CASEIN KINASE 1delta (CK 1delta) INHIBITORS AND THEIR USE IN THE TREATMENT OF NEURODEGENERATIVE 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 - 29 . (canceled) 
     
     
         30 . A method of treating a neurodegenerative disorder in a subject, comprising administering an effective amount of a casein kinase 1 delta (ck1δ) inhibitor compound of formula (IC), or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein 
         “Het C” represents pyridinyl, pyrimidinyl or quinazolinyl; 
         X c  and Y c  independently represent a bond or NH; 
         R 1c  and R 2c  independently represent phenyl, benzodioxinyl, pyridinyl, pyrazol-4-yl, thiophenyl or benzoxazolyl, wherein R 1c  and R 2c  may be substituted by one or more R 4c  groups; 
         R 4c  represents selected from hydroxyl, methoxy or —CONH 2 ; 
         p represents an integer from 0 to 2; 
         R 3c  represents halogen, halo C 1-6  alkyl, C 1-6  alkyl, hydroxyl, C 1-6  alkoxy, —S—C 1-6  alkyl, —CH 2 —S—C 1-6  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, 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 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 867. 
       
     
     
         31 . The method of  claim 30 , wherein “Het C” represents quinazolinyl. 
     
     
         32 . The method of  claim 30 , wherein one of X c  and Y c represents a bond and the other represents NH. 
     
     
         33 . The method of  claim 30 , wherein R 1c  and R 2c  independently represent phenyl, pyridinyl, pyrazol-4-yl or thiophenyl, wherein R 1c  and R 2c  may be substituted by one or more R 4c  groups selected from hydroxyl, methoxy or —CONH 2 . 
     
     
         34 . The method of  claim 33 , wherein R 1C  and R 2c  independently represent unsubstituted phenyl, unsubstituted pyridinyl or pyrazol-4-yl. 
     
     
         35 . The method of  claim 30 , wherein p is 0. 
     
     
         36 . The method of  claim 30 , wherein R 3c  represents ═O, cyano or pyridinyl. 
     
     
         37 . The method of  claim 36 , wherein p is 1 and R 3c  represents pyridinyl. 
     
     
         38 . The method of  claim 36 , wherein p is 2 and R 3c  represents ═O or cyano. 
     
     
         39 . The method of  claim 30 , wherein the compound of formula (IC) is selected from the group consisting of:
 2-Phenyl-N-(pyridin-4-yl)quinazolin-4-amine (Compound 700);   N-(2,3-Dihydro-1,4-benzadioxin-6-yl)-2-phenylquinazolin-4-amine (Compound 868);   4-{([2-(Thiophen-3-yl)quinazolin-4-yl]amino}benzamide (Compound 870);   2-Phenyl-N-(1H-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.   
     
     
         40 . The method of  claim 39 , wherein the compound of formula (IC) is 2-Phenyl-N-(pyridin-4-yl)quinazolin-4-amine (Compound 700) or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         41 . The method of wherein the neurodegenerative disorder is a tauopathy, 
     
     
         42 . The method of  claim 41 , 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), neuobasal 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. 
     
     
         43 . The method of  claim 42 , wherein the tauopathy comprises Alzheimer's disease.