Novel heterocycle compounds and uses thereof

Abstract

The invention relates to chemical compounds, or pharmaceutically acceptable salts thereof of the formula (Q) or (1), Which penetrate the blood-brain barrier, inhibit the formation and accumulation of beta-amyloid, and are useful in the treatment of neurodegenerative diseases, particularly Alzheimer's disease. Further, the compounds of the present invention inhibit certain kinases, thereby being useful for the treatment of cancers of the central nervous system.

What is claimed: 
     
         1 . A compound of formula (Q): 
       
         
           
           
               
               
           
         
         in free or salt form, wherein:
 A 1  is —C(R 7 )— or —N—; 
 A 2  and A 3  are independently —C— or —N—, wherein at least one of A 2  and A 3  must be N; and wherein when A 2  is —C—, it optionally is substituted with R 8 ; 
 W is —O— or —N(C 1-6 alkyl)-; 
 Y is —NHCO—, —CONH—, —NHSO 2 —, —NHCONH—, Or —NHCH 2 —; 
 D is a 5 or 6 membered aryl, hetaryl or hetcyclic ring having at least one N, S, or O ring atom, or a C ring atom forming an oxo (C═O) moiety; 
 R 1  is Ci-βalkyl, aryl, or hetaryl; optionally substituted except at the ortho position of the aryl or hetaryl with 1-6 halo, C 1-6 alkoxy, C 1-6 alkyl, or trifluoromethyl substituents; wherein the ortho aryl or hetaryl position is unsubstituted; 
 R 2  is Co-βalkyl, C 3-7 cycloalkyl, aryl, hetaryl, aryl(C 1-4 alkyl)-, hetcyclyl(C 0-4 alkyl)-, or —C 0-6 alkyl-N(C 0-6 alkyl)(C 0-6 alkyl), optionally substituted with C 1-6 alkyl; and 
 R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are independently selected from hydrogen, halo, C 1-4 alkyl, C 1-4 alkoxyl 
 
         and haloC 1-4 alkyl. 
       
     
     
         2 . The compound according to  claim 1  wherein the compound of formula (Q) is: 
       
         
           
           
               
               
           
         
         in free or salt form. 
       
     
     
         3 . The compound according to  claim 1  wherein the compound of formula (Q) is 
       
         
           
           
               
               
           
         
         in free or salt form. 
       
     
     
         4 . The compound according to  claim 1  wherein the compound of formula (Q) is 
       
         
           
           
               
               
           
         
         in free or salt form. 
       
     
     
         5 . The compound according to  claim 1  wherein the compound of formula (Q) is 
       
         
           
           
               
               
           
         
         in free or salt form. 
       
     
     
         6 . The compound according to  claim 1  wherein the compound of formula (Q) is: 
       
         
           
           
               
               
           
         
         in free or salt form. 
       
     
     
         7 . The compound according to  claim 1  wherein the compound of formula (Q) is: 
       
         
           
           
               
               
           
         
         in free or salt form. 
       
     
     
         8 . The compound according to  claim 1  wherein the compound of formula (Q) is: 
       
         
           
           
               
               
           
         
         in free or salt form. 
       
     
     
         9 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         in free or salt form, wherein:
 A 1  is CH or N; 
 A 2  and A 3  are independently CH or N, wherein at least one of A 2  and A 3  must be N; and 
 
         wherein when A 2  is C, it optionally is substituted with halo, methyl, methoxy, or trifluoromethyl;
 W is —O— or —N(C 0-6 alkyl)-; 
 Y is —NHCO—, —CONH—, —NHSO 2 —, —NHCONH—, Or —NHCH 2 —; 
 D is a 5 or 6 membered aryl, hetaryl or hetcyclic ring having at least one N, S, or O ring atom, or a C ring atom forming an oxo (C═O) moiety; 
 R 1  is C 1-6 alkyl, aryl, or hetaryl; optionally substituted except at the ortho position of the aryl or hetaryl with 1-6 halo, C 1-6 alkoxy, C 1-6 alkyl, or trifluoromethyl substituents; wherein the ortho aryl or hetaryl position is unsubstituted; and 
 R 2  is C 0-6 alkyl, C 3-7 cycloalkyl, aryl, hetaryl, aryl(C 1-4 alkyl)-, hetcyclyl(C 0-4 alkyl)-, or —C 0-6 alkyl-N(C 0-6 alkyl)(C 0-6 alkyl), optionally substituted with C 1-6 alkyl. 
 
       
     
     
         10 . A pharmaceutical composition which comprises a compound, in free or
 pharmaceutically acceptable salt form, as claimed in  claim 1 , in association with a pharmaceutically-acceptable diluent or carrier.   
     
     
         11 .- 22 . (canceled) 
     
     
         23 . A method for the treatment control and management of one or more diseases characterized by accumulation of abnormal protein aggregates comprising administering to a patient in need thereof, a compound according to  claim 1 , in free or pharmaceutically acceptable salt form. 
     
     
         24 . The method according to  claim 23 , wherein said disease is selected from a group consisting of Alzheimer's disease, progressive supranuclear palsy, Down Syndrome, memory and cognitive disorders, dementia, amyloid neuropathies, brain inflammation, nerve and brain trauma, vascular amyloidosis, cerebral hemorrhage with amyloidosis, Parkinson's disease, Huntington's disease, and prion disease. 
     
     
         25 . The method according to  claim 23 , wherein said disease or disorder is Alzheimer's disease. 
     
     
         26 . A method for the treatment of one or more hyperprofilerative diseases comprising administering to a patient in need thereof, a compound according to  claim 1 , in free or pharmaceutically acceptable salt form. 
     
     
         27 . The method according to  claim 26 , wherein said disease is selected from a group consisting of astrocytoma, medulloblastoma, oligdendroglioma, glioblastoma, glioma, ependymoma, meningioma, sarcoma, germ cell tumor, pinealoma, craniopharyngioma, and pituitary adenoma.