH—CO—NH—C 1-6  alkyl, aryl, C 3-8  cycloalkyl, monocyclic or bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring system, wherein said aryl, heterocyclyl or heteroaryl groups of R 3c  may be optionally substituted by one or more (e.g. 1, 2 or 3) R 4c  groups and wherein said C 1-6  alkyl groups of R 3c  may be optionally substituted by one or more hydroxyl groups; 
         with the proviso that the compound is other than compound number 161, 648, 658, 680, 726, 824, 867, 880, 892, 896, 901, 903, 906, 928 and 944. 
       
     
     
         2 . A pharmaceutical composition as defined in  claim 1 , wherein Het C represents a 6 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S, wherein said ring system is optionally fused to one further ring, such as a phenyl ring. 
     
     
         3 . A pharmaceutical composition as defined in  claim 2 , wherein Het C represents pyridinyl, pyrimidinyl or quinazolinyl, such as quinazolinyl. 
     
     
         4 . A pharmaceutical composition as defined in any one of  claims 1  to  3 , wherein X c  and Y c  independently represent a bond or NR 6c , such as NH. 
     
     
         5 . A pharmaceutical composition as defined in  claim 4 , wherein one of X c  and Y c  represents a bond and the other represents NH. 
     
     
         6 . A pharmaceutical composition as defined in any one of  claims 1  to  5 , wherein R 1c  and R 2c  independently represent aryl (e.g. phenyl), bicyclic heterocyclyl (e.g. benzodioxinyl), monocyclic heteroaryl (e.g. pyridinyl, pyrazolyl or thiophenyl) or bicyclic heteroaryl ring system (e.g. benzoxazolyl), wherein R 1c  and R 2c  may be substituted by one or more (e.g. 1) R 4c  groups selected from hydroxyl, C 1-6  alkoxy (e.g. methoxy) or CONH 2 . 
     
     
         7 . A pharmaceutical composition as defined in  claim 6 , wherein R 1c  and R 2c  independently represent aryl (e.g. phenyl) or monocyclic heteroaryl (e.g. pyridinyl, pyrazolyl or thiophenyl) wherein R 1c  and R 2c  may be substituted by one or more (e.g. 1) R o o groups selected from hydroxyl, C 1-6  alkoxy (e.g. methoxy) or CONH 2 . 
     
     
         8 . A pharmaceutical composition as defined in  claim 7 , wherein R 1c  and R 2c  independently represent unsubstituted aryl (e.g. phenyl) or unsubstituted monocyclic heteroaryl (e.g. pyridinyl or pyrazolyl). 
     
     
         9 . A pharmaceutical composition as defined in any one of  claims 1  to  8 , wherein p represents an integer from 0 to 2, such as 0. 
     
     
         10 . A pharmaceutical composition as defined in any one of  claims 1  to  8 , wherein R 3c  represents =O, cyano or a monocyclic heteroaryl ring system (e.g. pyridinyl). 
     
     
         11 . A pharmaceutical composition as defined in any one of  claims 1  to  10 , wherein the compound of formula (IC) is selected from any of compounds:
 43, 46, 49, 147, 152, 154, 178-181, 183-184, 294-295, 305, 329, 339-341, 366, 370-371, 376, 435, 455, 459, 462, 486, 520, 539-543, 546-549, 556-557, 567, 631-632, 640-642, 645, 657, 661, 668, 671, 674, 681, 700-702, 727, 735, 755, 817-818, 823, 826, 845 or 865-866, 868, 870, 888-890, 894, 946, 949-951, 953, 957, 973, 977, 981, 983, 985-986, 993 and 995 as described herein or a pharmaceutically acceptable salt or solvate thereof. 
 
     
     
