SELECTIVE, PARTIAL, AND ARRESTIN-BIASED 5-HT2A AGONISTS WITH UTILITY IN VARIOUS DISORDERS
Disclosed herein are novel serotonin 5-HT 2A receptor agonists with selectivity for the 5-HT 2A receptor subtype over other serotonin receptors. Some of these 5-HT 2A agonists exhibit functional selectivity and preferentially activate arrestin signaling over G protein-mediated signaling. Also disclosed are pharmaceutical compositions of the compounds and methods of treating certain diseases or conditions.
1 . A compound of formula (I) or a pharmaceutically acceptable salt thereof,
Wherein:
R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, deuterium, OC 1-6 alkyl, SC 1-6 alkyl, CN, OH, halogen, NO 2 , N(R m ) 2 , C(O)OR m , C(O)N(R m ) 2 , C(O)C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyleneO, C 1-6 alkyl, hydroxyC 1-6 alkyl, dihydroxyC 1-10 alkyl, C 3-6 cycloalkyl, C(═NC 1-6 alkyl)C 1-6 alkyl, OC(O)N(R m ) 2 , SH, C(O)SR m , OC 1-6 alkyleneOC 1-6 alkyl, OC 1-6 alkyleneO-haloC 1-6 alkyl, SC 1-6 alkyleneOC 1-6 alkyl, SC 1-6 alkyleneSC 1-6 alkyl, OC 1-6 alkyleneSC 1-6 alkyl, SC 1-6 alkyleneO-haloC 1-6 alkyl, SC 1-6 alkyleneS-haloC 1-6 alkyl, OC 1-6 alkyleneS-haloC 1-6 alkyl, C 1-6 alkylene-CN, OC 1-6 alkylene-CN, SC 1-6 alkylene-CN, OC 1-6 alkylene-N(R m ) 2 , C 2-6 alkynyl, C 2-6 alkenyl, SO 2 N(R m ) 2 , NRmSO 2 C 1-6 alkyl, C 1-6 alkylSO 2 (sulfone), S(O)OH, C 1-6 alkylS(O) (sulfoxide), nitroso, C 1-6 alkylOSO 2 , 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-6 alkylene-N(R m ) 2 , C 1-6 alkylene-N(R m )(COR m );
provided that at least one of R 1 and R 2 contains an oxygen bonded to the phenyl ring;
A is 4, 5, 6 or 7 membered ring optionally substituted with one or more substituents selected from the group consisting of OC 1-6 alkyl, SC 1-6 alkyl, CN, OH, halogen, NO 2 , N(R m ) 2 , C(O)OR m , C(O)N(R m ) 2 , C(O)C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyleneO, C 1-6 alkyl, hydroxyC 1-6 alkyl, dihydroxyC 1-10 alkyl, C(═NC 1-6 alkyl)C 1-6 alkyl, OC(O)N(R m ) 2 , SH, C(O)SR m , OC 1-6 alkyleneOC 1-6 alkyl, OC 1-6 alkyleneO-haloC 1-6 alkyl, SC 1-6 alkyleneOC 1-6 alkyl, SC 1-6 alkyleneSC 1-6 alkyl, OC 1-6 alkyleneSC 1-6 alkyl, SC 1-6 alkyleneO-haloC 1-6 alkyl, SC 1-6 alkyleneS-haloC 1-6 alkyl, OC 1-6 alkyleneS-haloC 1-6 alkyl, C 1-6 alkylene-CN, OC 1-6 alkylene-CN, SC 1-6 alkylene-CN, OC 1-6 alkylene-N(R m ) 2 , C 2-6 alkynyl, C 2-6 alkenyl, SO 2 N(R m ) 2 , NR m SO 2 C 1-6 alkyl, C 1-6 alkylSO 2 (sulfone), S(O)OH, C 1-6 alkylS(O) (sulfoxide), nitroso, C 1-6 alkylOSO 2 , C 3-6 cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 5-12 membered bicycloalkyl, and 5-12 membered hetero-bicycloalkyl, wherein the C 3-6 cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 5-12 membered bicycloalkyl, 5-12 