Multicyclic compounds and methods of use thereof

Abstract

Provided herein are multicyclic compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. The compounds provided herein are useful for the treatment, prevention, and/or management of various neurological disorders, including but not limited to, psychosis and schizophrenia.

1 - 39 . (canceled) 
     
     
         40 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
 one of X and Y is O, and the other is CH 2 ; or both X and Y are CH 2 ; 
 one of Z 1 , Z 2 , and Z 3  is S; and (i) two of Z 1 , Z 2 , and Z 3  are C; or (ii) one of Z 1 , Z 2 , and Z 3  is C and one of Z 1 , Z 2 , and Z 3  is N; 
 R 1  and R 2  are each independently (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optionally substituted; or (ii) —(CH 2 ) p —R 8 , wherein R 8  is SO 2 alkyl or SO 2 aryl, each of which is optionally substituted; or (iii) R 1  and R 2  together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl or heteroaryl; 
 R 3  and R 4  are each independently (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optionally substituted; or (ii) —(CH 2 ) p —R 9 , wherein R 9  is CF 3 , CN, nitro, amino, hydroxyl, or cycloalkoxyl, each of which is optionally substituted; or (iii) R 3  and R 4  together with the carbon atom to which they are attached form an optionally substituted cycloalkyl or heterocyclyl; or (iv) R 3  and R 1  together with the atoms to which they are attached form an optionally substituted heterocyclyl, and R 4  is (i) or (ii); or (v) R 3  and R 4  are combined together to form a double bond and together with R 1  and/or R 2  and the atoms to which they are attached form an optionally substituted heteroaryl; 
 R 5  is (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optionally substituted; or (ii) —(CH 2 ) p —R 10 , wherein R 10  is CF 3 , CN, nitro, amino, hydroxyl, or cycloalkoxyl, each of which is optionally substituted; or (iii) R 5  and R 1  together with the atoms to which they are attached form an optionally substituted heterocyclyl; 
 R 6  and R 7  are each independently (i) hydrogen, halo, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optionally substituted; or (ii) —(CH 2 ) p —R 11 , wherein R 11  is CF 3 , CN, nitro, amino, hydroxyl, cycloalkoxyl, heteroaryl, or heterocyclyl, each of which is optionally substituted; or (iii) R 6  and R 7  together with the atoms to which they are attached form an optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclyl ring; with the proviso that when one of Z 1 , Z 2 , and Z 3  is N, R 7  is absent; 
 m is 0, 1, or 2; 
 n is 0, 1, or 2; and 
 each occurrence of p is independently 0, 1, or 2. 
 
     
     
         41 . The compound of  claim 40 , having formula (IIa): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 6  and R 7  together with the atoms to which they are attached form an aryl or cycloalkyl ring, each of which is optionally substituted. 
     
     
         42 . The compound of  claim 41 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         43 . The compound of  claim 40 , having formula (V): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Z 1  is N and Z 3  is S, or Z 1  is S and Z 3  is N. 
     
     
         44 . The compound of  claim 43 , wherein X and Y are both CH 2 , and/or m is 0 and n is 1. 
     
     
         45 . The compound of  claim 43 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         46 . A compound of formula (VI): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
 two of Z 1 , Z 2 , and Z 3  are C, and one of Z 1 , Z 2 , and Z 3  is S; 
 R 1  and R 2  are each independently (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optionally substituted; or (ii) —(CH 2 ) p —R 8 , wherein R 8  is SO 2 alkyl or SO 2 aryl, each of which is optionally substituted; or (iii) R 1  and R 2  together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl or heteroaryl; 
 R 3  and R 4  are each independently (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optionally substituted; or (ii) —(CH 2 ) p —R 9 , wherein R 9  is CF 3 , CN, nitro, amino, hydroxyl, or cycloalkoxyl, each of which is optionally substituted; or (iii) R 3  and R 4  together with the carbon atom to which they are attached form an optionally substituted cycloalkyl or heterocyclyl; or (iv) R 3  and R 1  together with the atoms to which they are attached form an optionally substituted heterocyclyl, and R 4  is (i) or (ii); or (v) R 3  and R 4  are combined together to form a double bond and together with R 1  and/or R 2  and the atoms to which they are attached form an optionally substituted heteroaryl; 
 R 5  is (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optionally substituted; or (ii) —(CH 2 ) p —R 10 , wherein R 10  is CF 3 , CN, nitro, amino, hydroxyl, or cycloalkoxyl, each of which is optionally substituted; or (iii) R 5  and R 1  together with the atoms to which they are attached form an optionally substituted heterocyclyl; 
 R 6  and R 7  are each independently (i) hydrogen, halo, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optionally substituted; or (ii) —(CH 2 ) p —R 11 , wherein R 11  is CF 3 , CN, nitro, amino, hydroxyl, cycloalkoxyl, heteroaryl, or heterocyclyl, each of which is optionally substituted; or (iii) R 6  and R 7  together with the atoms to which they are attached form an optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclyl ring; and 
 m is 0, 1, or 2; 
 each occurrence of p is independently 0, 1, or 2. 
 
     
     
         47 . The compound of  claim 46 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         48 . A pharmaceutical composition comprising a compound of  claim 40 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier. 
     
     
         49 . The pharmaceutical composition of  claim 48 , which further comprises one or more additional active agents. 
     
     
         50 . A method of treating, preventing, or managing a neurological disorder, comprising administering to a subject a therapeutically or prophylactically effective amount of a compound of  claim 40 , or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         51 . The method of  claim 50  wherein said subject is a human. 
     
     
         52 . The method of  51 , wherein the disorder is schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizoid personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, drug-induced psychosis, psychoaffective disorder, aggression, delirium, Parkinson's psychosis, excitative psychosis, Tourette's syndrome, organic or NOS psychosis, seizure, agitation, post-traumatic stress disorder, behavior disorder, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, dyskinesias, Huntington's disease, dementia, mood disorder, anxiety, affective disorder, depression, major depressive disorder, dysthymia, bipolar disorder, manic disorder; seasonal affective disorder; attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, vertigo, epilepsy, pain, neuropathic pain, sensitization accompanying neuropathic pain, inflammatory pain, fibromyalgia, migraine, cognitive impairment, movement disorder, restless leg syndrome, multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, drowsy side effect of medications, insomnia, substance abuse or dependency, addiction, eating disorder, sexual dysfunction, hypertension, emesis, Lesche-Nyhane disease, Wilson's disease, autism, Huntington's chorea, and premenstrual dysphoria. 
     
     
         53 . The method of  claim 52 , wherein the disorder is psychosis or schizophrenia. 
     
     
         54 . A pharmaceutical composition comprising a compound of  claim 41 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier. 
     
     
         55 . A method of treating, preventing, or managing a neurological disorder, comprising administering to a subject a therapeutically or prophylactically effective amount of a compound of  claim 41 , or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         56 . A pharmaceutical composition comprising a compound of  claim 43 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier. 
     
     
         57 . A method of treating, preventing, or managing a neurological disorder, comprising administering to a subject a therapeutically or prophylactically effective amount of a compound of  claim 43 , or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         58 . A pharmaceutical composition comprising a compound of  claim 46 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier. 
     
     
         59 . A method of treating, preventing, or managing a neurological disorder, comprising administering to a subject a therapeutically or prophylactically effective amount of a compound of  claim 46 , or a pharmaceutically acceptable salt or stereoisomer thereof.