         12 . A pharmaceutical composition as defined in  claim 11 , wherein the compound of formula (IC) is selected from any of compounds:
 2-Phenyl-N-(pyridin-4-yl)quinazolin-4-amine (Compound 700);   N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-phenylquinazolin-4-amine (Compound 868);   4-{[2-(Thiophen-3-yl)quinazolin-4-yl]amino}benzamide (Compound 870);   2-Phenyl-N-(1 H-pyrazol-4-yl)quinazolin-4-amine (Compound 894);   2-[2-Methyl-4-(pyridin-4-yl)pyrimidin-5-yl]-1,3-benzoxazole (Compound 949);   2-[2-(Pyridin-2-yl)-4-(pyridin-4-yl)pyrimidin-5-yl]-1,3-benzoxazole (Compound 950);   5-(1,3-Benzoxazol-2-yl)-2-oxo-6-(pyridin-4-yl)-1,2-dihydropyridine-3-carbonitrile (Compound 951);   4-[(2-Phenylquinazolin-4-yl)amino]phenol (Compound 957);   N-(4-Methoxyphenyl)-2-(thiophen-2-yl)quinazolin-4-amine (Compound 973);   N-(4-Methoxyphenyl)-2-(pyridin-2-yl)quinazolin-4-amine (Compound 977);   6-Phenyl-2-(pyridin-2-yl)-N-(pyridin-4-yl)pyrimidin-4-amine (Compound 986); and   4-[(2-Phenylquinazolin-4-yl)amino]benzamide (Compound 993);   or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         13 . A pharmaceutical composition as defined in  claim 12 , wherein the compound of formula (IC) is selected from any of compounds:
 2-Phenyl-N-(pyridin-4-yl)quinazolin-4-amine (Compound 700); and   2-Phenyl-N-(1 H-pyrazol-4-yl)quinazolin-4-amine (Compound 894);   or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         14 . A pharmaceutical composition comprising a compound of formula (IA) or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein 
         “Het A” represents a 4 or 5 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S, wherein said ring system is optionally fused to one or more (e.g. 1-3) further rings to form a polycyclic ring system comprising up to 4 rings; 
         X and Y independently represent a bond, —C(R 7a )(R 8a )-, (CH 2 ) 2 , —O—, —S—, -CH 2 —O—, -(CH) 2 ) 2 —O—, NR 6a , —N(R 6c )—C(R 7a )(R 8a )-, —N(R 6a )—(CH 2 ) 2 -, —N(R 6 a)—(CH 2 ) 3 -, -CH 2 —N(R 6 a)—(CH 2 ) 2 -, —N(R 6a )—CO—, -CH 2 —NH—CO—(CH 2 ) 2 -,—N(R 6a )—CO—CH 2 -, —N(R 6a )—CO—(CH 2 ) 2 -, —CO—N(R 6a )—CH 2 - , =N—, —C(H)(CN)-, —C(=N—NH—COC 1-6  alkyl)-, -CH=C(R 6a )—CO—, =CH-, -CH=CH-, =CH—CO—, —N=CH-, —N=C(Me)-, —C(R 6a )=CH-, -NH—N=C(H)-, -NH—CO—C(=CH-heteroaryl)-, —C=C(Me) 2 -, -CH=CH—CO—N(R 6a )-, -CH=C(R 6a )—NH—CO—, -CH=C(R 6a )—CO —O—CH 2 -, —CS—S—CH 2 -, -NH—CS—NH-, -NH—CS—NH—CH 2 -, -NH—CS—NH—(CH 2 ) 2 -, -CH 2 —N(CSNH 2 )—CH 2 -, —S—CH 2 -, —S—(CH 2 ) 2 —O—, SO 2 , -NH—SO 2 -, -CH 2 —N(R 6a )—SO 2 -, CO, -CH 2 —CO—, -(CH 2 ) 2 —CO—, —O—CH 2 —CO—, -(CH 2 ) 2 —CO—, COO, -COO—C(R 7a )CO—, -CH=C(R 5a )—CONH-CH 2 -, —CO—CH 2 —N(R 6a )—CO—, —CO—CH 2 —C(R 6a )—CH 2 —CO—, —CO—CH 2 —N(R 6a )—CH 2 -, —CO—NH—N=C(R 7a )-, —S—CH 2 —CO—, —S—CH 2 —CO—N(R 6a )-, —S—CH 2 —CO—N(R 6a )—CH 2 -, —SO 2 —N(R 6a )—C(R 7a )(R 8a )—CONH-, —SO 2 —N(R 6a )—CH(—CH 2 -aryl)—CONH-CH 2 -, -CH(—S—C 1-6  alkyl)—C(Me)(OH)-, -CH 2 —C(R 6a )(OH)-, —C(OH)(CH(Me)(C 3-8  cycloalkyl))—CH 2 -, —C(OH)(R 6a )—CH 2 -, -CH(Me)—NH—CO—CH 2 -, —CO—N(R 6a )—CH 2 -, —CO—N(R 6a )—CH 2 —CH 2 -, —CO—N(R 6a )—CH 2 —CH 2 —CO—NH—CH 2 -, —CO—NH—C(—CONH 2 )=CH-, —CO—NH—CH(—CONH 2 )—CH 2 -, -CH 2 —C(H)(Me)—CH 2 —S—, —O—CH 2 —CO—NH-, —CH 2 —N(R 6a )—CO—CH 2 —O—, —N(R 6a )—CO—CH 2 —O—, —C(H)(—CH 2 -aryl), —C(H)(—CH 2 -heteroaryl)-, —C(NH-aryl)=N—N=CH-, —C(NH-aryl)=N—N=CH-, -NH—N=C(-aryl)-, -NH—N=C(-aryl)—CO—, -NH—C(=N—CO—C 1-6  alkyl)—NH—(CH 2 ) 2 -, —C(-NH-aryl)=N—N=CH-, -NH—C(—NH-aryl)=N—CONH-, —C(=CH-aryl)—CONH—CH 2 -, -CH=C(R 6a )—CONH-, -CH(—CH 2 -aryl)—NH—CO— or -CH(OH)-, wherein said aryl or heteroaryl groups of X and Y may be optionally substituted by one or more halogen, C 1-6  alkyl, C 1-6  alkoxy, NO 2  or hydroxyl groups; 
         R 5a  represents hydrogen, C 1-6  alkyl or cyano; 
         R 6a  represents hydrogen, C 1-6  alkyl, C 1-6  alkoxy, cyano, C 3-8  cycloalkyl, -CH 2—C   3-8  cycloalkyl, aryl, heteroaryl, —C 1-6  alkylene-aryl, —CO-aryl, —CO-heteroaryl or —C(R 7a )(R 8a )- heteroaryl, wherein said aryl groups of R 6a  may be optionally substituted by one or more halogen or C 1-6  alkoxy groups; 
         R 7a  and R 8a  independently represent hydrogen or C 1-6  alkyl; 
         R 1a  and R 2a  independently represent aryl, C 3-8  cycloalkyl, monocyclic or bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring system, wherein R 1a  and R 2a  may be substituted by one or more (e.g. 1, 2 or 3) R 4a  groups; 
         R 4a  represents halogen, C 1-6  alkyl, C 1-6  alkenyl, C 1-6  alkynyl, C 3-8  cycloalkyl, haloC 1-6  alkyl, hydroxyl, C 1-6  alkoxy, —C 1-6  alkenyl, haloC 1-6  alkoxy, -COOH, —CO—C 1-6  alkyl, -COO—C 1-6  alkyl, -CONH 2 , -CH 2 —CONH 2 , -NH—C 1-6  alkyl, -NH—C 2-6  alkenyl, -NH—CO—C 1-6  alkyl, —CO—NH—C 1-6  alkyl, —O—CH 2 —CO—NH—C 1-6  alkyl, -CH 2 —CH 2 —CO—NH—C 1-6  alkyl, —S—C 1-6  alkyl, —SO—C 1-6  alkyl, —SO 2 —C 1-6  alkyl, —SO 2 —NH—C 1-6  alkyl, —S—CH 2 —CO—C 2-6  alkenyl, —SO 2 —OH, amino, cyano, NO 2 , =O, —CO—NH—(OH 2 ) 2 )—OMe, -NH—C 3-8  cycloalkyl, —CO-heterocyclyl, —CO-aryl, —CO-heteroaryl, -COO—(CH 2 ) 2 -heterocyclyl, -OCH 2 -aryl, -OCH 2 -heteroaryl, -CH 2 —O—CO- aryl, —O-aryl, -NH—CO-heteroaryl, -NH—CO—CH 2 -aryl, -NH—aryl, -NH—SO 2 -aryl, aryl or heteroaryl groups, wherein said aryl, heterocyclyl or heteroaryl groups of R 4a  may be optionally substituted by one or more halogen, C 1-6  alkyl, C 1-6  alkoxy, =S or hydroxyl groups and wherein said C 1-6  alkyl or C 2-6  alkenyl groups of R 4a  may be optionally substituted by one or more hydroxyl, amino, cyano, C 1-6  alkoxy, CONH 2  or -COO—C 1-6  alkyl groups; 
         n represents an integer from 0 to 3; 
         R 3a  represents halogen, haloC 1-6  alkyl, C 1-6  alkyl, hydroxyl, C 1-6  alkoxy, —S—C 1-6  alkyl, -CH 2 —S—C 1-6  alkyl, —S—C 2-6  alkynyl, amino, cyano, NO 2 , =O, =S, —SO 2 —C 1-6  alkyl, -CONH 2 , —CO—C 1-6  alkyl, -COO—C 1-6  alkyl, -NH—C 1-6  alkyl, -NH—CO—C 1-6  alkyl, -NH—CO—CH=CH—CH 2 —N(Me) 2 , C 1-6  alkyl, —CO—NH—C 1-6  alkyl, —CO—NH—CH(Me)—COOH, —S—CH 2 —CO—N(Et) 2 , -NH—(CH 2 ) 2 —OH, -NH—(OH 2 ) 3 —OH, -NH—CH(Et)—CH 2 —OH, —CO—NH—(OH 2 ) 3 —OH, -CH(CH 2 OH) 2  or —S—CH 2 —CO—NH—CO—NH—C 1-6  alkyl, aryl, C 3-8  cycloalkyl, monocyclic or bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring system, wherein said aryl, heterocyclyl or heteroaryl groups of R 3a  may be optionally substituted by one or more (e.g. 1, 2 or 3) R 4a  groups and wherein said C 1-6  alkyl groups of R 3a  may be optionally substituted by one or more hydroxyl groups; 
         with the proviso that the compound is other than compound number 38, 138, 212, 243, 378, 415, 441, 480, 577, 579, 580, 587-589, 593, 598, 600, 629, 636, 678, 684, 747, 760, 802, 861, 871, 873, 879, 883, 897-899, 904-905, 907, 909, 915, 917-919, 922-923, 925, 929-930, 938-939, 961. 
       
