N-substituted indoles and other heterocycles for treating brain disorders

Abstract

The present invention provides N-substituted indoles and other heterocycles and methods of using the compounds for treating brain disorders.

1 .- 30 . (canceled) 
     
     
         31 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 X is CR 3 ; 
 R 1a  and R 1b  are each independently C 1-6  alkyl, C 3-8  cycloalkyl, or C 4-14  alkyl-cycloalkyl; 
 R 1c  is C 1-6  alkyl; 
 alternatively, two of R 1a , R 1b , and R 1c  are combined with the atoms to which they are attached to form a C 3-12  heterocycloalkyl; 
 R 2  and R 3  are each independently hydrogen, C 1-6  alkyl, halogen, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, C 3-8  cycloalkyl, C 3-14  alkyl-cycloalkyl, C 6-12  aryl, or C 7-18  alkyl-aryl; 
 R 4 , R 5 , R 6  and R 7  are each independently hydrogen, C 1-6  alkyl, halogen, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, —OR 8a , —C(O)OR 8b , C 3-8  cycloalkyl, or C 3-14  alkyl-cycloalkyl, wherein at least one of R 4 , R 5 , R 6  and R 7  is not H; 
 R 8a  is C 3-8  cycloalkyl, C 3-14  alkyl-cycloalkyl, C 4-10  heterocycloalkyl, C 4-16  alkyl-heterocycloalkyl, C 6-12  aryl, or C 7-18  alkyl-aryl; 
 R 8b  is H or C 1-6  alkyl; 
 alternatively, R 4  and R 5 , R 5  and R 6 , or R 6  and R 7  are combined with the atoms to which they are each attached to form a C 4-6  heterocycloalkyl; and 
 L is C 1-6  alkylene, 
 or a pharmaceutically acceptable salt and isomer thereof, and 
 wherein the compound is other than 
 
       
         
           
           
               
               
           
         
       
     
     
         32 . The compound of  claim 31 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I has the following structure: 
       
         
           
           
               
               
           
         
         wherein 
         R 1a , R 1b  and R 1c  are each Me; 
         alternatively, two of R 1a , R 1b , and R 1c  are combined with the atoms to which they are attached to form a C 3-8  heterocycloalkyl. 
       
     
     
         33 . The compound of  claim 31 , or a pharmaceutically acceptable salt thereof, wherein R 2  and R 3  are each independently hydrogen, C 1-6  alkyl, halogen, or C 1-6  alkoxy. 
     
     
         34 . The compound of  claim 31 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         35 . The compound of  claim 31 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         36 . The compound of  claim 31 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         37 . The compound of  claim 31 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         38 . The compound of  claim 31 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         39 . The compound of  claim 31 , or a pharmaceutically acceptable salt thereof, wherein R 1a  and R 1b  are combined with the atoms to which they are attached to form a C 3-8  heterocycloalkyl. 
     
     
         40 . The compound of  claim 31 , or a pharmaceutically acceptable salt thereof, wherein R 1a  and R 1c  are combined with the atoms to which they are attached to form a C 5-8  heterocycloalkyl. 
     
     
         41 . The compound of  claim 31 , or a pharmaceutically acceptable salt thereof, wherein
 X is CR 3 ;   R 1a  and R 1b  are each Me;   R 1c  is Me, Et, or Pr;   R 2  is H, Me, —F, or —OMe;   R 3  is H, Me, —F, or —OMe;   R 4  is H, Me, —F, —OMe or —O-benzyl;   R 5  is H, Me, —F, —Cl, —Br, —OMe, —CF 3 —OCF 3  or —O-benzyl;   R 6  is H, Me, —F, —OMe, —OCF 3 , or —O-benzyl;   alternatively, R 5  and R 6  are combined to form a 1,3-dioxole ring or 1,4-dioxane ring; and   R 7  is H, Me, —F, —OMe, or —O-benzyl.   
     
     
         42 . The compound of  claim 31 , wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         43 . The compound of  claim 31 , wherein the compound is a salt comprising fumaric acid or a pharmaceutically acceptable salt. 
     