membered hetero-bicycloalkyl, O—C 3-6 cycloalkyl, O-heterocycloalkyl 3-10-membered , O-aryl 6-10-membered , O-heteroaryl 5-10-membered , O-bicycloalkyl 5-12-membered , O-hetero-bicycloalkyl 5-12-membered , OC 1-2 alkylene-C 3-6 cycloalkyl, OC 1-2 alkylene-heterocycloalkyl 3-10-membered , OC 1-2 alkylene-aryl 6-10-membered , OC 1-2 alkylene-heteroaryl 5-10-membered , OC 1-2 alkylene-bicycloalkyl 5-12-membered , OC 1-2 alkylene-hetero-bicycloalkyl 5-12-membered , C 1-2 alkylene-C 3-6 cycloalkyl, C 1-2 alkylene-heterocycloalkyl 3-10-membered , C 1-2 alkylene-aryl 6-10-membered , C 1-2 alkylene-heteroaryl 5-10-membered , C 1-2 alkylene-bicycloalkyl 5-12-membered , C 1-2 alkylene-hetero-bicycloalkyl 5-12-membered , wherein each of these rings is optionally substituted with one or more substituents selected from the group consisting of OC 1-6 alkyl, SC 1-6 alkyl, CN, OH, halogen, NO 2 , N(R m ) 2 , C(O)OR m , C(O)N(R m ) 2 , C(O)C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyleneO, C 1-6 alkyl, hydroxyC 1-6 alkyl, C(=NC 1-6 alkyl)C 1-6 alkyl, OC(O)N(R m ) 2 , SH, C(O)SRm, OC 1-6 alkyleneOC 1-6 alkyl, OC 1-6 alkyleneO-haloC 1-6 alkyl, SC 1-6 alkyleneOC 1-6 alkyl, SC 1-6 alkyleneSC 1-6 alkyl, OC 1-6 alkyleneSC 1-6 alkyl, SC 1-6 alkyleneO-haloC 1-6 alkyl, SC 1-6 alkyleneS-haloC 1-6 alkyl, OC 1-6 alkyleneS-haloC 1-6 alkyl, C 1-6 alkylene-CN, OC 1-6 alkylene-CN, SC 1-6 alkylene-CN, OC 1-6 alkylene-N(R m ) 2 , C 2-6 alkynyl, C 2-6 alkenyl, SO 2 N(R m ) 2 , NRmSO 2 C 1-6 alkyl, C 1-6 alkylSO 2 (sulfone), S(O)OH, C 1-6 alkylS(O) (sulfoxide), nitroso, and C 1-6 alkylOSO 2 ;
alternatively, two adjacent substituents of A link up and together with A form a bicyclic or tricylic ring;
R m each is independently hydrogen or C 1-6 alkyl or halo-C 1-6 alkyl;
L 1 is C 1-3 alkylene, optionally R 1 and L 1 link up to form a ring; and
L 2 is a bond or C 1-3 alkylene optionally substituted with C 1-4 alkyl, C 3-6 cycloalkyl, haloC 1-4 alkyl, deuterium or F,
provided that the compound is not
wherein X is CN, Cl, Br or I.
2 . The compound of formula (I) or the pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is OC 1-3 alkyl.
3 . The compound of formula (I) or the pharmaceutically acceptable salt thereof of claim 1 , wherein R 2 is OC 1-3 alkyl.
4 . The compound of formula (I) or the pharmaceutically acceptable salt thereof of claim 1 , wherein R 4 is OC 1-3 alkyl.
5 . The compound of formula (I) or the pharmaceutically acceptable salt thereof of claim 1 , wherein R 6 is OC 1-3 alkyl.
6 . The compound of formula (I) or the pharmaceutically acceptable salt thereof of claim 1 , wherein
(a) R 1 and R 4 are each independently OC 1-3 alkyl;
(b) R 1 and R 5 are each independently OC 1-3 alkyl; or
(c) R 2 and R 5 are each independently OC 1-3 alkyl.