     
     
         15 . A pharmaceutical composition as defined in  claim 14 , wherein the compound of formula (IA) is selected from any of compounds:
 1, 4-17, 19-25, 36-37, 39-40, 42, 44-45, 52, 61, 71-76, 80-83, 86-91, 93-97, 102-107, 110-112, 114, 117-122, 139-143, 149-151, 153, 158-160, 163-170, 174-177, 185-197, 200, 202-203, 208-209, 211, 213-221, 223-224, 226, 228-229, 232, 234, 237-240, 256, 261-264, 267-268, 270, 272, 275-283, 296, 304, 313, 319, 321-323, 326-328, 332, 334-335, 342-345, 350, 356, 361-365, 367-369, 372, 377, 379, 383, 393, 398, 403, 406, 412-413, 416-423, 431-432, 434, 436, 438-440, 442-447, 460, 463, 465-466, 468-476, 478, 481, 487-488, 492-494, 499, 501, 506, 508-510, 512-515, 517-518, 521-522, 525, 527-529, 531-532, 534, 551-552, 554-555, 558, 562-563, 569, 573, 576, 578, 581-582, 584, 586, 599, 604-605, 610-614, 617, 619, 623-625, 628, 630, 633-635, 639, 643-644, 650-652, 654, 656, 664-667, 670, 672, 676-677, 679, 683, 695, 697-698, 704, 707-708, 710, 714, 717, 733, 736, 741-743, 750, 761-766, 768, 773, 782, 787, 791, 794, 807, 809-812, 815-816, 820, 841-843, 846, 849-856, 859-860, 862-864, 931, 947-948, 967, 970, 982, 984, 989, 991-992, 1000 and 1002 as described herein or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         16 . A pharmaceutical composition comprising a compound of formula (ID) or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein 
         “Het D” represents a 6 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S, wherein said ring system is fused to one or more (e.g. 1-3) further rings to form a polycyclic ring system comprising up to 4 rings; 
         Z d  represents a bond, —C(R 7d )(R 8d )-, -(CH 2 )—C(R 7d )(R 8d )-, —O—, —S—, -CH 2 —O—, -(CH 2 ) 2 —O—, NR 6d , —N(R 6d )—C(R 7d )(R 8d )-, —N(R 6d )—(CH 2 ) 2 -, —N(R 6d )—(CH 2 ) 3 -, -CH 2 —N(R 6d )—(CH 2 ) 2 -, —N(R 6d )—CO—, -CH 2 —NH—CO—(CH 2 ) 2 -, —N(R 6d )—CO—CH 2 -, —CO—N(R 6d )—CH 2 -, =N—, —C(H)(CN)-, —O(=N—NH—COC 1-6  alkyl)-, -CH=C(R 6d )—CO—, =CH-, —N=CH-, —N=C(Me)-, —C(R 6d )=CH-, -NH—CO—C(=CH-heteroaryl)-, —C=C(Me) 2 -, -CH=CH—CO-N(R 6d )-, -CH=C(R 6d )—NH—CO—, —CO—O—CH 2 -, -CH=C(R 6d )—CO—O—CH 2 -, —CS—S—CH 2 -, -NH—CO—NH-, -NH—CS—NH-, -NH—CS—NH-CH 2 -, -NH—CS—NH-(CH 2 ) 2 -, -CH 2 —N(CSNH 2 )—CH 2 -, —S—CH 2 -, —S—(CH 2 ) 2 —O—, SO 2 , -NH—SO 2 -, -CH 2 -NH—SO 2 -, CO, -CH 2 —CO—, -(CH 2 ) 2 —CO—, —O—CH 2 —CO—, -(CH 2 ) 2 —CO—, COO, -COO—C(R 7d )CO—, - CH=C(R 5d )—CONH—CH 2 -, —CO—CH 2 —N(R 6d )—CO—, —CO—CH 2 —C(R 6d )—CH 2 —CO—, —CO—CH 2 —N(R 6d )—CH 2 -, —CO—NH—N=C(R 7d )-, —S—CH 2 —CO—, —S-CH 2 —CO—N(R 6d )-, —S—CH 2 —CO—N(R 6d )—CH 2 -, —SO 2 —N(R 6d )—C(R 7d )(R 8d )—CONH-, —SO 2 —N(R 6d )—CH(—CH 2 -aryl)—CONH—CH 2 -, -CH(—S—C 1-6  alkyl)—C(Me)(OH)-, -CH 2 —C(R 6d )(OH)-, —C(OH)(CH(Me)(C 3-8  cycloalkyl))—CH 2 -, —C(OH)(R 6d )—CH 2 -, -CH(Me)—NH—CO—CH 2 -, —CO—N(R 6d )—CH 2 -, —CO—N(R 6d )—CH 2 —CH 2 -, —CO—N(R 6d )—CH 2 —CH 2 —CO—NH—CH 2 -, —CO—NH—C(—CONH 2 )=CH-, —CO—NH—CH(—CONH 2 )—CH 2 -, —CH 2 —C(H)(Me)—CH 2 —S—, —O—CH 2 —CO—NH-, -CH 2 —N(R 6d )—CO—CH 2 —O—, —N(R 6d )—CO—CH 2 —O—, —C(H)(—CH 2 -aryl), —C(H)(—CH 2 -heteroaryl)-, —C(NH-aryl)=N—N=CH-, —C(NH-aryl)=N—N=CH-, - NH—N=C(-aryl)-, -NH—N=C(-aryl)—CO—, -NH—C(=N—CO—C 1-6  alkyl)—NH—(OH 2 ) 2 -, —C(—NH- aryl)=N—N=CH-, -NH—C(—NH-aryl)=N—CONH-, —C(=CH-aryl)—CONH—CH 2 -, -CH=C(R 6d )- CONH-, -CH(—CH 2 -aryl)—NH—CO— or -CH(OH)-, wherein said aryl or heteroaryl groups of Z d  may be optionally substituted by one or more halogen, C 1-6  alkyl, C 1-6  alkoxy, NO 2  or hydroxyl groups; 
         R 5d  represents hydrogen, C 1-6  alkyl or cyano; 
         R 6d  represents hydrogen, C 1-6  alkyl, C 1-6  alkoxy, cyano, C 3-8  cycloalkyl, -CH 2 —C 3-8  cycloalkyl, aryl, heteroaryl, —C 1-6  alkylene-aryl, —CO-aryl, —CO-heteroaryl or —C(R 7d )(R 8d )- heteroaryl, wherein said aryl groups of R 6d  may be optionally substituted by one or more halogen or C 1-6  alkoxy groups; 
         R 7d  and R 8d  independently represent hydrogen or C 1-6  alkyl; 
         R 1d  represents aryl, C 3-8  cycloalkyl, monocyclic or bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring system, wherein R 1d  may be substituted by one or more (e.g. 1, 2 or 3) R 4d  groups; 
         R 4d  represents halogen, C 1-6  alkyl, C 1-6  alkenyl, C 1-6  alkynyl, C 3-8  cycloalkyl, haloC 1-6  alkyl, hydroxyl, C 1-6  alkoxy, —O—C 1-6  alkenyl, haloC 1-6  alkoxy, -COOH, —CO—C 1-6  alkyl, -COO—C 1-6  alkyl, -CONH 2 , -CH 2 —CONH 2 , -NH—C 1-6  alkyl, -NH—C 2-6  alkenyl, -NH—COO—C 1-6  alkyl, —CO—NH—C 1-6  alkyl, —O—CH 2 —CO—NH—C 1-6  alkyl, -CH 2 —CH 2 —CO—NH—C 1-6  alkyl, —S—C 1-6  alkyl, —SO—C 1-6  alkyl, —SO 2 —C 1-6  alkyl, —SO 2 —NH—C 1-6  alkyl, —S—CH 2 —CO—C 2-6  alkenyl, —SO 2 —OH, amino, cyano, NO 2 , =O, —CO—NH—(OH 2 ) 2 )—OMe, -NH—C 3-8  cycloalkyl, —CO-heterocyclyl, —CO- heteroaryl, -COO—(CH 2 ) 2 -heterocyclyl, -OCH 2 -aryl, -OCH 2 -heteroaryl, -CH 2 —O—CO-aryl, - O-aryl, -NH—CO-aryl, -NH—CO-heteroaryl, -NH—CO-CH 2 -aryl, aryl or heteroaryl groups, wherein said aryl, heterocyclyl or heteroaryl groups of R 4d  may be optionally substituted by one or more halogen, C 1-6  alkyl, C 1-6  alkoxy, =S or hydroxyl groups and wherein said C 1-6  alkyl or C 2-6  alkenyl groups of R 4d  may be optionally substituted by one or more hydroxyl, amino, cyano, C 1-6  alkoxy, CONH 2  or COO—C 1-6  alkyl groups; 
         q represents an integer from 0 to 3; 
         R 2d  represents halogen, haloC 1-6  alkyl, C 1-6  alkyl, hydroxyl, C 1-6  alkoxy, —S—C 1-6  alkyl, -CH 2 —S—C 1-6  alkyl, —S—C 2-6  alkynyl, amino, cyano, NO 2 , =O, =S, =NH, —SO 2 —C 1-6  alkyl, -CONH 2 , —CO—C 1-6  alkyl, -COO—C 1-6  alkyl, -NH—C 1-6  alkyl, -NH—CO—C 1-6  alkyl, -NH—CO-CH=CH—CH 2 —N(Me) 2 , C 1-6  alkyl, —CO—NH—C 1-6  alkyl, —CO—NH—CH(Me)-COOH, —S—CH 2 —CO—N(Et) 2 , -NH—(CH 2 ) 2 —OH, -NH—(CH 2 ) 3 —OH, -NH—CH(Et)-CH 2 —OH, —CO—NH—(CH 2 ) 3 —OH, -CH(CH 2 OH) 2  or —S—CH 2 —CO—NH—CO—NH—C 1-6  alkyl, wherein said C 1-6  alkyl groups of R 2d  may be optionally substituted by one or more hydroxyl groups; 
         with the proviso that the compound is other than compound number 273, 286, 467, 533, 544, 571, 591, 662, 783, 795, 806, 884, 887, 895, 902, 908, 921, 932, 934, 942, 959-960 and 1001. 
       