     
         44 . A compound of Formula II: 
       
         
           
           
               
               
           
         
       
       wherein:
 X is CR 3 ; 
 R 1a  and R 1b  are each independently C 1-6  alkyl, C 3-8  cycloalkyl, or C 4-14  alkyl-cycloalkyl; 
 alternatively, R 1a  and R 1b  are combined with the atoms to which they are attached to form a C 3-12  heterocycloalkyl; 
 R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are each independently hydrogen, C 1-6  alkyl, halogen, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, —C(O)C(O)N(R 8b R 8c ), C 3-8  cycloalkyl, C 3-14  alkyl-cycloalkyl, C 6-12  aryl, or C 7-18  alkyl-aryl; 
 R 8a  is C 3-8  cycloalkyl, C 3-14  alkyl-cycloalkyl, C 4-10  heterocycloalkyl, C 4-16  alkyl-heterocycloalkyl, C 6-12  aryl, C 7-18  alkyl-aryl; 
 R 8b  and R 8c  are each independently H or C 1-6  alkyl; 
 alternatively, R 4  and R 5 , R 5  and R 6 , or R 6  and R 7  are combined with the atoms to which they are each attached to form a C 4-6  heterocycloalkyl; and 
 L is C 1-6  alkylene, 
 or pharmaceutically acceptable salts and isomers thereof, 
 wherein when R 1a  and R 1b  are both Me, and L is methylene, then at least one of R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  is not hydrogen and the compound is other than: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein when R 1a  and R 1b  are Me, L is ethylene, and X is CR 3 , then at least one of R 2 , R 3 , R 4 , R 5 , R 6  and R 7  is not hydrogen; 
         wherein when R 5  is Br, Cl, F, or C 1-3  alkoxy, then at least one of R 2 , R 3 , R 4 , R 6 , or R 7  is not hydrogen; and 
         wherein when R 5  is F, then at least one of R 2 , R 3 , R 4 , R 6 , or R 7  is not hydrogen and R 6  is not F. 
       
     
     
         45 . The compound of  claim 44 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula II has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         46 . The compound of  claim 44 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula II has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         47 . The compound of  claim 44 , or a pharmaceutically acceptable salt thereof, wherein
 R 4 , R 5 , R 6  and R 7  are each independently hydrogen, F, Cl, —OMe, —OCF 3  or —O-benzyl;   alternatively, R 5  and R 6  are combined with the atoms to which they are each attached to form a 1,3-dioxole ring or 1,4-dioxane ring.   
     
     
         48 . The compound of  claim 44 , wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         49 . The compound of  claim 44 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         50 . The compound of  claim 44 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         51 . The compound of  claim 44 , wherein the compound is a salt comprising fumaric acid or a pharmaceutically acceptable salt. 
     
     
         52 . A pharmaceutical composition comprising a compound of  claim 31 , and a pharmaceutically acceptable excipient. 
     