7 . The compound of formula (I) or the pharmaceutically acceptable salt thereof of claim 1 , wherein R 3 is selected from the group consisting of OC 1-6 alkyl, SC 1-6 alkyl, CN, halogen, NO 2 , N(R m ) 2 , haloC 1-6 alkyl, and C 1-6 alkyl, and R 4 is selected from the group consisting of hydrogen, OC 1-6 alkyl, SC 1-6 alkyl, CN, OH, halogen, NO 2 , N(R m ) 2 , haloC 1-6 alkyl, and C 1-6 alkyl.
8 . The compound of formula (I) or the pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 and R 4 are each independently OC 1-3 alkyl; R 3 is NO 2 , haloC 1-6 alkyl, or C 1-6 alkyl.
9 . The compound of formula (I) or the pharmaceutically acceptable salt thereof of claim 1 , wherein L 1 is ethylene.
10 . The compound of formula (I) or the pharmaceutically acceptable salt thereof of claim 1 , wherein L 2 is methylene.
11 . The compound of formula (I) or the pharmaceutically acceptable salt thereof of claim 1 , wherein two adjacent substituents of A link up and together with A form a bicyclic ring or tricyclic ring.
12 . The compound of formula (I) or the pharmaceutically acceptable salt thereof of claim 1 , wherein two adjacent substituents of A link up and together with A form a bicyclic ring selected from the group consisting of indanyl, 1,2,3,4-tetrahydronaphthalenyl, benzimidazolyl, benzofuranyl, benzoselenophene, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, chromanyl, chromenyl, cinnolinyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, indazolyl, isobenzofuranyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, methylenedioxyphenyl, naphthyridinyl, naphthalenyl, octahydroisoquinolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl, and tetrahydroquinolinyl, wherein the bicyclic ring is optionally substituted with one or more substituents selected from the group consisting of OC 1-6 alkyl, SC 1-6 alkyl, CN, OH, halogen, NO 2 , N(R m ) 2 , C(O)OR m , C(O)N(R m ) 2 , C(O)C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyleneO, C 1-6 alkyl, hydroxyC 1-6 alkyl, and dihydroxyC 1-10 alkyl.
13 . The compound of formula (I) or the pharmaceutically acceptable salt thereof of claim 1 , wherein A is represented as
Wherein R 6 and R 7 are independently selected from the group consisting of H, OC 1-6 alkyl, SC 1-6 alkyl, CN, OH, halogen, N(R m ) 2 , C(O)OR m , C(O)N(R m ) 2 , C(O)C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyleneO, C 1-6 alkyl, hydroxyC 1-6 alkyl, C(═NC 1-6 alkyl)C 1-6 alkyl, OC(O)N(R m ) 2 , SH, C(O)SR m , OC 1-6 alkyleneOC 1-6 alkyl, OC 1-6 alkyleneO-haloC 1-6 alkyl, SC 1-6 alkyleneOC 1-6 alkyl, SC 1-6 alkyleneSC 1-6 alkyl, OC 1-6 alkyleneSC 1-6 alkyl, SC 1-6 alkyleneO-haloC 1-6 alkyl, SC 1-6 alkyleneS-haloC 1-6 alkyl, OC 1-6 alkyleneS-haloC 1-6 alkyl, C 1-6 alkylene-CN, OC 1-6 alkylene-CN, SC 1-6 alkylene-CN, OC 1-6 alkylene-N(R m ) 2 , C 2-6 alkynyl, C 2-6 alkenyl, SO 2 N(R m ) 2 , NRmSO 2 C 1-6 alkyl, C 1-6 alkylSO 2 (sulfone), S(O)OH, C 1-6 alkylS(O) (sulfoxide), nitroso, C 1-6 alkylOSO 2 , C 3-6 cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 5-12 membered bicycloalkyl, 5-12 membered hetero-bicycloalkyl, O—C 3-6 