     
     
         17 . A pharmaceutical composition as defined in  claim 16 , wherein the compound of formula (ID) is selected from any of compounds:
 29, 34, 41, 65-70, 92, 109, 116, 126, 130-137, 162, 182, 231, 246, 252-255, 258, 274, 290-293, 297-298, 317-318, 330-331, 347-349, 352, 450-454, 483, 536-538, 545, 550, 564-565, 572, 620, 637, 655, 663, 675, 682, 686, 691, 696, 706, 711, 724, 728-729, 737, 744-745, 748, 752, 774-776, 781, 797-799, 832, 834, 954, 958, 964-965, 971, 974-976, 978-980, 994 or 997-998 as described herein or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         18 . A pharmaceutical composition comprising a compound of formula (IE) or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein 
         “Het E” represents a 6 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S; 
         Z e  represents a bond, —C(R 7e )(R 8e )-, (CH 2 ) 2 , —O—, —S—, -CH 2 —O—, -(CH 2 ) 2 —O—, NR 6e , -N(R 6e )—C(R 7e )(R 8e )-, —N(R 6e )—(CH 2 ) 2 -, —N(R 6e )—(CH 2 ) 3 -, -CH 2 —N(R 6e )—(CH 2 ) 2 -, —N(R 6e )—CO—, -CH 2 —NH—CO—(CH 2 ) 2 -, —N(R 6e )—CO—CH 2 -, —CO—N(R 6e )—CH 2 -, =N—, —C(H)(CN)-, —C(=N—NH—COC 1-6  alkyl)-, —C(R 6e )=N—NH—Co—, -CH=C(R 6e )—CO—, =CH-, —N=CH-, —N=C(Me)-, —C(R 6e )=CH-, - NH—CO—C(=CH-heteroaryl)-, —C=C(Me) 2 -, -CH=CH—CO—N(R 6e )-, -CH=C(R 6e )—NH—CO—, —CH=C(R 6e )—CO—O—CH 2 -, —CS—S—CH 2 -, -NH—CH—NH-, —N(R 6e )—CO—N(R 7e )-, -NH—CS—N(R 6e )—CH(R 7e )-, —CO—NH—CS—N(R 6e )-, -NH—CS—NH—(CH 2 ) 2 -, -CH 2 —N(CSNH 2 )—CH 2 -, —S—CH 2 -, —S—(CH 2 ) 2 —O—, SO 2 , -NH—SO 2 -, -CH 2 —N(R 6e )—SO 2 -, CO, -CH 2 —CO—, -(CH 2 ) 2 —CO—, —O—CH 2 —CO—, - (CH 2 ) 2 —COO, COO, -COO—C(R 7e )CO—, -CH=C(R 5e )—CONH—CH 2 -, —CO—CH 2 —N(R 6e )—CO—, —CO—CH 2 —C(R 6e )—CH 2 —CO—, —C(R 6e )—CO—CH 2 -, —CO—CH 2 —N(R 6e )—CH 2 -, —CO—NH—N=C(R 7e )-, —S—CH 2 —CO—, —S—CH 2 —CO—N(R 6e )-, —S-CH 2 —CO—N(R 6e )—CH 2 -, —SO 2 —N(R 6e )—C(R 7e )(R 8e )—CONH- , —SO 2 —N(R 6e )—CH(—CH 2 -aryl)—CONH—CH 2 -, —CH(—S—C 1-6  alkyl)—C(Me)(OH)-, -CH 2 —C(R 6e )(OH)-, —C(OH)(CH(Me)(C 3-8  cycloalkyl))—CH 2 -, —C(OH)(R 6e )—CH 2 -, -CH(Me)—NH—CO—CH 2 -, —CO—N(R 6e )—CH 2 -, —CO—N(R 6e )—CH 2 —CH 2 -, —CO—N(R 6e )—CH 2 —CH 2 —O—CO—, —Co—N(R 6e )—CH 2 —CH 2 —CO—NH—CH 2 -, —CO—NH—C(—CONH 2 )=CH-, —CO—NH—CH(—CONH 2 )—CH 2 -, -CH 2 —C(H)(Me)—CH 2 —S—, —O—CH 2 —CO—NH-, -CH 2 —N(R 6e )—CO—CH 2 —O—, —N(R 6e )—CO—CH 2 —O—, —C(H)(—CH 2 -aryl), —C(H)(—CH 2 -heteroaryl)-, —C(NH-aryl)=N—N=CH-, —C(NH-aryl)=N—N=CH-, -NH—N=C(-aryl)-, -NH—C(R 6e )=N—SO 2 -, -NH—N=C(-aryl)—CO—, -NH—C(=N—CO)(R 6e )-, -NH—C(=N—CO—C 1-8  alkyl)—NH—(OH 2 ) 2 -, —C(—NH-aryl)=N—N=CH-, -NH—C(—NH-aryl)=N—CONH-, —C(=CH- aryl)—CONH—CH 2 -, -CH=C(R 6e )—CONH-, -CH(—CH 2 -aryl)—NH—CO— or -CH(OH)-, wherein said aryl or heteroaryl groups of Z e  may be optionally substituted by one or more halogen, 
         C 1-6  alkyl, C 1-6  alkoxy, NO 2  or hydroxyl groups; 
         R y e represents hydrogen, C 1-6  alkyl or cyano; 
         R h e represents hydrogen, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylamino, cyano, C 3-8  cycloalkyl, - CH 2 -C 3-8  cycloalkyl, aryl, heteroaryl, —C 1-8  alkylene-aryl, —C 1-8  alkylene-heteroaryl, -NH—CO- aryl, —CO-aryl, —CO-heteroaryl or —C(R 7e )(R 8e )-heteroaryl, wherein said aryl groups of Rhe may be optionally substituted by one or more halogen or C 1-8  alkoxy groups; 
         R 7e  and R 8e  independently represent hydrogen or C 1-8  alkyl; 
         R 6e  represents aryl, C 3-8  cycloalkyl, monocyclic or bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring system, wherein R 1d  may be substituted by one or more (e.g. 1, 2 or 3) R 4e  groups; 
         R 4e  represents halogen, C 1-8  alkyl, C 1-8  alkenyl, C 1-8  alkynyl, C 3-8  cycloalkyl, haloC 1-8  alkyl, hydroxyl, C 1-8  alkoxy, —O—C 1-8  alkenyl, haloC 1-8  alkoxy, -COOH, —CO—C 1-8  alkyl, -COO—C 1-6  alkyl, -CONH 2 , —SO 2 NH 2 , -CH 2 —CONH 2 , -NH—C 1-8  alkyl, -NH—C 2-8  alkenyl, -NH—CO—C 1-6  alkyl, —CO—NH—C 1-8  alkyl, -NH—NH 2 , —O—CH 2 —CO—NH—C 1-6  alkyl, -CH 2 —CH 2 —CO—NH—C 1-8  alkyl, —S—C 1-6  alkyl, —SO—C 1-6  alkyl, —SO 2 —C 1-8  alkyl, —SO 2 —NH—C 1-8  alkyl, —S—CH 2 —CO—C 2-8  alkenyl, —SO 2 —OH, amino, cyano, NO 2 , =O, —CO—NH—(OH 2 ) 2 )—OMe, -NH—C 3-8  cycloalkyl, —CO- heterocyclyl, —CO-heteroaryl, -COO—(CH 2 ) 2 -heterocyclyl, -OCH 2 -aryl, -OCH 2 -heteroaryl, - CH 2 —O—CO-aryl, —O-aryl, —CO—NH-aryl, -NH—SO 2 -aryl, -NH—CO-heteroaryl, -NH—C 1-4  alkylene-heteroaryl, -NH—CO—CH 2 -aryl, aryl or heteroaryl groups, wherein said C 1-6  alkynyl, aryl, heterocyclyl or heteroaryl groups of R 4e  may be optionally substituted by one or more halogen, C 1-6  alkyl, C 1-6  alkoxy, =S or hydroxyl groups and wherein said C 1-6  alkyl or C 2-6  alkenyl groups of R 4e  may be optionally substituted by one or more hydroxyl, amino, cyano, C 1-6  alkoxy, CONH 2  or -COO—C 1-6  alkyl groups; 
         r represents an integer from 0 to 3; 
         R 2e  represents halogen, haloC 1-6  alkyl, C 1-6  alkyl, C 1-6  alkynyl, hydroxyl, C 1-6  alkoxy, —SO 1-6  alkyl, -CH 2 —S—C 1-6  alkyl, —SO— 2-6  alkynyl, amino, cyano, NO 2 , =O, =S, —SO 2 —C 1-6  alkyl, - CONH 2 , —CO—C 1-6  alkyl, -COO—C 1-6  alkyl, -NH—C 1-6  alkyl, -NH—CO—C 1-6  alkyl, -NH—CO—CH=CH-CH 2 -N(Me) 2 , C 1-6  alkyl, —CO—NH—C 1-6  alkyl, —CO—NH—CH(Me)—COOH, —S—CH 2 —CO—N(Et) 2 , -NH—(OH 2 ) 2 —OH, -NH—(OH 2 ) 3 —OH, -NH—CH(Et)—CH 2 —OH, —CO—NH—(OH 2 ) 3 —OH, - CH(CH 2 OH) 2  or —S—CH 2 —CO—NH—CO—NH—C 1-6  alkyl, wherein said C 1-6  alkyl or C 1-6  alkynyl, groups of R e e may be optionally substituted by one or more hydroxyl or alkylamino groups; 
         with the proviso that the compound is other than compound number 250, 647, 685, 751, 769, 803, 874, 876, 893, 900, 911, 913-914, 916, 920, 927, 936-937, 940, 943 and 945. 
       
