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US-20260124173-A1 - THERAPEUTIC ALKALOID COMPOUNDS

US20260124173A1US 20260124173 A1US20260124173 A1US 20260124173A1US-20260124173-A1

Abstract

Disclosed are compounds useful for inhibiting SERT, and related methods of preparing and using these compounds.

Inventors

  • Jacob M. Hooker
  • Michael S. Placzek

Assignees

  • SENSORIUM THERAPEUTICS, INC.

Dates

Publication Date
20260507
Application Date
20251216

Claims (20)

  1. 1 - 21 . (canceled)
  2. 22 . A compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein ring A is wherein * denotes the attachment points of ring A to the compound of formula (I), and wherein each R 1 is independently deuterium, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, —OR a , —NR a R b , —CHO, —C(O)R a , —CO 2 R a , —C(O) NR a R b , —CN, nitro, or —P(O)OR a OR b ; wherein each hydrogen atom in alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by halo, alkyl, alkanol, aryl, —OR a , —NR a R b , —CHO, —C(O)R a , —CO 2 R a , —C(O) NR a R b , —CN, nitro, or —P(O)OR a OR b ; m is 0, 1, 2, or 3; each of R 2 and R 3 is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or aryl; wherein each hydrogen atom in alkyl cycloalkyl, alkenyl, alkynyl, and aryl is optionally substituted by halo, deuterium, cycloalkyl, aryl, or OR a ; or R a and R b are independently H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or if an instance of R 1 is —NR a R b , then R a and R b may combine with the nitrogen atom to which they are attached to form heterocycloalkyl or heteroaryl; R 4 is H, C 1-4 alkyl, or C 1-6 haloalkyl; and R 5 is C 1-4 alkyl optionally substituted with C 3-6 cycloalkyl, 3- to 6-membered heterocycle, phenyl or 5- to 6-membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycle, phenyl or heteroaryl are each independently optionally substituted with one or more deuterium, C 1-4 alkoxy, C 1-4 haloalkyl, halo, cyano, amino, carboxy, acetyl, or amide.
  3. 23 . The compound of claim 22 , wherein R 4 is methyl.
  4. 24 . The compound of claim 23 , wherein R 5 is methyl.
  5. 25 . The compound of claim 24 , wherein each R 1 is independently halo, C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, C 3-6 cycloalkyl, —OR a , —NR a R b , —CHO, —C(O)R a , —CO 2 R a , —C(O) NR a R b , —CN, nitro, or —P(O)OR a OR b ; wherein each hydrogen atom in alkyl, alkenyl, alkynyl, or cycloalkyl is optionally substituted by halo, C 1-4 alkyl, C 1-4 alkanol, —OR a , —NR a R b , —CHO, —C(O)R a , —CO 2 R a , —C(O)NR a R b , —CN, nitro, or —P(O)OR a OR b ; and R a and R b are each independently H, or C 1-4 alkyl.
  6. 26 . The compound of claim 25 , wherein each R 1 is independently halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, acetyl, cyano, C 3-6 cycloalkyl, or C(O)NR a R b ; R a and R b are each C 1-4 alkyl.
  7. 27 . The compound of claim 26 , wherein a. R 2 and R 3 are each independently H, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or C 1-4 alkyl optionally substituted with C 3-6 cycloalkyl, phenyl, C 2-4 alkenyl or C 2-4 alkynyl; or b. R 2 and R 3 together with the atoms to which they are attached combine to form a 5- to 6-membered heterocyclyl, wherein each hydrogen atom in the heterocyclyl is optionally substituted by halo or OR a ; and R a is C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy.
  8. 28 . The compound of claim 27 , wherein one of R 2 and R 3 is not H.
  9. 29 . The compound of claim 28 , wherein R 2 and R 3 are each independently H, C 1-4 haloalkyl, —(CH 2 )—(C 3-6 cycloalkyl), —(CH 2 )—(C 1-4 alkoxy), C 3-6 cycloalkyl, or benzyl.
  10. 30 . The compound of claim 29 , wherein ring A is
  11. 31 . The compound of claim 30 , wherein the compound is a compound of Formula (II-C), or a pharmaceutically acceptable salt thereof.
  12. 32 . The compound of claim 31 , wherein R 2 and R 3 are each independently methyl.
  13. 33 . The compound of claim 32 , wherein m is 0 or 1.
  14. 34 . The compound of claim 22 , wherein the compound is or a pharmaceutically acceptable salt thereof.
  15. 35 . The compound of claim 22 , wherein the compound is or a pharmaceutically acceptable salt thereof.
  16. 36 . The compound of claim 22 , wherein the compound is or a pharmaceutically acceptable salt thereof.
  17. 37 . The compound of claim 22 , wherein the compound is or a pharmaceutically acceptable salt thereof.
  18. 38 . The compound of claim 27 , wherein R 2 and R 3 together with the atoms to which they are attached combine to form a 5- to 6-membered heterocyclyl, wherein each hydrogen atom in the heterocyclyl is optionally substituted by halo or OR a ; and R a is C 1-4 alkyl, or C 1-4 haloalkyl.
  19. 39 . The compound of claim 37 , wherein R a is methyl and the halo is fluoro.
  20. 40 . A compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein ring A is wherein * denotes the attachment points of ring A to the compound of formula (I); and wherein each R 1 is independently deuterium, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, —OR a , —NR a R b , —CHO, —C(O)R a , —CO 2 R a , C(O)NR a R b , —CN, nitro, or —P(O)OR a OR b ; wherein each hydrogen atom in alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by halo, alkyl, alkanol, aryl, —OR a , —NR a R b , —CHO, —C(O)R a , —CO 2 R a , —C(O) NR a R b , —CN, nitro, or —P(O)OR a OR b ; m is 0, 1, 2, or 3; each of R 2 and R 3 is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or aryl; wherein each hydrogen atom in alkyl cycloalkyl, alkenyl, alkynyl, and aryl is optionally substituted by halo, deuterium, cycloalkyl, aryl, or OR a ; or R a and R b are independently H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or if an instance of R 1 is —NR a R b , then R a and R b may combine with the nitrogen atom to which they are attached to form heterocycloalkyl or heteroaryl; R 4 is H, C 1-4 alkyl, or C 1-6 haloalkyl; and R 5 is methyl.

