COMPOSITIONS AND METHODS FOR TREATMENT OF DISEASES AND DISORDERS
Provided herein are compounds of Formula (I), Formula (I-A), Formula (I-B), or pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I), Formula (I-A), Formula (I-B) or pharmaceutically acceptable salt thereof, and methods of using a compound of Formula (I), Formula (I-A), Formula (I-B) or pharmaceutically acceptable salt thereof. The current invention reports compounds to reduce REM sleep and/or non-REM sleep in a subject which can be effective in treating diseases or disorder where sleep is dysregulated. The methods of the disclosure include methods of treating sleep dysfunction, sleep disorder, stress related disorders, neuropsychiatric diseases, neurological conditions and/or neurodevelopmental disorders, using the compound of Formula (I), Formula (I-A), and/or Formula (I-B).
1 . A method of treating a stress-related disorder, neuropsychiatric disorder, or neurodevelopment disorder in a subject comprising administering to the subject a compound of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is independently at each position-hydrogen, —C 1 -C 6 alkyl, or —C 1 -C 6 haloalkyl;
R 2 , R 3 , and R 7 are independently -hydrogen, -heterocycle, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, -halogen, -cyano, —OR 1 , —S(O)(═NH)R 1 , —S(O) 2 R 1 , —S(O)R 1 or —SR 1 ,
wherein at least one of R 2 and R 3 is hydrogen;
R 4 , R 5 , and R 6 are each independently -hydrogen, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, -halogen, -cyano, —OR 1 , —SR 1 , —(C═O)(R 14 ), —O(C═O)(R 14 ), —NO 2 , or —NH(C═O)(R 14 ), wherein R 14 is C 1 -C 6 alkyl, OH, or OC 1 -C 6 alkyl;
R 8 and R 9 are each independently -hydrogen, —C 1 -C 6 alkyl, —C 1 -C 4 alkyl, —C 3 -C 6 cycloalkyl, —C 3 -C 10 cycloalkyl, —CH 2 OH, or —CH 2 O—C 1 -C 4 alkyl;
R 10 and R 11 are each independently -hydrogen, -halogen, —C 1 -C 6 alkyl, —OH, —C 1 -C 4 alkyl, —C 3 -C 6 cycloalkyl, or —CH 2 O—C 1 -C 4 alkyl;
R 12 is -hydrogen, —CH 2 OH, —CH 2 O—C 1 -C 9 alkyl, —C 3 -C 10 cycloalkyl, —CH 2 OH, or —CH 2 O—C 1 -C 4 alkyl; and
R 13 is -hydrogen, —C 1 -C 9 alkyl, —C 3 -C 10 cycloalkyl, —CH 2 OH, or —CH 2 O—C 1 -C 4 alkyl, and
wherein:
the stress-related disorder is selected from the group consisting of depression, anxiety, post-traumatic stress disorder (PTSD), acute stress disorder, adjustment disorder, reactive attachment disorder, disinhibited social engagement disorder, or unspecified traumatic stress disorder, and
wherein:
the neuropsychiatric disorder is selected from the group consisting of schizophrenia, body dysmorphic disorder, alcohol use disorder, drug or substance use disorder, or obsessive-compulsive disorder; and
the neurodevelopment disorder is selected from the group consisting of attention deficit hyperactivity disorder (ADHD); developmental language disorder; communication, speech, or language disorders; expressive language disorder; fluency disorder; social communication disorder; speech sound disorder; Asperger syndrome; autism spectrum disorder (ASD); intellectual disabilities (IDs) or intellectual development disorder (IDD); global developmental delay (GDD); motor disorder; apraxia of speech; or neurogenetic disorder.
2 . The method of claim 1 , wherein the motor disorder is developmental coordination disorder, stereotypic movement disorder, or a tic disorder.
3 . The method of claim 1 , wherein the neurogenetic disorder is Fragile X syndrome, Down syndrome, Rett syndrome, Angelman syndrome, Prader-Willi syndrome, Tuberous sclerosis complex, hypogonadotropic hypogonadal syndromes, dyslexia, dyscalculia or fetal alcohol spectrum disorders (FASD).
4 . The method of claim 1 , where the depression is selected from the group consisting of depressive disorder, a disruptive mood dysregulation disorder, psychotic depression, a premenstrual dysphoric disorder, antenatal depression, postnatal depression, a bipolar disorder, a cyclothymic disorder, a dysthymic disorder, an unspecified depressive disorder, or seasonal affective disorder.
5 . The method of claim 4 , wherein the bipolar disorder is bipolar disorder I.
6 . The method of claim 4 , wherein the bipolar disorder is bipolar disorder II.
7 . The method of claim 1 , wherein the anxiety is a generalized anxiety disorder, a social anxiety disorder, a separation anxiety disorder, a panic disorder, selective mutism, an unspecified anxiety disorder, or a phobia related disorder.
8 . The method of claim 1 , wherein each R 1 is —C 1 -C 6 alkyl.
9 . The method of claim 1 , wherein R 2 , R 3 , and R 7 are each independently -hydrogen, -heterocycle, —C 1 -C 6 alkyl, -halogen, -cyano, —S(O)(═NH)R 1 , —S(O) 2 R 1 , —S(O)R 1 or —SR 1 .
10 . The method of claim 1 , wherein R 2 is -hydrogen, -heterocycle, —C 1 -C 6 alkyl, -halogen, -cyano, —S(O)(═NH)R 1 , —S(O) 2 R 1 , —S(O)R 1 or —SR 1 .
11 . The method of claim 1 , wherein R 3 is -hydrogen.
12 . The method of claim 1 , wherein R 7 is -hydrogen.
13 . The method of claim 1 , wherein R 8 and R 9 are each independently -hydrogen, —C 1 -C 6 alkyl, or —CH 2 OH.
14 . The method of claim 1 , wherein R 10 and R 11 are each independently -hydrogen or —OH.
15 . The method of claim 1 , wherein R 12 is -hydrogen.
16 . The method of claim 1 , wherein R 13 is -hydrogen.
17 . The method of claim 1 , wherein the compound is:
18 . The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
19 . The method of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.