Selective, partial, and arrestin-biased 5-ht2a agonists with utility in various disorders

Patent metadata

Field	Value
Publication number	US-2024254087-A1
Application number	US-202218560113-A
Country	US
Kind code	A1
Filing date	May 11, 2022
Priority date	May 11, 2021
Publication date	Aug 1, 2024
Grant date	—

Abstract

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.

First claim

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-

Assignees

• Saint Josephs Univ
• Medical College Wisconsin Inc
• Univ California

Inventors

• Wallach Jason
• Mccorvy John
• Halberstadt Adam

Classifications

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/24

  Antidepressants · CPC title