     
     
         19 . A pharmaceutical composition as defined in  claim 18 , wherein the compound of formula (IE) is selected from any of compounds:
 18, 50, 55-56, 62, 77, 85, 108, 115, 144, 146, 148, 198-199, 201, 222, 230, 245, 247, 251, 265, 284, 287, 300, 306, 337-338, 346, 381-382, 392, 426, 429-430, 479, 561, 566, 583, 603, 606-608, 621-622, 646, 659-660, 687-688, 690, 699, 715, 718, 720-723, 730-732, 739, 771-772, 780, 793, 813-814, 822, 829-830, 835-837, 840, 848, 885-886, 941, 966 or 988 as described herein or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         20 . A pharmaceutical composition comprising a compound of formula (IF) or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein 
         “Het F” represents a heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S, wherein said ring system is fused to one or more (e.g. 1-3) further rings to form a polycyclic ring system comprising up to 4 rings; 
         R 1f  represents halogen, C 1-6  alkyl, C 1-6  alkenyl, C 1-6  alkynyl, C 3-8  cycloalkyl, haloC 1-6  alkyl, hydroxyl, C 1-6  alkoxy, —O—C 1-6  alkenyl, haloC 1-6  alkoxy, -COOH, —CO—C 1-6  alkyl, -COO-C 1-6  alkyl, -CONH 2 , -CH 2 -CONH 2 , -NH-C 1-6  alkyl, -NH-C 2-6  alkenyl, -NH—CO—C 1-6  alkyl, —CO—NH—C 1-6  alkyl, —O—CH 2 —CO—NH-C 1-6  alkyl, -CH 2 —CH 2 —CO-NH-C 1-6  alkyl, —S—C 1-6  alkyl, —SO—C 1-6  alkyl, —SO 2 —C 1-6  alkyl, —SO 2 —NH—C 1-6  alkyl, —S—CH 2 —CO—C 2-6  alkenyl, —SO 2 —OH, amino, cyano, NO 2 , =O, —CO—NH—(CH 2 ) 2 )—OMe, -NH—C 3-8  cycloalkyl, wherein said C 1-6  alkyl or C 2-6  alkenyl groups of R 1f  may be optionally substituted by one or more hydroxyl, amino, cyano, C 1-6  alkoxy, CONH 2  or -COO—C 1-6  alkyl groups; 
         s represents an integer from 1 to 3; 
         with the proviso that the compound is other than compound number 592 or 595. 
       
     
     