cycloalkyl, O-heterocycloalkyl 3-10-membered , O-aryl 6-10-membered , O-heteroaryl 5-10-membered , O-bicycloalkyl 5-12-membered , O-hetero-bicycloalkyl 5-12-membered , OC 1-2 alkylene-C 3-6 cycloalkyl, OC 1-2 alkylene-heterocycloalkyl 3-10-membered , OC 1-2 alkylene-aryl 6-10-membered , OC 1-2 alkylene-heteroaryl 5-10-membered , OC 1-2 alkylene-bicycloalkyl 5-12-membered , OC 1-2 alkylene-hetero-bicycloalkyl 5-12-membered , C 1-2 alkylene-C 3-6 cycloalkyl, C 1-2 alkylene-heterocycloalkyl 3-10-membered , C 1-2 alkylene-aryl 6-10-membered , C 1-2 alkylene-heteroaryl 5-10-membered , C 1-2 alkylene-bicycloalkyl 5-12-membered , and C 1-2 alkylene-hetero-bicycloalkyl 5-12-membered , wherein each of the ring is optionally substituted; provided that at least one of R 6 and R 7 is not H;
R 8 , R 9 and R 10 are independently selected from the group consisting of H, OC 1-6 alkyl, SC 1-6 alkyl, CN, OH, halogen, N(R m ) 2 , C(O)OR m , C(O)N(R m ) 2 , C(O)C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyleneO, C 1-6 alkyl, hydroxyC 1-6 alkyl, C(═NC 1-6 alkyl)C 1-6 alkyl, OC(O)N(R m ) 2 , SH, C(O)SR m , OC 1-6 alkyleneOC 1-6 alkyl, OC 1-6 alkyleneO-haloC 1-6 alkyl, SC 1-6 alkyleneOC 1-6 alkyl, SC 1-6 alkyleneSC 1-6 alkyl, OC 1-6 alkyleneSC 1-6 alkyl, SC 1-6 alkyleneO-haloC 1-6 alkyl, SC 1-6 alkyleneS-haloC 1-6 alkyl, OC 1-6 alkyleneS-haloC 1-6 alkyl, C 1-6 alkylene-CN, OC 1-6 alkylene-CN, SC 1-6 alkylene-CN, OC 1-6 alkylene-N(R m ) 2 , C 2-6 alkynyl, C 2-6 alkenyl, SO 2 N(R m ) 2 , NR m SO 2 C 1-6 alkyl, C 1-6 alkylSO 2 (sulfone), S(O)OH, C 1-6 alkylS(O) (sulfoxide), nitroso, and C 1-6 alkylOSO 2 .
14 . The compound of formula (I) or the pharmaceutically acceptable salt thereof of claim 13 , wherein R 6 is selected from the group consisting of C 3-6 cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 5-12 membered bicycloalkyl, 5-12 membered hetero-bicycloalkyl, O—C 3-6 cycloalkyl, O-heterocycloalkyl 3-10-membered , O-aryl 6-10-membered , O-heteroaryl 5-10-membered , O-bicycloalkyl 5-12-membered , O-hetero-bicycloalkyl 5-12-membered , OC 1-2 alkylene-C 3-6 cycloalkyl, OC 1-2 alkylene-heterocycloalkyl 3-10-membered , OC 1-2 alkylene-aryl 6-10-membered , OC 1-2 alkylene-heteroaryl 5-10-membered , OC 1-2 alkylene-bicycloalkyl 5-12-membered , OC 1-2 alkylene-hetero-bicycloalkyl 5-12-membered , C 1-2 alkylene-C 3-6 cycloalkyl, C 1-2 alkylene-heterocycloalkyl 3-10-membered , C 1-2 alkylene-aryl 6-10-membered , C 1-2 alkylene-heteroaryl 5-10-membered , C 1-2 alkylene-bicycloalkyl 5-12-membered , C 1-2 alkylene-hetero-bicycloalkyl 5-12-membered , wherein each of the rings is optionally substituted.
15 . The compound of formula (I) or the pharmaceutically acceptable salt thereof of claim 13 , wherein R 6 is an optionally substituted ring system selected from the group consisting of adamantanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, tetrahydrofuranyl, ferrocenyl, furanyl, furazanyl, imidazolinyl, imidazolyl, norbornyl, norbornenyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, phenyl, piperazinyl, pyrimidinyl, piperonyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl.
