Novel heterocycle compounds and uses thereof

Abstract

The invention relates to chemical compounds, or pharmaceutically acceptable salts thereof of the formula (I): 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 (I): 
       
         
           
           
               
               
           
         
       
       in free or salt form, wherein:
 A 1  is CH or N; 
 R 1  is C 1-6 alkyl, C 1-6 cycloalkyl, or aryl optionally substituted with alkyl, haloalkyl, alkyloxy, or halo group; 
 R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are independently hydrogen, halo, C 1-4 alkyl, C 1-4 alkyloxy, or trifluoromethyl; 
 or R 5  and R 6 , together with carbon atoms to which they are attached, form a 5 or 6 member hetcyclic ring; 
 Y is —NHCO—, —CONH—, —NHSO 2 —, —NHCONH—, or —NHCH 2 —; 
 D is a 5 or 6 member 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; provided that D is not a substituted phenyl group if A 1 =N and R 2 ═R 3 ═R 4 ═R 5 ═R 6 ═H and R 7 ═CH 3  and Y═NHCO; and 
 R 8  is C 0-6 alkyl, C 3-7 cycloalkyl, aryl, hetaryl, 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. 
 
     
     
         2 . The compound according to  claim 1  selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       in free or salt form. 
     
     
         3 . The compound according to  claim 1  or  2 , wherein said compound is: 
       
         
           
           
               
               
           
         
       
       in free or salt form. 
     
     
         4 . The compound according to  claim 1  or  2 , wherein said compound is: 
       
         
           
           
               
               
           
         
       
       in free or salt form. 
     
     
         5 . A pharmaceutical composition which comprises a compound, in free or pharmaceutically acceptable salt form, as claimed in any of the preceding claims, in association with a pharmaceutically-acceptable diluent or carrier. 
     
     
         6 . A compound, in free or pharmaceutically acceptable salt form, as claimed in any one of the preceding claims for use as a medicament. 
     
     
         7 . Use of a compound, in free or salt form, as claimed in any of  claims 1 - 4 , in the manufacture of a medicament for use in the treatment 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, or prion disease. 
     
     
         8 . Use of a compound, in free or salt form, as claimed in any of  claims 1 - 4  in the manufacture of a medicament for use in the treatment of Alzheimer's disease. 
     
     
         9 . Use of a compound, in free or salt form, as claimed in any one of  claims 1 - 4 , in the manufacture of a medicament for use in the treatment of astrocytoma, medulloblastoma, oligdendroglioma, glioblastoma, glioma, ependymoma, meningioma, sarcoma, germ cell tumor, pinealoma, craniopharyngioma, or pituitary adenoma. 
     
     
         10 . A pharmaceutical composition comprising an effective amount of a compound, in free or pharmaceutically acceptable salt form, as claimed in any one of  claims 1 - 4 , for use in the treatment, control and management of diseases characterized by accumulation of abnormal protein aggregates. 
     
     
         11 . A pharmaceutical composition comprising an effective amount of a compound, in free or pharmaceutically acceptable salt form, as claimed in any one of  claims 1 - 4 , for use in the treatment, control and management of diseases characterized by accumulation of abnormal protein aggregates in the brain. 
     
     
         12 . A pharmaceutical composition comprising an effective amount of a compound, in free or pharmaceutically acceptable salt form, as claimed in any one of  claims 1 - 4  for use in the treatment, control and management 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, prion disease. 
     
     
         13 . The pharmaceutical composition according to  claim 12  for use in the treatment, control and management of Alzheimer's disease. 
     
     
         14 . A pharmaceutical composition comprising an effective amount of a compound, in free or pharmaceutically acceptable salt form, as claimed in any one of  claims 1 - 4  for use in the treatment, control and management of vascular, neurological, or neurodegenerative disorders related to the abnormal expression or accumulation of tau or amyloid proteins. 
     
     
         15 . A pharmaceutical composition comprising an effective amount of a compound, in free or pharmaceutically acceptable salt form, as claimed in any one of  claims 1 - 4  for use in the treatment, control and management of abnormal protein aggregates of amyloid plaques, neurofibrillary tangles, or precipitates of tau or amyloid proteins. 
     
     
         16 . A pharmaceutical composition which comprises a compound, in free or pharmaceutically acceptable salt form, as claimed in any one of  claims 1 - 4  in association with a pharmaceutically-acceptable diluent or carrier for use in the treatment of hyperproliferative diseases. 
     
     
         17 . A pharmaceutical composition which comprises a compound, in free or pharmaceutically acceptable salt form, as claimed in any one of  claims 1 - 4  in association with a pharmaceutically-acceptable diluent or carrier for use in the treatment of cancers of the brain or central nervous system. 
     
     
         18 . A pharmaceutical composition which comprises a compound, in free or pharmaceutically acceptable salt form, as claimed in any one of  claims 1 - 4  in association with a pharmaceutically-acceptable diluent or carrier for use in the treatment of astrocytoma, medulloblastoma, oligdendroglioma, glioblastoma, glioma, ependymoma, meningioma, sarcoma, germ cell tumor, pinealoma, craniopharyngioma, or pituitary adenoma. 
     
     
         19 . 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 any of  claims 1 - 4 , in free or pharmaceutically acceptable salt form. 
     
     
         20 . The method according to  claim 19 , 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. 
     
     
         21 . The method according to  claim 19  or  20 , wherein said disease or disorder is Alzheimer's disease. 
     
     
         22 . A method for the treatment of one or more hyperprofilerative diseases comprising administering to a patient in need thereof, a compound according to any of  claims 1 - 4 , in free or pharmaceutically acceptable salt form. 
     
     
         23 . The method according to  claim 22 , 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.