         21 . A pharmaceutical composition as defined in  claim 20 , wherein the compound of formula (IF) is selected from any of compounds:
 53, 79, 124-125, 205, 289, 299, 301-302, 353-355, 397, 500 or 511 as described herein or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         22 . A pharmaceutical composition comprising a compound of formula (IG) or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein 
         Z g  represents a bond, —C(R 7g g)(R 8g )-, (CH 2 ) 2 , —O—, —S—, -CH 2 —O—, -(CH 2 ) 2 —O—, NR 6g , —N(R 6g )—C(R 7g )(R 8g )-, —N(R 6g )—(CH 2 ) 2 -, —N(R 6g )—(CH 2 ) 3 -, -CH 2 —N(R 6g )—(CH 2 ) 2 -, —N(R 6g )—CO—, -CH 2 —NH—CO—(CH 2 ) 2 -, —N(R 6g )—CO—CH 2 -, =N—, —C(H)(CN)-, —C(=N—NH—COC 1-6  alkyl)-, -CH=C(R 6g )—CO—, =CH-, —N=CH-, —N=C(Me)-, —C(R 6g )=CH-, -NH—CO—C(=CH-heteroaryl)-, —C=C(Me) 2 -, - CH=CH—CO—N(R 6g )-, -CH=C(R 6g )—NH—CO—, -CH=C(R 6g )—CO—O—CH 2 -, —CS—S—CH 2 -, -NH—CS—NH-, -NH—CS—NH—CH 2 -, -NH—CS—NH—(CH 2 ) 2 -, -CH 2 —N(CSNH 2 )—CH 2 -, —S—CH 2 -, —S—(CH 2 ) 2 —O—, SO 2 , -NH—SO 2 -, -CH 2 —NH—SO 2 -, CO, -CH 2 —CO—, -(CH 2 ) 2 —CO—, —O—CH 2 —CO—, -(CH 2 ) 2 —CO—, COO, -COO—C(R 7g )CO—, -CH=C(R 5g )—CONH-CH 2 -, —CO—CH 2 —N(R 6g )—CO—, —CO—CH 2 —C(R 6g )—CH 2 —CO—, —CO—CH 2 —N(R 6g )—CH 2 -, —CO—NH—N=C(R 7g )-, —S—C(R 6g )(R 7g )—CO—, —S—CH 2 —CO—N(R 6g )-, —S-CH 2 -CO-N(R 6g )—CH 2 -, —SO 2 -N(R 6g )—C(R 7g )(R 8g )—CONH-, —SO 2 —N(R 6g )—CH(—CH 2 - aryl)—CONH—CH 2 -, -CH(—S—C 1-6 alkyl)-C(Me)(OH)-, -CH 2 —C(R 6g )(OH)-, —C(OH)(CH(Me)(C 3-8  cycloalkyl))—CH 2 -, —C(OH)(R 6g )—CH 2 -, -CH(Me)—NH—CO—CH 2 -, —CO—N(R 6g )—CH 2 -, —CO—N(R 6g )—CH 2 —CH 2 -, —CO—N(R 6g )—CH 2 —CH 2 —CO—NH—CH 2 -, —CO—NH—C(—CONH 2 )=CH-, —CO—NH—CH(—CONH 2 )—CH 2 -, -CH 2 —C(H)(Me)—CH 2 —S—, —O—CH 2 —CO—NH-, -CH 2 —N(R 6g )—CO—CH 2 —O—, —N(R 6g )—CO—CH 2 —O—, —C(H)(—CH 2 -aryl)-, —C(H)(—CH 2 -heteroaryl)-, —C(NH-aryl)=N—N=CH-, —C(NH-aryl)=N—N=CH-, -NH—N=C(-aryl)-, -NH—N=C(-aryl)—CO—, -NH—C(=N—CO-C 1-6 alkyl)—NH—(CH 2 ) 2 -, —C(—NH-aryl)=N—N=CH-, -NH—C(—NH-aryl)=N—CONH-, —O (=CH-aryl)—CONH—CH 2 -, -CH=C(R 6g )—CONH-, -CH(—CH 2 -aryl)—NH—CO— or -CH(OH)-, wherein said aryl or heteroaryl groups of Z g  may be optionally substituted by one or more halogen, C 1-6  alkyl, C 1-6 alkoxy, NO 2  or hydroxyl groups; 
         R 5g  represents hydrogen, C 1-6  alkyl or cyano; 
         R 6g  represents hydrogen, C 1-6  alkyl, C 1-6 alkoxy, cyano, cycloalkyl, -CH 2 —C 3-8  cycloalkyl, aryl, heteroaryl, -C 1-6  alkylene-aryl, —CO-aryl, —CO-heteroaryl or —C(R 7g )(R 8g )- heteroaryl, wherein said aryl groups of R 6g  may be optionally substituted by one or more halogen or C 1-6 alkoxy groups; 
         R 7g  and R 8g  independently represent hydrogen or C 1-6  alkyl; 
         R 1g  represents aryl, C 3-8  cycloalkyl, monocyclic or bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring system, wherein R 1g  may be substituted by one or more (e.g. 1, 2 or 3) R 4g  groups; 
         R 4g  represents halogen, C 1-6  alkyl, C 1-6  alkenyl, C 1-6 alkynyl, cycloalkyl, haloC 1-6  alkyl, hydroxyl, C 1-6 alkoxy, —O—C 1-6  alkenyl, haloC 1-6 alkoxy, -COOH, -COO—C 1-6  alkyl, -CONH 2 , -CH 2 —CONH 2 , -NH—C 1-6  alkyl, -NH—C 2-6  alkenyl, -NH—CO—C 1-6  alkyl, —CO—NH 2 —C 1-6  alkyl, —O—CH 2 —CO—NH—C 1-6 alkyl, —CH 2 —CH 2 —CO—NH—C 1-6  alkyl, —S—C 1-6  alkyl, —SO—C 1-6  alkyl, —SO 2 —C 1-6 alkyl, —SO 2 —NH—C 1-6  alkyl, —S—CH 2 —CO—C 2-6  alkenyl, —SO 2 —OH, amino, cyano, NO 2 , =O, —CO—NH—(OH 2 ) 2 )—OMe, -NH—C 3-8  cycloalkyl, —CO-heterocyclyl, —CO- heteroaryl, -COO—(CH 2 ) 2 -heterocyclyl, -OCH 2 -aryl, -OCH 2 -heteroaryl, -CH 2 —O—CO-aryl, —O-aryl, -NH—CO-heteroaryl, -NH—CO—CH 2 -aryl, aryl or heteroaryl groups, wherein said aryl, heterocyclyl or heteroaryl groups of R 4g  may be optionally substituted by one or more halogen, C 1-6  alkyl, C 1-6 alkoxy, =S or hydroxyl groups and wherein said C 1-6  alkyl or C 2-6  alkenyl groups of R 4g  may be optionally substituted by one or more hydroxyl, amino, cyano, C 1-6 alkoxy, CONH 2  or -COO—C 1-6  alkyl groups; 
         t represents an integer from 0 to 3; 
         R e g represents halogen, haloC 1-6 alkyl, C 1-6  alkyl, hydroxyl, C 1-6 alkoxy, —S—C 1-6  alkyl, -CH 2 —S—C 1-6 alkyl, —S—C 2-6 alkynyl, amino, cyano, NO 2 , =O, =S, —SO 2 —C 1-6  alkyl, -CONH 2-6  alkyl, -COO—C 1-6  alkyl, -NH—C 1-6  alkyl, -NH—CO—C 1-6  alkyl, -NH—CO—CH=CH—CH 2 —N(Me) 2 , C 1-6  alkyl, —CO—NH—C 1-6  alkyl, —CO—NH—CH(Me)—COOH, —S—CH 2 —CO—N(Et) 2 , -NH—(CH 2 ) 2 —OH, -NH—(CH 2 ) 3 —OH, -NH—CH(Et)—CH 2 —OH, —CO—NH—(CH 2 ) 3 —OH, -CH(CH 2 OH) 2  or —S—CH 2 —CO—NH—CO—NH—C 1-6  alkyl, wherein said C 1-6  alkyl groups of R 2e  may be optionally substituted by one or more hydroxyl groups; 
