Casein kinase 1delta (ck 1delta) inhibitors

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 (IB) or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein 
         “Het B” represents a 5 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 represents a bond, —C(R 7b )(R 8b )—, (CH 2 ) 2 , —O—, —S—, —CH 2 —O—, —(CH 2 ) 2 —O—, NR 6b , —N(R 6b )—C(R 7b )(R 8b )—, —N(R 6b )—(CH 2 ) 2 —, —N(R 6b )—(CH 2 ) 3 —, —CH 2 —N(R 6b )—(CH 2 ) 2 —, —N(R 6b )—CO—, —CH 2 —NH—CO—(CH 2 ) 2 —, —N(R 6b )—CO—CH 2 —, ═N—, —N(R 7b )—CH═, —C(H)(CN)—, —C(═N—NH—COC 1-6  alkyl)-, —CH═C(R 6b )—CO—, ═CH—, —N═CH—, —N═C(Me)—, —C(R 6b )═CH—, —NH—CO—C(═CH-heteroaryl)-, —C(═C(R 7b )(R 8b ))—, —CH═CH—CO—N(R 6b )—, —CH═C(R 6b )—CO—NH—CH 2 —, —CH═C(R 6b )—NH—CO—, —CH═C(R 6b )—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—C(R 5b )(R 6b )—, —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 7b )CO—, —CH═C(R 5b )—CONH—CH 2 —, —CO—CH 2 —N(R 6b )—CO—, —CO—CH 2 —C(R 6b )—CH 2 —CO—, —CO—CH 2 —N(R 6b )—CH 2 —, —CO—NH—N═C(R 7b )—, —S—CH 2 —CO—, —S—CH 2 —CO—N(R 6b )—, —S—CH 2 —CO—N(R 6b )—CH 2 —, —SO 2 —N(R 6b )—C(R 7b )(R 8b )—CONH—, —SO 2 —N(R 6b )—CH(—CH 2 -aryl)-CONH—CH 2 —, —CH(—S—C 1-6  alkyl)-C(Me)(OH)—, —CH 2 —C(R 6b )(OH)—, —C(OH)(CH(Me)(C 3-8  cycloalkyl))-CH 2 —, —C(OH)(R 6b )—CH 2 —, —CH(Me)-NH—CO—CH 2 —, —CO—N(R 6b )—CH 2 —, —C(H)(R 6b )—CO—N(R 5b )—CH 2 —, —CO—N(R 6b )—CH 2 —CH 2 —, —CO—N(R 6b )—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 6b )—CO—CH 2 —O—, —N(R 6b )—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—CO—CH 2 —N(R 6b )—, —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 6b )—CONH—, —CH(—CH 2 -aryl)-NH—CO— or —CH(OH)—, wherein said aryl or heteroaryl groups of Z may be optionally substituted by one or more halogen, C 1-6  alkyl, C 1-6  alkoxy, NO 2  or hydroxyl groups; 
         R 5b  represents hydrogen, C 1-6  alkyl or cyano; 
         R 6b  represents hydrogen, C 1-6  alkyl, C 1-6  alkoxy, cyano, COOH, —COOC 1-6  alkyl, C 3-8  cycloalkyl, —CH 2 —C 3-8  cycloalkyl, aryl, heteroaryl, —C 1-6  alkylene-aryl, —CO-aryl, —O—CO-heteroaryl, —CO-heteroaryl or —C(R 7b )(R 8b )-heteroaryl, wherein said aryl groups of R 6b  may be optionally substituted by one or more halogen or C 1-6  alkoxy groups; 
         R 7b  and R 8b  independently represent hydrogen or C 1-6  alkyl; 
         R 1b  represents aryl, C 3-8  cycloalkyl, monocyclic or bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring system, wherein R 1b  may be substituted by one or more (e.g. 1, 2 or 3) R 4b  groups; 
         R 4b  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 2 , —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, —CH 2 —CO—NH—C 3-8  cycloalkyl, —CO-heterocyclyl, —CO-heteroaryl, —COO—(CH 2 ) 2 -heterocyclyl, —CH 2 -aryl, —OCH 2 -aryl, —OCH 2 -heteroaryl, —CH 2 —O—CO-aryl, —O-aryl, —NH—CO-aryl, —NH—CO-heteroaryl, —NH—CO—CH 2 -aryl, —NH-aryl, aryl or heteroaryl groups, wherein said aryl, heterocyclyl or heteroaryl groups of R 4b  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 4b  may be optionally substituted by one or more hydroxyl, amino, cyano, C 1-6  alkoxy, CONH 2  or —COO—C 1-6  alkyl groups; 
         m represents an integer from 0 to 3; 
         R 2b  represents halogen, haloC 1-6  alkyl, C 1-6  alkyl, C 3-8  cycloalkyl, 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—(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 2b  may be optionally substituted by one or more cyano or hydroxyl groups; 
         with the proviso that the compound is other than compound number 54, 373, 458, 496, 585, 590, 594, 596-597, 601-602, 649, 703, 778, 877, 891, 910, 912, 926 and 962-963. 
       
