Butyl and butynyl benzyl amine compounds

Abstract

Certain substituted butyl and butynyl benzyl amine compounds are histamine H 3 receptor and/or serotonin transporter modulators useful in the treatment of histamine H 3 receptor- and/or serotonin-mediated diseases.

1 - 38 . (canceled) 
     
     
         39 . A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by histamine H 3  receptor and/or serotonin transporter activity, comprising administering to the subject in need of such treatment an effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 one of R 1a  and R 1b  is 
 
       
         
           
           
               
               
           
         
          and the other is —H; 
         R 2  and R 3  are each independently selected from the group consisting of: —H; a —C 1-6 alkyl group unsubstituted or substituted with —OH, —OC 1-4 alkyl, —NH 2 , —N(R a )R b , or —F; —CO 2 C 1-4 alkyl; and a monocyclic cycloalkyl group unsubstituted or substituted with —C 1-4 alkyl, —OH, halo, or —CF 3 ;
 where R a  and R b  are each independently —H, —C 1-6 alkyl, or monocyclic cycloalkyl, or R a  and R b  taken together with their nitrogen of attachment form a monocyclic heterocycloalkyl group; 
 provided that R 2  and R 3  are not both H; 
 
         or, alternatively, 
         R 2  and R 3  taken together with the nitrogen to which they are attached form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted on a carbon ring member with one, two, or three R d  moieties and substituted on a nitrogen ring member with an R e  moiety;
 where each R d  moiety is independently selected from the group consisting of: —C 1-6 alkyl; —C 1-4 alkyl-OH; halo; —OH; —OC 1-6 alkyl; ipso-substituted —OC 2-3 alkylO—; —CN; —NO 2 ; —N(R g )R h ; —C(O)N(R g )R h ; —N(R g )SO 2 C 1-6 alkyl; —C(O)C 1-6 alkyl; —S(O) 0-2 —C 1-6 alkyl; —SO 2 N(R g )R h ; —SCF 3 ; —CF 3 ; —OCF 3 ; —CO 2 H; and —CO 2 C 1-6 alkyl;
 where R g  and R h  are each independently —H or —C 1-6 alkyl, or R g  and R h  taken together with their nitrogen of attachment form a monocyclic heterocycloalkyl group; and 
 
 where R e  is selected from the group consisting of: —H; a —C 1-6 alkyl or —C(O)C 1-6 alkyl group unsubstituted or substituted with halo, —CN, —OH, —OC 1-4 alkyl, or —CF 3 ; —C(O)CF 3 ; —S(O) 0-2 —C 1-6 alkyl; —CO 2 C 1-6 alkyl; and a phenyl, monocyclic carbon-linked heteroaryl, monocyclic cycloalkyl, or monocyclic carbon-linked heterocycloalkyl group, each unsubstituted or substituted with —C 1-4 alkyl, halo, —ON, —OH, —OC 1-4 alkyl, or —CF 3 ; 
 
         R 4  is —OH, —OC 1-6 alkyl, —CF 3 , —C 1-6 alkyl, or halo; 
         m is 0 or 1; 
         Y is —O—, —OCH 2 —, —S—, —SO—, or —SO 2 —; 
         Cyc is a phenyl or monocyclic carbon-linked heteroaryl group, unsubstituted or substituted with one, two, or three R k  moieties;
 where each R k  moiety is independently selected from the group consisting of: —C 1-6 alkyl, —CHF 2 , —CF 3 , —C 2-6 alkenyl, —C 2-6 alkynyl, —OH, —OC 1-6 alkyl, —OCHF 2 , —OCF 3 , —OC 3-6 alkenyl, —OC 3-6 alkynyl, —ON, —NO 2 , —N(R l )R m , —N(R l )C(O)R m , —N(R l )SO 2 C 1-6 alkyl, —C(O)C 1-6 alkyl, —C(O)N(R l )R m , —SO 2 N(R l )R m , —SCF 3 , halo, —CO 2 H, and —CO 2 C 1-6 alkyl; or two R k  moieties on adjacent carbon atoms of attachment together are —OC 1-4 alkyleneO- to form a cyclic ring which is unsubstituted or substituted with one or two fluoro substituents;
 where R l  and R m  are each independently —H or —C 1-6 alkyl; 
 
