Psilocin derivatives as serotonergic psychedelic agents for the treatment of cns disorders

Abstract

The present application relates to psilocin derivatives of Formula (I), to processes for their preparation, to compositions comprising them and to their use in activation of a serotonin receptor in a cell, as well as to treating diseases, disorders or conditions by activation of a serotonin receptor in a cell.

1 . A method for treating a disease, disorder or condition that is treated by activation of a serotonin receptor comprising administering, to a subject having the disease, disorder or condition, a therapeutically effective amount of one or more compounds Formula IG, or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein 
         R 3 , R 4 , R 5  and R 6  are independently selected from the group consisting of hydrogen and deuterium; 
         R 7  and R 8  are independently selected from the group consisting of hydrogen, and unsubstituted C 1-6 alkyl; or 
         R 7  and R 8  are taken together with the atoms to which they are attached form a 3- to 7-membered heterocyclic ring; 
         R 10  is selected from the group consisting of hydrogen, halogen, cyano and lower alkyl; and 
         Q′ is selected from 
       
       
         
           
           
               
               
           
         
         wherein one or more of R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 10  optionally comprises deuterium, and 
         wherein the disease, disorder or condition is a mental disorder. 
       
     
     
         2 . The method of  claim 1 , wherein Q′ is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The method of  claim 2 , wherein Q′ is 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 1 , wherein R 3 , R 4 , R 5  and R 6  are hydrogen. 
     
     
         5 . The method of  claim 3 , wherein R 3 , R 4 , R 5  and R 6  are hydrogen. 
     
     
         6 . The method of  claim 1  having the following structure: 
       
         
           
           
               
               
           
         
         wherein 
         R 7  and R 8  are independently selected from the group consisting of hydrogen, and unsubstituted C 1-6 alkyl; or 
         R 7  and R 8  are taken together with the atoms to which they are attached form a 3- to 6-membered heterocyclic ring, or 
         a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         7 . The method of  claim 6 , wherein R 7  and R 8  are independently selected from the group consisting of hexyl, pentyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-propyl, iso-propyl, ethyl, and methyl. 
     
     
         8 . The method of  claim 7 , wherein R 7  and R 8  are independently selected from the group consisting of n-butyl, iso-butyl, sec-butyl, tert-butyl, n-propyl, isopropyl, ethyl, and methyl. 
     
     
         9 . The method of  claim 1 , wherein R 10  is hydrogen. 
     
     
         10 . The method of  claim 3 , wherein R 10  is hydrogen 
     
     
         11 . The method of  claim 1 , wherein the one or more compounds of Formula IG are selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         12 . The method of  claim 1 , wherein the one of more compounds of Formula IG are selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         13 . The method of  claim 1  herein the compound of Formula IG is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         14 . The method of  claim 1 , wherein the disease, disorder or condition is a central nervous system (CNS) disease, disorder or condition or a neurological disease, disorder or condition. 
     
     
         15 . The method of  claim 1 , wherein the disease, disorder or condition is a mental illness. 
     
     
         16 . The method of  claim 15 , wherein the mental illness is selected from anxiety disorders, depression, mood disorders, psychotic disorders, impulse control disorders, substance use disorders, addiction disorders, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), panic disorders, eating disorders, stress response syndromes, dissociative disorders, depersonalization disorder, factitious disorders, sexual and gender disorders, and somatic symptom disorders, and combinations thereof. 
     
     
         17 . The method of  claim 15 , wherein the mental illness is selected from autism spectrum disorders, Tourette's syndrome, treatment-resistant depression, alcohol use disorder, nicotine addiction, attention deficit hyperactivity disorder (ADHD), trichotillomania, binge eating disorder (BED), compulsive gambling, general anxiety disorder (GAD), phobias, anorexia, bulimia, apathy, anhedonia, depression in Alzheimer's disease, depression in terminally ill cancer patients, major depressive disorder, depression associated with life-threatening disease, anxiety associated with life-threatening disease, end-of-life depression, and combinations thereof. 
     
     
         18 . The method of  claim 1 , wherein the disease, disorder or condition is psychosis or psychotic symptoms. 
     
     
         19 . The method of  claim 14 , wherein the neurological disease, disorder or condition is selected from a neurodevelopmental disease and a neurodegenerative disease. 
     
     
         20 . The method of  claim 1 , wherein the disease, disorder or condition is selected from Alzheimer's disease, presenile dementia, senile dementia, vascular dementia, Lewy body dementia, cognitive impairment, Parkinson's disease, Parkinson dementia, corticobasal degeneration, supranuclear palsy, epilepsy, CNS trauma, CNS infections, CNS inflammation, stroke, multiple sclerosis, Huntington's disease, mitochondrial disorders, Fragile X syndrome, Angelman syndrome, hereditary ataxias, neuro-otological and eye movement disorders, neurodegenerative diseases of the retina, amyotrophic lateral sclerosis, tardive dyskinesias, hyperkinetic disorders, Tourette's syndrome, schizophrenia, autism spectrum disorders, tuberous sclerosis, Rett syndrome, cerebral palsy, anorexia nervosa (“AN”), bulimia nervosa (“BN”), binge eating disorder (“BED”), trichotillomania, dermotillomania, nail biting, migraine, fibromyalgia, and peripheral neuropathy of any etiology, and combinations thereof. 
     
     
         21 . The method of  claim 1 , wherein the subject is a human. 
     
     
         22 . The method of  claim 1 , wherein the one or more compounds of Formula IG, one or more compounds Formula IG, or a pharmaceutically acceptable salt or solvate thereof, are comprised in a pharmaceutical composition.