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.

What is claimed is: 
     
         1 - 39 . (canceled) 
     
     
         40 . A compound of formula (Ma): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
 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 (—NH 2 ), 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; 
 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 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5  is H. 
     
     
         42 . The compound of  claim 40 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 1. 
     
     
         43 . The compound of  claim 40 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is 0. 
     
     
         44 . The compound of  claim 40 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1  and R 2  are each independently hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optionally substituted. 
     
     
         45 . The compound of  claim 44 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one or more halo. 
     
     
         46 . The compound of  claim 44 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1  and R 2  are each independently hydrogen or alkyl. 
     
     
         47 . The compound of  claim 40 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3  and R 4  are each independently hydrogen or alkyl. 
     
     
         48 . The compound of  claim 40 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 6  and R 7  are each independently hydrogen, halo, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optionally substituted. 
     
     
         49 . The compound of  claim 48 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 6  and R 7  are each independently hydrogen, halo, or alkyl. 
     
     
         50 . The compound of  claim 40 , wherein R 1 , R 2 , R 6 , and R 7  are each independently hydrogen or optionally substituted C 1 -C 4  alkyl. 
     
     
         51 . The compound of  claim 50 , wherein R 1 , R 2 , R 6 , and R 7  are each independently hydrogen or unsubstituted methyl or ethyl. 
     
     
         52 . The compound of  claim 47 , wherein R 1 , R 2 , R 6 , and R 7  are each independently hydrogen or optionally substituted C 1 -C 4  alkyl. 
     
     
         53 . The compound of  claim 40 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or stereoisomer thereof. 
       
     
     
         54 . A compound, wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or stereoisomer thereof. 
       
     
     
         55 . The compound of  claim 40 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or stereoisomer thereof. 
       
     
     
         56 . A pharmaceutical composition comprising a compound of  claim 40 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier. 
     
     
         57 . A method of treating neurological disorder, comprising administering to a subject a therapeutically effective amount of a compound of  claim 40 , or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         58 . The method of  claim 57 , wherein the neurological 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, or premenstrual dysphoria. 
     
     
         59 . A method of preparing a compound of formula (IIIa): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or stereoisomer thereof, the method comprising: 
         (a) treating a hydroxyalkyl thiophene of formula (i): 
       
       
         
           
           
               
               
           
         
         with an amino-aldehyde acetal and an acid, to produce a compound of formula (IIIa), wherein:
 m is 0; 
 n is 1; 
 R 1  and R 2  are each independently hydrogen or C 1 -C 4  alkyl; 
 R 3  and R 4  are each independently hydrogen or C 1 -C 4  alkyl; 
 R 5  is hydrogen; and 
 R 6  and R 7  are each independently hydrogen, halo, or C 1 -C 4  alkyl. 
 
       
     
     
         60 . The method according to  claim 59 , wherein the acid is trifluoromethyl sulfonic acid. 
     
     
         61 . The method according to  claim 59 , wherein R 1  is hydrogen or C 1 -C 4  alkyl and R 2  is hydrogen. 
     
     
         62 . The method according to  claim 59 , wherein R 3  and R 4  are hydrogen. 
     
     
         63 . The method according to  claim 59 , wherein the amino-aldehyde acetal is an amino-aldehyde dimethyl acetal of formula (ii): 
       
         
           
           
               
               
           
         
         wherein: 
         m is 0; 
         n is 1; 
         R 1  and R 2  are each independently hydrogen or C 1 -C 4  alkyl; 
         R 3  and R 4  are each independently hydrogen or C 1 -C 4  alkyl; and 
         R 5  is hydrogen. 
       
     
     
         64 . The method according to  claim 59 , wherein the amino-aldehyde acetal comprises an amino-aldehyde diethyl acetal. 
     
     
         65 . The method of  claim 59 , wherein the compound of formula (IIIa) or a pharmaceutically acceptable salt or stereoisomer thereof is selected from the following compounds or pharmaceutically acceptable salts or stereoisomers thereof: 
       
         
           
           
               
               
           
         
       
     
     
         66 . The method according to  claim 59 , wherein the compound of formula (IIIa) or a pharmaceutically acceptable salt or stereoisomer thereof is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or stereoisomer thereof. 
       
     
     
         67 . The method of  claim 59 , comprising combining 2-(2-bromothiophen-3-yl)ethanol, aminoacetaldehyde diethyl acetal, 1,4-dioxane, and triflic acid, and isolating said compound, to obtain 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or stereoisomer thereof. 
       
     
     
         68 . A compound of formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or stereoisomer thereof, 
         prepared by the method of  claim 59 .