     
         53 . A method for increasing neuronal plasticity, comprising contacting a neuronal cell with a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, in an amount sufficient to increase neuronal plasticity of the neuronal cell, wherein:
 X is N or CR 3 ; 
 R 1a , R 1b  and R 1c  are each independently hydrogen, C 1-6  alkyl, C 3-8  cycloalkyl, or C 4-14  alkyl-cycloalkyl; 
 alternatively, two of R 1a , R 1b , and R 1c  are combined with the atoms to which they are attached to form a C 3-12  heterocycloalkyl; 
 R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are each independently hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, halogen, C 1-6  haloalkyl, C 1-6  alkylamine, C 1-6  alkoxy, C 1-6  haloalkoxy, —NO 2 , —CN, —C(O)R 8b , —C(O)OR 8b , —OC(O)R 8b , —OC(O)OR 8b , —N(R 8b R 8c ), —N(R 8b )C(O)R 8c , —C(O)N(R 8b R 8 ), —N(R 8b )C(O)OR 8c , —OC(O)N(R 8b R 8 ), —N(R 8b )C(O)N(R 8c R 8d ), —C(O)C(O)N(R 8b R 8c ), —S(O 2 )R 8b , —S(O) 2 N(R 8b R 8 ), C 3-8  cycloalkyl, C 3-14  alkyl-cycloalkyl, C 4-10  heterocycloalkyl, C 4-16  alkyl-heterocycloalkyl, C 6-12  aryl, C 7-18  alkyl-aryl, C 5-10  heteroaryl, or C 4-16  alkyl-heteroaryl; 
 R 8a  is C 3-8  cycloalkyl, C 3-14  alkyl-cycloalkyl, C 4-10  heterocycloalkyl, C 4-16  alkyl-heterocycloalkyl, C 6-12  aryl, C 7-18  alkyl-aryl, C 5-10  heteroaryl, or C 4-16  alkyl-heteroaryl; 
 R 8b , R 8c  and R 8d  are each independently H or C 1-6  alkyl; 
 alternatively, one of R 1a , R 1b , or R 1c  is combined with R 2  to form a C 5-12  heterocycloalkyl; 
 alternatively, R 2  and R 3  are combined with the atoms to which they are each attached to form a C 4-8  cycloalkyl, C 4-10  heterocycloalkyl, or C 6-12  aryl; 
 alternatively, R 4  and R 5 , R 5  and R 6 , or R 6  and R 7  are combined with the atoms to which they are each attached to form a C 3-6  cycloalkyl, C 3-6  heterocycloalkyl, C 6-12  aryl, or C 5-10  heteroaryl; and 
 L is C 1-6  alkylene. 
 
     
     
         54 . A method of treating a brain disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, thereby treating the brain disorder, wherein:
 X is N or CR 3 ; 
 R 1a , R 1b  and R 1c  are each independently hydrogen, C 1-6  alkyl, C 3-8  cycloalkyl, or C 4-14  alkyl-cycloalkyl; 
 alternatively, two of R 1a , R th , and R 1c  are combined with the atoms to which they are attached to form a C 3-12  heterocycloalkyl; 
 R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are each independently hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, halogen, C 1-6  haloalkyl, C 1-6  alkylamine, C 1-6  alkoxy, C 1-6  haloalkoxy, —NO 2 , —CN, —C(O)R 8b , —C(O)OR 8b , —OC(O)R 8b , —OC(O)OR 8b , —N(R 8b R 8c ), —N(R 8b )C(O)R 8c , —C(O)N(R 8b R 8c ), —N(R 8b )C(O)OR 8c , —OC(O)N(R 8b R 8c ), —N(R 8b )C(O)N(R 8c R 8d ), —C(O)C(O)N(R 8b R 8c ), —S(O 2 )R 8b , —S(O) 2 N(R 8b R 8c ), C 3-8  cycloalkyl, C 3-14  alkyl-cycloalkyl, C 4-10  heterocycloalkyl, C 4-16  alkyl-heterocycloalkyl, C 6-12  aryl, C 7-18  alkyl-aryl, C 5-10  heteroaryl, or C 4-16  alkyl-heteroaryl; 
 R 8a  is C 3-8  cycloalkyl, C 3-14  alkyl-cycloalkyl, C 4-10  heterocycloalkyl, C 4-16  alkyl-heterocycloalkyl, C 6-12  aryl, C 7-18  alkyl-aryl, C 5-10  heteroaryl, or C 4-16  alkyl-heteroaryl; 
 R 8b , R 8c  and R 8d  are each independently H or C 1-6  alkyl; 
 alternatively, one of R 1a , R 1b , or R 1c  is combined with R 2  to form a C 5-12  heterocycloalkyl; 
 alternatively, R 2  and R 3  are combined with the atoms to which they are each attached to form a C 4-8  cycloalkyl, C 4-11 ) heterocycloalkyl, or C 6-12  aryl; 
 alternatively, R 4  and R 5 , R 5  and R 6 , or R 6  and R 7  are combined with the atoms to which they are each attached to form a C 3-6  cycloalkyl, C 3-6  heterocycloalkyl, C 6-12  aryl, or C 5-10  heteroaryl; and 
 L is C 1-6  alkylene. 
 
     
     
         55 . The method of  claim 54 , wherein the brain disorder is a neurodegenerative disorder, Alzheimer's, or Parkinson's disease. 
     