16 . The compound of formula (I) or the pharmaceutically acceptable salt thereof of claim 13 , wherein R 6 is selected from the group consisting of H, OC 1-6 alkyl, SC 1-6 alkyl, CN, OH, halogen, N(R m ) 2 , C(O)OR m ), C(O)N(R m ) 2 , C(O)C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyleneO, C 1-6 alkyl, and hydroxyC 1-6 alkyl; and
R 7 is selected from the group consisting of H, OC 1-6 alkyl, SC 1-6 alkyl, CN, OH, halogen, N(R m ) 2 , C(O)C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyleneO, C 1-6 alkyl, hydroxyC 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 5-12 membered bicycloalkyl, 5-12 membered hetero-bicycloalkyl, O—C 3-6 cycloalkyl, O-heterocycloalkyl 3-10-membered , O-aryl 6-10-membered , O-heteroaryl 5-10-membered , O-bicycloalkyl 5-12-membered , O-hetero-bicycloalkyl 5-12-membered , OC 1-2 alkylene-C 3-6 cycloalkyl, OC 1-2 alkylene-heterocycloalkyl 3-10-membered , OC 1-2 alkylene-aryl 6-10-membered , OC 1-2 alkylene-heteroaryl 5-10-membered , OC 1-2 alkylene-bicycloalkyl 5-12-membered , OC 1-2 alkylene-hetero-bicycloalkyl 5-12-membered , C 1-2 alkylene-C 3-6 cycloalkyl, C 1-2 alkylene-heterocycloalkyl 3-10-membered , C 1-2 alkylene-aryl 6-10-membered , C 1-2 alkylene-heteroaryl 5-10-membered , C 1-2 alkylene-bicycloalkyl 5-12-membered , C 1-2 alkylene-hetero-bicycloalkyl 5-12-membered , wherein each of the ring is optionally substituted.
17 . The compound of formula (I) or the pharmaceutically acceptable salt thereof of claim 13 , wherein R 8 is selected from the group consisting of OC 1-6 alkyl, SC 1-6 alkyl, CN, OH, halogen, N(R m ) 2 , haloC 1-6 alkyl, haloC 1-6 alkyleneO, C 1-6 alkyl, C(═NC 1-6 alkyl)C 1-6 alkyl, OC(O)N(R m ) 2 , SH, C(O)SR m , OC 1-6 alkyleneOC 1-6 alkyl, OC 1-6 alkyleneO-haloC 1-6 alkyl, SC 1-6 alkyleneOC 1-6 alkyl, SC 1-6 alkyleneSC 1-6 alkyl, OC 1-6 alkyleneSC 1-6 alkyl, SC 1-6 alkyleneO-haloC 1-6 alkyl, SC 1-6 alkyleneS-haloC 1-6 alkyl, OC 1-6 alkyleneS-haloC 1-6 alkyl, C 1-6 alkylene-CN, OC 1-6 alkylene-CN, SC 1-6 alkylene-CN, OC 1-6 alkylene-N(R 11 ) 2 , C 2-6 alkynyl, C 2-6 alkenyl, SO 2 N(R m ) 2 , NR m SO 2 C 1-6 alkyl, C 1-6 alkylSO 2 (sulfone), S(O)OH, C 1-6 alkylS(O) (sulfoxide), nitroso, and C 1-6 alkylOSO 2 .
