Carbamoyl phenylalaninol compounds as taar1 agonists

A method for treating a trace amine-associated receptor 1 (TAAR1)-associated disorder selected from a sleep disorder, narcolepsy, cataplexy, idiopathic hypersomnia, shift work sleep disorder, excessive daytime sleepiness, attention deficit hyperactivity disorder, schizophrenia, depression, anxiety, psychosis, addiction, glucose homeostasis disorder, type II diabetes, metabolic syndrome, binge eating disorder, obesity and immune disorders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a carbamoyl phenylalaninol compound which is a compound of Formula I:

• or a pharmaceutically acceptable salt or ester thereof;
• wherein R is a member selected from the group consisting of alkyl of 1 to 8 carbon atoms, halogen, alkoxy of 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, and thioalkoxy of 1 to 3 carbon atoms;
• x is an integer of 0 to 3, with the proviso that R may be the same or different when x is 2 or 3;
• R1 and R2 are independently selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms, aryl, arylalkyl, cycloalkyl of 3 to 7 carbon atoms;
• or
• R1 and R2 can be joined to form a 5- to 7-membered heterocycle that is unsubstituted or substituted with one or more alkyl or aryl groups, wherein the heterocycle can comprise 1 to 2 nitrogen atoms and 0 to 1 oxygen atom, wherein the nitrogen atoms are not directly connected with each other or with the oxygen atom, wherein such compound activates TAAR1, thereby treating the TAAR1-associated disorder.

A method for treating a trace amine-associated receptor 1 (TAAR1)-associated disorder selected from a sleep disorder, narcolepsy, cataplexy, idiopathic hypersomnia, shift work sleep disorder, excessive daytime sleepiness, attention deficit hyperactivity disorder, schizophrenia, depression, anxiety, psychosis, addiction, glucose homeostasis disorder, type II diabetes, metabolic syndrome, binge eating disorder, obesity and immune disorders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a carbamoyl phenylalaninol compound which is a compound of Formula II:

• or a pharmaceutically acceptable salt thereof, wherein:
• X is CH2, O, NH, or S;
• Y is C═O, C═S, or SO2;
• R is optionally substituted C1-8 alkyl, halogen, optionally substituted C1-4 alkoxy, cyano, hydroxy, optionally substituted trifluoromethyl, or C1-4 thioalkoxy;
• n is 0, 1, 2, or 3, with the proviso that R may be the same or different when x is 2 or 3;
• and
• R1 and R2 can be the same or different and are independently selected from the group consisting of hydrogen, optionally substituted C1-8 alkyl, optionally substituted amide, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, and optionally substituted C3-7 cycloalkyl;
• or R1 and R2 can be joined to form a 5- to 7-membered heterocycle optionally substituted with alkyl or aryl groups, wherein the cyclic compound can comprise 1 to 2 nitrogen atoms and 0 to 1 oxygen atom, wherein the nitrogen atoms are not directly connected with each other or with the oxygen atom;
• wherein when Y is C═O, X is not O, wherein such compound activates TAAR1, thereby treating the TAAR1-associated disorder.