     
         56 . The method of  claim 54 , wherein the brain disorder is a psychological disorder, depression, addiction, anxiety, or a post-traumatic stress disorder. 
     
     
         57 . The method of  claim 56 , wherein the brain disorder is depression. 
     
     
         58 . The method of  claim 56 , wherein the brain disorder is addiction. 
     
     
         59 . The method of  claim 54 , wherein the brain disorder is treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or substance use disorder. 
     
     
         60 . The method of  claim 54 , wherein the brain disorder is stroke or traumatic brain injury. 
     
     
         61 . The method of  claim 54 , comprising administering one or more additional therapeutic agent that is lithium, Olanzapine (Zyprexa), Quetiapine (Seroquel), Risperidone (Risperdal), Ariprazole (Abilify), Ziprasidone (Geodon), Clozapine (Clozaril), divalproex sodium (Depakote), lamotrigine (Lamictal), valproic acid (Depakene), carbamazepine (Equetro), topiramate (Topamax), levomilnacipran (Fetzima), duloxetine (Cymbalta, Yentreve), venlafaxine (Effexor), citalopram (Celexa), fluvoxamine (Luvox), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), clomipramine (Anafranil), amitriptyline (Elavil), desipramine (Norpramin), imipramine (Tofranil), nortriptyline (Pamelor), phenelzine (Nardil), tranylcypromine (Parnate), diazepam (Valium), alprazolam (Xanax), or clonazepam (Klonopin). 
     
     
         62 . A method for increasing at least one of translation, transcription or secretion of neurotrophic factors, comprising contacting a neuronal cell with a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, in an amount sufficient to increase neuronal plasticity of the neuronal cell, wherein:
 X is N or CR 3 ; 
 R 1a , R 1b  and R 1c  are each independently hydrogen, C 1-6  alkyl, C 3-8  cycloalkyl, or C 4-14  alkyl-cycloalkyl; 
 alternatively, two of R 1a , R 1b , and R 1c  are combined with the atoms to which they are attached to form a C 3-12  heterocycloalkyl; 
 R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are each independently hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, halogen, C 1-6  haloalkyl, C 1-6  alkylamine, C 1-6  alkoxy, C 1-6  haloalkoxy, —NO 2 , —CN, —C(O)R 8b , —C(O)OR 8b , —OC(O)R 8b , —OC(O)OR 8b , —N(R b R 8c ), —N(R 8b )C(O)R 8c , —C(O)N(R 8b R 8c ), —N(R 8b )C(O)OR 8c , —OC(O)N(R 8b R 8c ), —N(R 8b )C(O)N(R 8c R 8d ), —C(O)C(O)N(R 8b R 8c ), —S(O 2 )R 8b , —S(O) 2 N(R 8b R 8c ), C 3-8  cycloalkyl, C 3-14  alkyl-cycloalkyl, C 4-10  heterocycloalkyl, C 4-16  alkyl-heterocycloalkyl, C 6-12  aryl, C 7-18  alkyl-aryl, C 5-10  heteroaryl, or C 4-16  alkyl-heteroaryl; 
 R 8a  is C 3-8  cycloalkyl, C 3-14  alkyl-cycloalkyl, C 4-10  heterocycloalkyl, C 4-16  alkyl-heterocycloalkyl, C 6-12  aryl, C 7-18  alkyl-aryl, C 5-10  heteroaryl, or C 4-16  alkyl-heteroaryl; 
 R 8b , R 8c  and R 8d  are each independently H or C 1-6  alkyl; 
 alternatively, one of R 1a , R 1b , or R 1c  is combined with R 2  to form a C 5-12  heterocycloalkyl; 
 alternatively, R 2  and R 3  are combined with the atoms to which they are each attached to form a C 4-8  cycloalkyl, C 4-10  heterocycloalkyl, or C 6-12  aryl; 
 alternatively, R 4  and R 5 , R 5  and R 6 , or R 6  and R 7  are combined with the atoms to which they are each attached to form a C 3-6  cycloalkyl, C 3-6  heterocycloalkyl, C 6-12  aryl, or C 5-10  heteroaryl; and 
 L is C 1-6  alkylene.