     
     
         2 . A pharmaceutical composition as defined in  claim 1 , wherein:
 “Het B” represents a 5 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S, wherein said ring system is fused to a 6 membered ring to form a bicyclic heterocyclic ring system;   Z represents a bond, —C(R 7b )(R 8b )—, —O—, —S—, —CH 2 —O—, —N(R 6b )—C(R 7b )(R 8b )—, —N(R 6b )—(CH 2 ) 2 —, —N(R 6b )—(CH 2 ) 3 —, —N(R 6b )—CO—, —N(R 6b )—CO—CH 2 —, —N(R 7b )—CH═, ═CH—, —N═CH—, —C(R 6b )═CH—, —C(═C(R 7b )(R 8b ))—, SO 2 , —CH 2 —NH—SO 2 —, CO, —O—CH 2 —CO—, —SO 2 —N(R 6b )—C(R 7b )(R 8b )—CONH—, —SO 2 —N(R 6b )—CH(—CH 2 -aryl)-CONH—CH 2 —, —CH(—S—C 1-6  alkyl)-C(Me)(OH)—, —C(H)(R 6b )—CO—N(R 6b )—CH 2 —, —O—CH 2 —CO—NH—, —N(R 6b )—CO—CH 2 —O—, —C(H)(—CH 2 -aryl)-, —C(NH-aryl)═N—N═CH—, —NH—CO—CH 2 —N(R 6b )—, —NH—N═C(-aryl)-, —NH—C(═N—CO—C 1-6  alkyl)-NH—(CH 2 ) 2 —, —C(═CH-aryl)-CONH—CH 2 — or —CH(—CH 2 -aryl)-NH—CO— wherein said aryl or heteroaryl groups of Z may be optionally substituted by one or more halogen, C 1-6  alkyl, C 1-6  alkoxy, NO 2  or hydroxyl groups;   R 5b  represents hydrogen;   R 6b  represents hydrogen, methyl, C 1-6  alkoxy, —COOH, —CO-aryl, —O—CO-heteroaryl or —CO-heteroaryl, wherein said aryl groups of R 6b  may be optionally substituted by one or more halogen or C 1-6  alkoxy groups;   R 7b  and R 8b  independently represent hydrogen or C 1-6  alkyl;   R 1b  represents a monocyclic aryl or heteroaryl ring system, wherein R 1b  may be substituted by one or more (e.g. 1, 2 or 3) R 4b  groups;   R 4b  represents halogen, hydroxyl, —O—C 1-6  alkenyl, —COO—C 1-6  alkyl, —NH—C 1-6  alkyl, —SO 2 —NH 2 , amino, cyano, ═O, —CH 2 —CO—NH—C 3-8  cycloalkyl, —CH 2 -aryl, —OCH 2 -heteroaryl, —O-aryl, —NH—CO-aryl, —NH-aryl or heteroaryl groups, wherein said aryl, heterocyclyl or heteroaryl groups of R 4b  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 4b  may be optionally substituted by one or more hydroxyl, amino, cyano, C 1-6  alkoxy, CONH 2  or —COO—C 1-6  alkyl groups;   m represents an integer from 0 to 2; and   R 2b  represents halogen, haloC 1-6  alkyl, C 1-6  alkyl, C 3-8  cycloalkyl, hydroxyl, C 1-6  alkoxy, —S—C 1-6  alkyl, amino, cyano, NO 2 , ═O, —CONH 2 , —CO—C 1-6  alkyl, —COO—C 1-6  alkyl, C 1-6  alkyl, —CO—NH—C 1-6  alkyl or —CO—NH—CH(Me)-COOH, wherein said C 1-6  alkyl groups of R 2b  may be optionally substituted by one or more cyano or hydroxyl groups.   
     