 
         R 5  is —H or —C 1-6 alkyl; 
         R 6  is —H; or —C 1-6 alkyl, —C 3-6 alkenyl, —C 3-6 alkynyl, monocyclic cycloalkyl, or —C 1-6 alkyl-(monocyclic cycloalkyl), each unsubstituted or substituted with —C 1-4 alkyl, —OH, —OC 1-4 alkyl, halo, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CN, —CO 2 H, or —CO 2 C 1-4 alkyl; and 
         R 7  is —H; or —C 1-6 alkyl, —C 3-6 alkenyl, —C 3-6 alkynyl, monocyclic cycloalkyl, —C 1-6 alkyl-(monocyclic cycloalkyl), or —CO 2 C 1-4 alkyl, each unsubstituted or substituted with —C 1-4 alkyl, —OH, —OC 1-4 alkyl, halo, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CN, —CO 2 H, or —CO 2 C 1-4 alkyl; 
         or R 6  and R 7  taken together with their nitrogen of attachment form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with —C 1-4 alkyl, —OC 1-4 alkyl, or halo; 
         or a pharmaceutically acceptable salt or pharmaceutically acceptable prodrug thereof. 
       
     
     
         40 . The method according to  claim 39 , wherein the disease, disorder, or medical condition is selected from the group consisting of: cognitive disorders, sleep disorders, psychiatric disorders, and other disorders. 
     
     
         41 . The method according to  claim 39 , wherein the disease, disorder, or medical condition is selected from the group consisting of: dementia, Alzheimer's disease, cognitive dysfunction, mild cognitive impairment, pre-dementia, attention deficit hyperactivity disorders, attention-deficit disorders, and learning and memory disorders. 
     
     
         42 . The method according to  claim 39 , wherein the disease, disorder, or medical condition is selected from the group consisting of: learning impairment, memory impairment, and memory loss. 
     
     
         43 . The method according to  claim 39 , wherein the disease, disorder, or medical condition is selected from the group consisting of: insomnia, disturbed sleep, narcolepsy with or without associated cataplexy, cataplexy, disorders of sleep/wake homeostasis, idiopathic somnolence, excessive daytime sleepiness, circadian rhythm disorders, fatigue, lethargy, and jet lag. 
     
     
         44 . The method according to  claim 39 , wherein the disease, disorder, or medical condition is selected from the group consisting of: sleep apnea, perimenopausal hormonal shifts, Parkinson's disease, multiple sclerosis, depression, chemotherapy, and shift work schedules. 
     
     
         45 . The method according to  claim 39 , wherein the disease, disorder, or medical condition is selected from the group consisting of: schizophrenia, bipolar disorders, manic disorders, depression, obsessive-compulsive disorder, and post-traumatic stress disorder. 
     
     
         46 . The method according to  claim 39 , wherein the disease, disorder, or medical condition is selected from the group consisting of: motion sickness, vertigo, epilepsy, migraine, neurogenic inflammation, eating disorders, obesity, substance abuse disorders, and sexual dysfunction. 
     
     
         47 . The method according to  claim 39 , wherein the disease, disorder, or medical condition is selected from the group consisting of: depression, disturbed sleep, fatigue, lethargy, cognitive impairment, memory impairment, memory loss, learning impairment, attention-deficit disorders, and eating disorders. 
     
     
         48 . (canceled) 
     
     
         49 . The method according to  claim 39 , wherein the disease, disorder, or medical condition is selected from the group consisting of: age-related cognitive decline, REM-behavioral disorder, benign postural vertigo, tinitus, movement disorders, restless leg syndrome, eye-related disorders, macular degeneration, and retinitis pigmentosis.