Heteroaryl compounds and methods of use thereof

Abstract

Provided herein are heteroaryl compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. In one embodiment, the compounds provided herein are useful for the treatment, prevention, and/or management of various disorders, such as CNS disorders and neurological disorders, including, but not limited to, e.g., psychosis, schizophrenia, depression, movement disorders, and Parkinson's disease.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
 n is 2, 3, or 4; 
 W is O, NR 5 , or CH 2 ; 
 X is CH; 
 Y is N or CH; 
 each R 10  and each R 11  are independently H, F, OH, or (C 1 -C 4 )alkyl; 
 (i) R 1  is amido, sulfonamido, optionally substituted imidazolyl, or optionally substituted pyrazolyl; and R 2  is H, halogen, CN, (C 1 -C 4 )alkyl, or (C 1 -C 3 )alkoxyl; or (ii) R 1  and R 2  together with the carbon atoms to which they are attached form a 5-, 6-, or 7-membered aryl, heteroaryl, cycloalkyl, or heterocyclyl ring, each of which is optionally substituted with one to three R 6 ; 
 R 3  and R 4  together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl Q; 
 Q is 
 
       
         
           
           
               
               
           
         
         R 5  is H or (C 1 -C 3 )alkyl; 
         each R 6  is independently OH, keto, halogen, CN, (C 1 -C 3 )alkyl, or (C 1 -C 3 )alkoxyl; 
         R 7  is 5- to 10-membered aryl or heteroaryl, each optionally substituted with one to three substituents; and 
         Ring Ar is a benzo, pyrazolo, pyrido, thieno, pyrimido, pyrazino, furano, pyridazino, thiazolo, or imidazolo ring, each optionally substituted with one to three substituents; 
         provided that: 
         (i) when Q is 
       
       
         
           
           
               
               
           
         
          then 
       
       
         
           
           
               
               
           
         
          is not 
       
       
         
           
           
               
               
           
         
          and 
         (ii) when Ar is an optionally substituted benzo ring, then 
       
       
         
           
           
               
               
           
         
          is not 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound of  claim 1 , wherein n is 4. 
     
     
         3 . The compound of  claim 1 , wherein W is O. 
     
     
         4 . The compound of  claim 1 , wherein R 10  and R 11  is H. 
     
     
         5 . The compound of  claim 1 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       wherein R 8  is (C 1 -C 5 )alkyl or optionally substituted phenyl. 
     
     
         6 . The compound of  claim 1 ,
 wherein   
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1 ,
 wherein Q is   
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1 , having formula (III-a): 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 8 , wherein R 7  is phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, or naphthyl, each of which is optionally substituted with one to three substituents, independently selected from halo, cyano, alkylamino, dialkylamino, (C 1 -C 3 )alkyl optionally substituted with one or more fluoro, and (C 1 -C 3 )alkoxyl optionally substituted with one or more fluoro. 
     
     
         10 . The compound of  claim 8 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1 , having formula (III-b): 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 11 , wherein R 7  is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or naphthyl, each of which is optionally substituted with one to three substituents, independently selected from halo, cyano, alkylamino, dialkylamino, (C 1 -C 3 )alkyl optionally substituted with one or more fluoro, and (C 1 -C 3 )alkoxyl optionally substituted with one or more fluoro. 
     
     
         13 . The compound of  claim 11 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 1 , having formula (III-c): 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 14 , wherein R 7  is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or naphthyl, each of which is optionally substituted with one to three substituents, independently selected from halo, cyano, alkylamino, dialkylamino, (C 1 -C 3 )alkyl optionally substituted with one or more fluoro, and (C 1 -C 3 )alkoxyl optionally substituted with one or more fluoro. 
     
     
         16 . The compound of  claim 14 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 1 , having formula (III-d): 
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound of  claim 17 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 17 , wherein R 7  is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or naphthyl, each of which is optionally substituted with one to three substituents, independently selected from halo, cyano, alkylamino, dialkylamino, (C 1 -C 3 )alkyl optionally substituted with one or more fluoro, and (C 1 -C 3 )alkoxyl optionally substituted with one or more fluoro. 
     
     
         20 . The compound of  claim 17 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 1 , wherein Q is 
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound of  claim 1 , having formula (IV-a): 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound of  claim 22 , wherein Ring Ar is a benzo or thieno ring, each of which is optionally substituted with one to three substituents, independently selected from halo, cyano, alkylamino, dialkylamino, (C 1 -C 3 )alkyl optionally substituted with one or more fluoro, and (C 1 -C 3 )alkoxyl optionally substituted with one or more fluoro. 
     
     
         24 . The compound of  claim 22 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         25 . The compound of  claim 1 , having formula (IV-b): 
       
         
           
           
               
               
           
         
       
     
     
         26 . The compound of  claim 25 , wherein Ring Ar is a pyrazolo, thieno, pyrimido, pyrazino, thiazolo, imidazolo, furano, or pyridazino ring, each of which is optionally substituted with one to three substituents, independently selected from halo, cyano, alkylamino, dialkylamino, (C 1 -C 3 )alkyl optionally substituted with one or more fluoro, (C 1 -C 3 )alkoxyl optionally substituted with one or more fluoro, optionally substituted phenyl, and optionally substituted pyridyl. 
     