     
         3 . A pharmaceutical composition as defined in  claim 1  or  claim 2 , wherein Het B represents a 5 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S, wherein said ring system is fused to a 6 membered ring to form a bicyclic heterocyclic ring system. 
     
     
         4 . A pharmaceutical composition as defined in  claim 3 , wherein Het B represents benzoxazolyl, indolyl or indolizinyl. 
     
     
         5 . A pharmaceutical composition as defined in any one of  claims 1  to  4 , wherein R 1b  represents a monocyclic aryl or heteroaryl ring system, wherein R 1b  may be substituted by one or more (e.g. 1, 2 or 3) R 4b  groups. 
     
     
         6 . A pharmaceutical composition as defined in  claim 5 , wherein R 1b  represents a monocyclic aryl group such as phenyl optionally substituted by one or more (e.g. 1) R 4b  groups or a monocyclic heteroaryl group such as thienyl, pyrimidinyl or pyrazolinyl optionally substituted by one or more (e.g. 1 or 2) R 4b  groups. 
     
     
         7 . A pharmaceutical composition as defined in any one of  claims 1  to  6 , wherein R 4b  represents halogen, hydroxyl, —O—C 1-6  alkenyl, —COO—C 1-6  alkyl, —NH—C 1-6  alkyl, —SO 2 —NH 2 , amino, cyano, ═O, —CH 2 —CO—NH—C 3-8  cycloalkyl, —CH 2 -aryl, —OCH 2 -heteroaryl, —O-aryl, —NH—CO-aryl, —NH-aryl or heteroaryl groups, wherein said aryl, heterocyclyl or heteroaryl groups of R 4b  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 4b  may be optionally substituted by one or more hydroxyl, amino, cyano, C 1-6  alkoxy, CONH 2  or —COO—C 1-6  alkyl groups. 
     
     
         8 . A pharmaceutical composition as defined in  claim 7 , wherein R 4b  represents halogen (e.g. fluorine), amino or heteroaryl (e.g. pyridyl). 
     
     
         9 . A pharmaceutical composition as defined in any one of  claims 1  to  8 , wherein Z represents a bond, —C(R 7b )(R 8b )—, —O—, —S—, —CH 2 —O—, —N(R 6b )—C(R 7b )(R 8b )—, —N(R 6b )—(CH 2 ) 2 —, —N(R 6b )—(CH 2 ) 3 —, —N(R 6b )—CO—, —N(R 6b )—CO—CH 2 —, —N(R 7b )—CH═, ═CH—, —N═CH—, —C(R 6b )═CH—, —C(═C(R 7b )(R 8b ))—, SO 2 , —CH 2 —NH—SO 2 —, CO, —O—CH 2 —CO—, —SO 2 —N(R 6b )—C(R 7b )(R 8b )—CONH—, —SO 2 —N(R 6b )—CH(—CH 2 -aryl)-CONH—CH 2 —, —CH(—S—C 1-6  alkyl)-C(Me)(OH)—, —C(H)(R 6b )—CO—N(R 5b )—CH 2 —, —O—CH 2 —CO—NH—, —N(R 6b )—CO—CH 2 —O—, —C(H)(—CH 2 -aryl), —C(NH-aryl)═N—N═CH—, —NH—CO—CH 2 —N(R 6b )—, —NH—N═C(-aryl)-, —NH—C(═N—CO—C 1-6  alkyl)-NH—(CH 2 ) 2 —, —C(═CH-aryl)-CONH—CH 2 — or —CH(—CH 2 -aryl)-NH—CO— wherein said aryl or heteroaryl groups of Z may be optionally substituted by one or more halogen, C 1-6  alkyl, C 1-6  alkoxy, NO 2  or hydroxyl groups. 
     