         with the proviso that the compound is other than compound number 789, 839 and 924. In one embodiment, the compound of formula (IG) is selected from any of compounds: 
         98-101, 248, 257, 259-260, 266, 271, 380, 394, 449, 461, 464, 477, 502-504, 523, 530, 535, 574, 673, 713, 779, 788, 825, 881-882, 935, 956, 968, 972 or 996 as described herein or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         23 . A pharmaceutical composition as defined in  claim 22 , wherein the compound of formula (IG) is selected from any of compounds:
 98, 101, 248, 257, 259-260, 266, 271, 380, 394 or 530 as described herein or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         24 . A pharmaceutical composition comprising a compound of formula (IH) or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein “Het H1” and “Het H2” independently represent a 5 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S; 
         Z h  represents a bond, —C(R 7h )(R 8h )-, (CH 2 ) 2 , —O—, —S—, -CH 2 ——, -(CH 2 ) 2 —O—, NR 6h , —N(R 6h )—C(R 6h )(R 7h )-, —N(R 6h )—(CH 2 ) 2 -, —N(R 6h )—(CH 2 ) 3 -, -CH 2 —N(R 6h )—(CH 2 ) 2 -, —N(R 6h )—CO—, -CH 2 —NH—CO—(CH 2 ) 2 -, —N(R 6h )—CO—CH 2 -, =N—, —C(H)(CN)-, —C(=N—NH-COC 1-6  alkyl)-, -CH=C(R 6h )—CO—, =CH-, —N=CH-, —N=C(Me)-, —C(R 6h )=CH-, -NH—CO—C(=CH-heteroaryl)-, —C=C(Me) 2 -, - CH=CH—CO—N(R 6h )-, -CH=C(R 6h )—NH—CO—, -CH=C(R 6h )—CO—O—CH 2 -, —CS—S—CH 2 -, -NH—CS—NH-, -NH—CS—NH—CH 2 -, -NH—CS—NH—(CH 2 ) 2 -, -CH 2 —N(CSNH 2 )—CH 2 -, —S—CH 2 -, —S—(CH 2 ) 2 —O—, SO 2 , -NH—SO 2 -, -CH 2 —NH-SO 2 -, CO, -CH 2 —CO—, -(CH 2 ) 2 —CO—, —O—CH 2 —CO—, -(CH 2 ) 2 —CO—, COO, -COO-C(R 7h )CO—, -CH=C(R 5h )—CONH-CH 2 -, —CO—CH 2 —N(R 6h )—CO—, —CO—CH 2 —C(R 6h )—CH 2 —CO—, —CO—CH 2 —N(R 6h )—CH 2 -, —CO—NH—N=C(R 7h )-, —S—CH 2 —CO—, —S—CH 2 —CO—N(R 6h )-, —S—CH 2 —CO—N(R 6h )—CH 2 -, —SO 2 —N(R 6h )—C(R 7h )(R 8h )—CONH-, —SO 2 —N(R 6h )—CH(-CH 2 -aryl)—CONH—CH 2 -, —CH(—S—C 1-6  alkyl)—C(Me)(OH)-, -CH 2 —C(R 6h )(OH)-, —C(OH)(CH(Me)(C 3-8  cycloalkyl))—CH 2 -, —C(OH)(R 6h )—CH 2 -, -CH(Me)—NH—CO—CH 2 -, —CO—N(R 6h )—CH 2 -, —CO—N(R 6h )—CH 2 —CH 2 -, —CO—N(R 6h )—CH 2 —CH 2 —CO—NH—CH 2 -, —CO—NH—C(—CONH 2 )=CH-, —CO—NH—CH(—CONH 2 )—CH 2 -, -CH 2 —C(H)(Me)—CH 2 —S—, —O—CH 2 —CO—NH-, -CH 2 —N(R 6h )—CO—CH 2 —O—, —N(R 6h )—CO-CH 2 —O—, —C(H)(—CH 2 -aryl)-, —C(H)(—CH 2 -heteroaryl)-, —C(NH-aryl)=N—N=CH-, —C(NH-aryl)=N—N=CH-, -NH—N=C(-aryl)-, -NH—N=C(-aryl)—CO—, -NH—C(=N—CO—C 1-6  alkyl)—NH—(CH 2 ) 2 -, —C(—NH-aryl)=N—N=CH-, -NH—C(—NH-aryl)=N—CONH-, —C(=CH-aryl)—CONH—CH 2 -, -CH=C(R 6h )—CONH-, -CH(—CH 2 -aryl)—NH—CO— or -CH(OH)-, wherein said aryl or heteroaryl groups of Z h  may be optionally substituted by one or more halogen, C 1-6  alkyl, C 1-6  alkoxy, NO 2  or hydroxyl groups; 
         R 5h  represents hydrogen, C 1-6  alkyl or cyano; 
         R 6h  represents hydrogen, C 1-6  alkyl, C 1-6  alkoxy, cyano, C 3-8  cycloalkyl, -CH 2 —C 3-8  cycloalkyl, aryl, heteroaryl, —C 1-6  alkylene-aryl, —CO-aryl, —CO-heteroaryl or —C(R 7h )(R 8h )- heteroaryl, wherein said aryl groups of R 6h  may be optionally substituted by one or more halogen or C 1-6  alkoxy groups; 
         R 7h  and R 8h  independently represent hydrogen or C 1-6  alkyl; 
         R 1h  and R 2h  independently represent halogen, C 1-6  alkyl, C 1-6  alkenyl, C 1-6  alkynyl, C 3-8  cycloalkyl, haloC 1-6  alkyl, hydroxyl, C 1-6  alkoxy, —O—C 1-6  alkenyl, haloC 1-6  alkoxy, -COOH, —CO—C 1-6  alkyl, -COO—C 1-6  alkyl, -CONH 2 , -CH 2 —CONH 2 , -NH—C 1-6  alkyl, -NH—C 2-6  alkenyl, - NH—CO—C 1-6  alkyl, —CO—NH—C 1-6  alkyl, —O—CH 2 —CO—NH—C 1-6  alkyl, -CH 2 —CH 2 —CO—NH—C 1-6  alkyl, —S—C 1-6  alkyl, —SO—C 1-6  alkyl, —SO 2 —C 1-6  alkyl, —SO 2 —NH—C 1-6  alkyl, —S—CH 2 —CO—-C 2-6  alkenyl, —SO 2 —OH, amino, cyano, NO 2 , =O, —CO—NH—(OH 2 ) 2 )—OMe, -NH—C 3-8  cycloalkyl, —CO-heterocyclyl, —CO-heteroaryl, -COO—(CH 2 ) 2 -heterocyclyl, -OCH 2 -aryl, -OCH 2 - heteroaryl, -CH 2 —O—CO-aryl, —O-aryl, -NH—CO-heteroaryl, -NH—CO-CH 2 -aryl, aryl or heteroaryl groups, wherein said aryl, heterocyclyl or heteroaryl groups of R 1h  and R 2h  may be optionally substituted by one or more halogen, C 1-6  alkyl, C 1-6  alkoxy, =S or hydroxyl groups and wherein said C 1-6  alkyl or C 2-6  alkenyl groups of R 1h  and R 2h  may be optionally substituted by one or more hydroxyl, amino, cyano, C 1-6  alkoxy, CONH 2  or -COO—C 1-6  alkyl groups; 
         u and v independently represent an integer from 0 to 3; 
         with the proviso that the compound is other than compound number 757 and 878. 
       
