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: 
     
         1 - 39 . (canceled) 
     
     
         40 . A compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or stereoisomer thereof. 
       
     
     
         41 . The compound of  claim 40 , or a pharmaceutically acceptable salt thereof, selected from: 
       
         
           
           
               
               
           
         
         or a mixture thereof. 
       
     
     
         42 . A compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         43 . A compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         44 . A pharmaceutical composition comprising a compound of  claim 40 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier. 
     
     
         45 . The pharmaceutical composition of  claim 44 , which further comprises one or more additional active agents. 
     
     
         46 . 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. 
     
     
         47 . The method of  claim 46 , wherein said subject is a human. 
     
     
         48 . The method of  claim 46 , 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. 
     
     
         49 . The method of  claim 46 , wherein the disorder is psychosis or schizophrenia. 
     
     
         50 . A pharmaceutical composition comprising a compound or a mixture of  claim 41 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier. 
     
     
         51 . The pharmaceutical composition of  claim 50 , which further comprises one or more additional active agents. 
     
     
         52 . 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. 
     
     
         53 . The method of  claim 52 , wherein said subject is a human. 
     
     
         54 . The method of  claim 52 , 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. 
     
     
         55 . The method of  claim 52 , wherein the disorder is psychosis or schizophrenia. 
     
     
         56 . A pharmaceutical composition comprising a compound of  claim 42 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. 
     
     
         57 . The pharmaceutical composition of  claim 56 , which further comprises one or more additional active agents. 
     
     
         58 . 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 42 , or a pharmaceutically acceptable salt thereof. 
     
     
         59 . The method of  claim 58 , wherein said subject is a human. 
     
     
         60 . The method of  claim 58 , 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. 
     
     
         61 . The method of  claim 58 , wherein the disorder is psychosis or schizophrenia. 
     
     
         62 . A pharmaceutical composition comprising a compound of  claim 43 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. 
     
     
         63 . The pharmaceutical composition of  claim 62 , which further comprises one or more additional active agents. 
     
     
         64 . 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 thereof. 
     
     
         65 . The method of  claim 64 , wherein said subject is a human. 
     
     
         66 . The method of  claim 64 , 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. 
     
     
         67 . The method of  claim 64 , wherein the disorder is psychosis or schizophrenia. 
     
     
         68 . A method of producing N-methyl (3-methyl-5,6-dihydro-4H-cyclopenta[b]thien-4-yl)methanamine: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or stereoisomer thereof, by treating (3-methyl-5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)methanamine with ethyl chloroformate to produce ethyl ((3-methyl-5,6-dihydro-4H-cyclopenta[b]thien-4-yl)methyl)carbamate, and treating said ethyl ((3-methyl-5,6-dihydro-4H-cyclopenta[b]thien-4-yl)methyl)carbamate with LAH to form N-methyl (3-methyl-5,6-dihydro-4H-cyclopenta[b]thien-4-yl)methanamine. 
       
     
     
         69 . The method according to  claim 68 , further comprising further comprising resolving 
       
         
           
           
               
               
           
         
       
     
     
         70 . The method according to  claim 69 , further comprising isolating 
       
         
           
           
               
               
           
         
       
     
     
         71 . The method according to  claim 69 , further comprising isolating