     
         10 . A pharmaceutical composition as defined in  claim 9 , wherein Z represents a bond or CO. 
     
     
         11 . A pharmaceutical composition as defined in any one of  claims 1  to  10 , wherein m represents an integer from 0 to 2, such as 0 or 2. 
     
     
         12 . A pharmaceutical composition as defined in any one of  claims 1  to  11 , wherein R 2b  represents halogen, haloC 1-6  alkyl, C 1-6  alkyl, C 3-8  cycloalkyl, hydroxyl, C 1-6  alkoxy, —S—C 1-6  alkyl, amino, cyano, NO 2 , ═O, —CONH 2 , —CO—C 1-6  alkyl, —COO—C 1-6  alkyl, C 1-6  alkyl, —CO—NH—C 1-6  alkyl or —CO—NH—CH(Me)—COOH, wherein said C 1-6  alkyl groups of R 2b  may be optionally substituted by one or more cyano or hydroxyl groups. 
     
     
         13 . A pharmaceutical composition as defined in  claim 12 , wherein R 2b  represents amino or —CONH 2 . 
     
     
         14 . A pharmaceutical composition as defined in  claim 1 , wherein the compound of formula (IB) is selected from any of compounds 2-3, 26-28, 30-33, 35, 47-48, 51, 57-60, 63-64, 78, 84, 113, 123, 127-129, 145, 155-157, 171-173, 204, 206-207, 210, 225, 227, 233, 235-236, 241-242, 244, 249, 269, 285, 288, 303, 307-312, 314-316, 320, 324-325, 333, 336, 351, 357-360, 374-375, 384-391, 396, 399-402, 404-405, 407-411, 414, 424-425, 427-428, 437, 448, 456-457, 482, 484-485, 489-491, 495, 497-498, 505, 507, 516, 519, 524, 526, 553, 559-560, 568, 570, 575, 609, 615-616, 618, 626-627, 638, 653, 669, 692-694, 705, 709, 712, 716, 719, 725, 734, 738, 740, 746, 749, 753-754, 756, 758-759, 767, 770, 777, 784-785, 790, 792, 796, 800-801, 804-805, 808, 819, 821, 827-828, 831, 833, 838, 844, 847, 857-858, 869, 872, 875, 933, 952, 955, 969, 987, 990 or 999 as described herein or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         15 . A pharmaceutical composition as defined in  claim 14 , wherein the compound of formula (IB) is selected from any one of:
 5-(1,3-benzoxazol-2-yl)-4-(pyridin-4-yl)pyrimidin-2-amine (Compound 324);   2-[3-(pyridin-4-yl)-1H-pyrazol-4-yl]-1,3-benzoxazole (Compound 952);   2-amino-3-[(4-fluorophenyl)carbonyl]indolizine-1-carboxamide (Compound 987); and   2-amino-1-[(4-fluorophenyl)carbonyl]-1H-indole-3-carboxamide (Compound 999);   or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         16 . A compound of formula (IB) as defined in any one of  claims 1  to  15  for use in therapy. 
     
     
         17 . A compound of formula (IB) as defined in any one of  claims 1  to  15  for use as a casein kinase delta (CK1δ) inhibitor in the treatment of a neurodegenerative disorder, such as tauopathies. 
     
     
         18 . The compound as defined in  claim 17 , 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. 
     
     
         19 . The compound as defined in  claim 17  or  claim 18 , wherein the tauopathy comprises Alzheimer's disease.