     
     
         25 . A pharmaceutical composition as defined in  claim 24 , wherein the compound of formula (IH) is selected from any of compounds:
 395, 433, 689 or 786 as described herein or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         26 . A compound of formula (IA), (IC), (ID), (IE), (IF), (IG) or (IH) as defined in any one of  claims 1  to  25  for use in therapy. 
     
     
         27 . A compound of formula formula (IA), (IC), (ID), (IE), (IF), (IG) or (IH) as defined in any one of  claims 1  to  25  for use as a casein kinase delta (CK1δ) inhibitor in the treatment of a neurodegenerative disorder, such as tauopathies. 
     
     
         28 . A compound as defined in  claim 27 , wherein the tauopathy is selected from Alzheimer's disease, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), Pick's disease, corticobasal degeneration, multisystem atrophy (MSA), neurobasal degeneration with iron accumulation, type 1 (Hallervorden-Spatz), argyrophilic grain dementia, Down's syndrome, diffuse neurofibrillary tangles with calcification, dementia pugilistica, Gerstmann-Straussler-Scheinker disease, myotonic dystrophy, Niemann-Pick disease type C, progressive subcortical gliosis, prion protein cerebral amyloid angiopathy, tangle only dementia, postencephalitic parkinsonism, subacute sclerosing panencephalitis, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis/parkinsonism-dementia complex, non-Guamanian motor neuron disease with neurofibrillary tangles/dementia, and Parkinson's disease. 
     
     
         29 . A compound as defined in  claim 27  or  claim 28 , wherein the tauopathy comprises Alzheimer's disease.