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 compound of Formula (I) or a pharmaceutically acceptable salt, solvate and/or prodrug thereof: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from hydrogen, C 1 -C 3  alkyl, C(O)R 12 , CO 2 R 12 , C(O)N(R 12 ) 2 , S(O)R 12  and SO 2 R 12 ; 
         R 2  is selected from hydrogen and C 1 -C 4 alkyl 
         R 3 , R 4 , R 5  and R 6  are independently selected from hydrogen and C 1 -C 6 alkyl; 
         R 7  and R 8  are independently selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted C 3 -C 7 heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, or 
         R 7  and R 8  are taken together with the nitrogen atom therebetween to form a 3- to 7-membered heterocyclic ring optionally including 1 to 2 additional ring heteromoieties selected from O, S, S(O), SO 2 , N and NR 13 , 
         wherein said C 3 -C 7 cycloalkyl and 3- to 7-membered heterocyclic ring are each further optionally substituted with a substituent selected from, halogen, CO 2 R 13 , C(O)N(R 13 ) 2 , SO 2 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl and a 3- to 6-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, N, S(O), SO 2  and NR 13 ; 
         R 9 , R 19  and R 11  are independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 ) 2 , SR 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, CO 2 R 13 , C(O)N(R 13 ) 2 , SOR 13 , SO 2 R 13 , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 7 cycloalkyl and a 3- to 7-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO 2 , N and NR 13 , wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 7 cycloalkyl and 3- to 7-membered heterocyclic ring groups are optionally substituted by one or more substituents independently selected from CN, OR 13 , N(R 13 ) 2  and SR 13 , and wherein said C 3 -C 7 cycloalkyl and 3- to 7-membered heterocyclic ring are each further optionally substituted with a substituent selected from halogen, CO 2 R 13 , C(O)N(R 13 ) 2 , SO 2 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl and a 3- to 6-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO 2 , N and NR 13 ; 
         Y is selected from halogen and X-A; 
         X is selected from O, NR 13 , S, S(O) and SO 2 ; A is selected from hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 7 cycloalkyl, C 4 -C 6 cycloalkenyl, heterocycloalkyl, aryl, heteroaryl and P(O)(OR 12 ) 2 ; 
         each R 12  is independently selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted C 3 -C 7 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 6 alkyleneC 3 -C 7 cycloalkyl, substituted or unsubstituted C 1 -C 6 alkyleneC 3 -C 7 heterocycloalkyl, substituted or unsubstituted C 1 -C 6 alkylenearyl, and substituted or unsubstituted C 1 -C 6 alkyleneheteroaryl; 
         each R 13  is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 7 cycloalkyl, and a 3- to 7-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO 2 , N and NR 14 , wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 7 cycloalkyl and 3- to 7-membered heterocyclic ring groups are optionally substituted by one or more substituents independently selected from CN, OR 14 , N(R 14 ) 2  and SR 14 , and wherein said C 3 -C 7 cycloalkyl and 3- to 7-membered heterocyclic ring are each further optionally substituted with a substituent selected from halogen, CO 2 R 14 , C(O)N(R 14 ) 2 , SO 2 R 14 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl and a 3- to 6-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO 2 , N and NR 14 , 
         R 14  is selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; 
         wherein at least one of R 3 , R 4 , R 5  and R 6  is deuterium or at least one of R 3 , R 4 , R 5  and R 6  comprises deuterium, and 
         wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof. 
       
     
     
         2 . A pharmaceutical composition comprising one or more compounds of  claim 1  and pharmaceutically acceptable carrier. 
     
     
         3 . A method for activating a serotonin receptor in a subject comprising administering the compound of  claim 1 , or a pharmaceutically acceptable salt, solvate or prodrug thereof, to the subject. 
     
     
         4 . A method of treating a subject having a condition that is treated by activation of a serotonin receptor, comprising administering the compound of  claim 1 , or a pharmaceutically acceptable salt, solvate or prodrug thereof. 
     
     
         5 . The method of  claim 4 , wherein the condition is a neurological or psychiatric disorder. 
     
     
         6 . The method of  claim 4 , wherein the condition is psychosis or psychotic symptoms. 
     
     
         7 . The method of  claim 4 , wherein the condition is a mental illness disorder. 
     
     
         8 . The method of  claim 7 , wherein the mental illness disorder is selected from generalized anxiety disorders, phobias, depression, mood disorders, psychotic disorders, eating disorders, impulse control disorders, addiction disorders, personality disorders, dissociative disorders, factitious disorders, sexual disorders, gender disorders, somatic symptom disorders, attentional disorders, tic disorders, sleep-related disorders, and a combination thereof. 
     
     
         9 . The method of  claim 7 , wherein the mental illness disorder is selected from panic disorder, social anxiety disorder, hopelessness, loss of pleasure, fatigue, suicidal thoughts, bipolar disorder, cancer-related depression, anxiety, cyclothymic disorder, hallucinations, delusions, schizophrenia, anorexia nervosa, bulimia nervosa, binge eating disorder, pyromania, kleptomania, compulsive gambling, alcohol addiction; drug addiction, antisocial personality disorder, obsessive-compulsive personality disorder, paranoid personality disorder; obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), stress response syndromes, sexual dysfunction, gender identity disorder, paraphilia, attentional deficit disorder, attentional deficit hyperactivity disorder, Tourette's syndrome, and a combination thereof. 
     
     
         10 . The method of  claim 7 , wherein the mental illness disorder is selected from hallucinations, delusions, and a combination thereof. 
     
     
         11 . The method of  claim 10 , wherein the hallucinations are selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, equilibrioceptive hallucinations, nociceptive hallucinations, thermoceptive hallucinations, chronoceptive hallucinations and a combination thereof. 
     
     
         12 . The method of  claim 7 , wherein the mental illness disorder comprises cognitive impairment, ischemia, neurodegeneration, refractory substance use disorders, sleep disorders, pain, obesity, eating disorders, seizure disorders, neuronal cell death, excitotoxic cell death, or a combination thereof. 
     
     
         13 . The method of  claim 4 , wherein the condition is a CNS disorder that is a form of dementia. 
     
     
         14 . The method of  claim 4 , comprising administering the compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         15 . The method of  claim 4 , wherein the subject is a feline or canine and the condition is anxiety, fear, stress, sleep disturbances, cognitive dysfunction, aggression, or a combination thereof.