     
         27 . The compound of  claim 25 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         28 . The compound of  claim 1 , having formula (IV-c): 
       
         
           
           
               
               
           
         
       
     
     
         29 . The compound of  claim 28 , wherein Ring Ar is a benzo, pyrazolo, thieno, pyrimido, pyrazino, thiazolo, imidazolo, furano, or pyridazino ring, each of which is optionally substituted with one to three substituents, independently selected from halo, cyano, alkylamino, dialkylamino, (C 1 -C 3 )alkyl optionally substituted with one or more fluoro, (C 1 -C 3 )alkoxyl optionally substituted with one or more fluoro, optionally substituted phenyl, and optionally substituted pyridyl. 
     
     
         30 . The compound of  claim 28 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         31 . The compound of  claim 1 , having formula (IV-d): 
       
         
           
           
               
               
           
         
       
     
     
         32 . The compound of  claim 31 , wherein Ring Ar is a benzo, pyrazolo, thieno, pyrimido, pyrazino, thiazolo, imidazolo, furano, or pyridazino ring, each of which is optionally substituted with one to three substituents, independently selected from halo, cyano, alkylamino, dialkylamino, (C 1 -C 3 )alkyl optionally substituted with one or more fluoro, (C 1 -C 3 )alkoxyl optionally substituted with one or more fluoro, optionally substituted phenyl, and optionally substituted pyridyl. 
     
     
         33 . The compound of  claim 31 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         34 . The compound of  claim 1 , having formula (IV-e): 
       
         
           
           
               
               
           
         
       
     
     
         35 . The compound of  claim 34 , wherein Ring Ar is a benzo, pyrazolo, thieno, pyrimido, pyrazino, thiazolo, imidazolo, furano, or pyridazino ring, each of which is optionally substituted with one to three substituents, independently selected from halo, cyano, alkylamino, dialkylamino, (C 1 -C 3 )alkyl optionally substituted with one or more fluoro, (C 1 -C 3 )alkoxyl optionally substituted with one or more fluoro, optionally substituted phenyl, and optionally substituted pyridyl. 
     
     
         36 . The compound of  claim 34 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         37 . The compound of  claim 1 , having formula (IV-f): 
       
         
           
           
               
               
           
         
       
     
     
         38 . The compound of  claim 37 , wherein R 1  is —NHCO(C 1 -C 3 )alkyl, —NHS(O) 2 (C 1 -C 3 )alkyl, 
       
         
           
           
               
               
           
         
       
     
     
         39 . The compound of  claim 37 , wherein Ring Ar is a benzo ring, optionally substituted with one to three substituents, independently selected from halo, cyano, alkylamino, dialkylamino, (C 1 -C 3 )alkyl optionally substituted with one or more fluoro, and (C 1 -C 3 )alkoxyl optionally substituted with one or more fluoro. 
     
     
         40 . The compound of  claim 37 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         41 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient, diluent, or carrier. 
     
     
         42 . The pharmaceutical composition of  claim 41 , which further comprises one or more additional active agents. 
     
     
         43 . A method of treating, preventing, or managing a CNS or neurological disorder, comprising administering to a subject a therapeutically or prophylactically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         44 . The method of  claim 43 , wherein the disorder is Parkinson's disease, movement disorder, ataxia, dystonia, essential tremor, Huntington's disease, multiple system atrophy, myoclonus, progressive supranuclear palsy, rett syndrome, secondary parkinsonism, spasticity, tardive dyskinesia, Wilson's disease, dyskinesia, or restless leg syndrome. 
     
     
         45 . The method of  claim 43 , wherein the disorder is schizophrenia, psychosis, schizophrenia-related disorder, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizoaffective disorder, schizophreniform disorder, paraphrenia, paranoid personality disorder, schizoid personality disorder, schizotypal personality disorder, delusional disorder, a disease having a psychosis component, psychotic disorder, brief psychotic disorder, Alzheimer's psychosis, Parkinson's psychosis, shared psychotic disorder, substance-induced psychotic disorder, psychotic disorder due to a general medical condition, psychoaffective disorder, aggression, delirium, excitative psychosis, Tourette's syndrome, manic disorder, organic psychosis, or NOS psychosis. 
     
     
         46 . The method of  claim 43 , wherein the disorder is affective disorder; depression; major depressive episode of the mild, moderate or severe type; a manic or mixed mood episode; a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post-stroke depression; major depressive disorder; unipolar depression; treatment resistant depression; dysthymic disorder, minor depressive disorder, premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive disorder superimposed on a psychotic disorder; a bipolar disorder; bipolar I disorder; bipolar II disorder; cyclothymic disorder; seasonal affective disorder; attention deficit disorder; or attention deficit hyperactivity disorder. 
     
     
         47 . The method of  claim 43 , wherein the disorder is addiction or substance abuse or dependency. 
     
     
         48 . The method of  claim 43 , wherein the disorder is posttraumatic stress disorder, behavior disorder, neurodegenerative disease, Alzheimer's disease, dementia, mood disorder, anxiety, obsessive-compulsive disorder, vertigo, pain, neuropathic pain, sensitization accompanying neuropathic pain, inflammatory pain, fibromyalgia, migraine, cognitive disorder, cognitive impairment, cognitive impairment associated with schizophrenia, cognitive deficit in Alzheimer's disease, cognitive deficit in Parkinson's disease, multiple sclerosis, sleep disorder, eating disorder, or autism. 
     
     
         49 . The method of  claim 43 , further comprising administering to the subject a second active agent.