18 . The compound of formula (I) or the pharmaceutically acceptable salt thereof of claim 1 , which is represented by
Wherein
Compound
R 6
R 7
R 8
R 10
R 3
25N-NBOH
OH
H
H
H
NO 2
(3)
25N-NBOMe
OCH 3
H
H
H
NO 2
(4)
25N-NBOEt
OCH 2 CH 3
H
H
H
NO 2
(5)
25N-NBMe
CH 3
H
H
H
NO 2
(6)
25N-NBF
F
H
H
H
NO 2
(7)
25N-NBCl
Cl
H
H
H
NO 2
(8)
25N-NBBr
Br
H
H
H
NO 2
(9)
25N-NBI
I
H
H
H
NO 2
(10)
25N-NBOCF 2 H
OCF 2 H
H
H
H
NO 2
(11)
25N-NBOCF 3
OCF 3
H
H
H
NO 2
(12)
25N-NBMDF 2
OCF 2 O
H
H
NO 2
(13)
25N-NBCF 3
CF 3
H
H
H
NO 2
(14)
25N-NBNO 2
NO 2
H
H
H
NO 2
(15)
25N-N-1-Nap
(CH) 4
H
H
NO 2
(16)
25N-NBPh
Ph
H
H
H
NO 2
(17)
25N-NB-2-OH-3-Me
OH
CH 3
H
H
NO 2
(18)
25N-NB-2-MeO-3-F
OCH 3
F
H
H
NO 2
(19)
25N-NB-2,5-DiMeO
OCH 3
H
H
OCH 3
NO 2
(20)
25N-NB-3-OH
H
OH
H
H
NO 2
(21)
25N-NB-3-Me
H
CH 3
H
H
NO 2
(22)
25N-NB-4-Me
H
H
CH 3
H
NO 2
(23)
25N-NB-3-F
H
F
H
H
NO 2
(24)
25N-NB-4-F
H
H
F
H
NO 2
(25)
25D-NBOMe
OCH 3
H
H
H
CH 3
(26)
25D-N1-Nap
(CH) 4
H
H
CH 3
(27)
25D-NBPh
Ph
H
H
H
CH 3
(28)
19 . A pharmaceutical composition comprising the compound of formula (I) or the pharmaceutically acceptable salt thereof of claim 1 and a pharmaceutically acceptable carrier.
20 . A method of treating a disease or condition, comprising administering to a subject in need thereof the compound of formula (I) or the pharmaceutically acceptable salt thereof of claim 1 .
21 . The method of claim 20 , wherein the disease or condition is a psychiatric or neurological disease or condition or sign or symptom selected from the group consisting of attention deficient disorder, attention deficit hyperactivity disorder (ADHD), adult attention-deficit/hyperactivity disorder, learning disorders, neurocognitive disorders, Tic disorders, autism spectrum disorder, Tourette's disorder, schizophrenia, negative symptoms of schizophrenia, cognitive symptoms of schizophrenia, substance/medication-induced psychotic disorder, psychotic disorder due to another medical condition, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, disruptive mood dysregulation disorder, depression, post-partum depression, persistent depressive disorder, major depressive episode, major depressive disorder, treatment-resistant depression, post-traumatic stress disorder, reactive attachment disorder, disinhibited social engagement disorder, personality disorders, psychopathy, cyclothymic disorder, manic episode, hypomanic episode, bipolar disorder, delusional disorder, obsessive compulsive disorder, hoarding disorder, premenstrual dysphoric disorder, somatic symptom and related disorders, intellectual disabilities, communication disorders, motor disorders, catalepsy, catatonia, agitation, hypertension, sleep disorders, sexual dysfunctions anxiety disorders, adjustment disorders, body dysmorphic disorder, Trichotillomania, excoriation disorder, substance/medication-induced obsessive-compulsive and related disorder, dementias, neurodegenerative diseases, seasonal affective disorder, pseudobulbar affect, cluster headache, headaches, migraines, Tension-type headaches, tinnitus, hallucinations, delusions, epilepsies, cyclic vomiting syndrome, cannabinoid hyperemesis, nausea, restless leg syndrome, weight loss or binge eating, anorexia nervosa, bulimia nervosa, alcoholism, nicotine dependence, substance use disorders, non-substance related disorders, oppositional defiant disorder, intermittent explosive disorder, conduct disorder, pyromania, kleptomania, paraphilic disorders, medication induced movement disorders, and adverse effects of other medications.
22 . The method of claim 20 , wherein the disease or condition is selected from the group consisting of autoimmune diseases, acute pain, chronic pain, neuropathic pain, cancer, cough, infections, tinnitus, hearing loss, loss of taste, loss of smell, endocrine diseases and disorders, diabetes, gastrointestinal tract related diseases, urinary tract diseases, blood diseases, cardiovascular disease, inflammatory diseases, arthritis, paralysis, or spinal cord injury.
23 . (canceled)
24 . (canceled)
25 . (canceled)
26 . The method of claim 20 , wherein the subject has taken a hallucinogen.
27 . (canceled)
28 . (canceled)
29 . (canceled)
30 . (canceled)
31 . (canceled)