Description

RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional patent application Ser. No. 63/548,083, filed Nov. 10, 2023; and U.S. Provisional patent application Ser. No. 63/651,580, filed May 24, 2024; the contents of each of which are hereby incorporated by reference in their entirety. TECHNICAL FIELD The present disclosure relates to the field of medicine, including the discovery of alkaloid compounds useful for eliciting antidepressant and/or anxiolytic effects by inhibiting, in part, the serotonin transporter protein (5-HT). BACKGROUND Serotonin (5-HT) is an essential neurotransmitter for the normal function of the central nervous system. This neurotransmission system in the brain controls various important behaviors, including sleep awake cycle, mood, temperature, appetite, etc. In addition, several commonly used anti-anxiety drugs. Certain SERT inhibitors, including the selective serotonin transporter inhibitors, also called selective serotonin reuptake inhibitors (SSRIs), are used as therapeutic antidepressant drugs. They are believed to exert their effect by increasing extracellular 5-HT levels in the serotoninergic terminal fields such as the hippocampus and prefrontal cortex. A fundamental evaluation in drug development is the assessment of absorption, distribution, metabolism, excretion, and pharmacokinetics (ADME/PK). One of the primary ADME screens that a novel chemical entity is subjected to is an in vitro metabolic stability screen. Drug stability upon exposure to human liver hepatocytes or microsomes is a common in vitro assay to approximate in vivo, liver-based drug metabolism. There remains a need for therapeutic compounds that inhibit SERT with desired ADME and PK properties, such as extended half-life and metabolic stability, to provide adequate duration of action for therapeutic use. SUMMARY Described herein are compounds of Formula (I), or a pharmaceutically acceptable salt thereof: wherein ring A is wherein * denotes the attachment points of ring A to the compound of formula (I), and wherein each R1 is independently deuterium, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, —ORa, —NRaRb, —CHO, —C(O)Ra, —CO2Ra, —C(O)NRaRb, —CN, nitro, or —P(O)ORaORb; wherein each hydrogen atom in alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by halo, alkyl, alkanol, aryl, —ORa, —NRaRb, —CHO, —C(O)Ra, —CO2Ra, —C(O) NRaRb, —CN, nitro, or —P(O)ORaORb;m is 0, 1, 2, or 3;each of R2 and R3 is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or aryl; wherein each hydrogen atom in alkyl cycloalkyl, alkenyl, alkynyl, and aryl is optionally substituted by halo, deuterium, cycloalkyl, aryl, or ORa; orR2 and R3 together with the atoms to which they are attached combine to form heterocyclyl or heteroaryl, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo or ORa;Ra and Rb are independently H, alkyl (e.g., methyl), alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or if an instance of R1 is —NRaRb, then Ra and Rb may combine with the nitrogen atom to which they are attached to form heterocycloalkyl or heteroaryl;R4 is H, C1-4 alkyl or C1-6 haloalkyl; andR5 is C1-4 alkyl. In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (II-A), or a pharmaceutically acceptable salt thereof: wherein R1, m, R2, R3 and R5 are as disclosed with respect to Formula (I) herein. In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (II-B), or a pharmaceutically acceptable salt thereof: wherein R1, m, R2, R3 and R5 are as disclosed with respect to Formula (I) herein. In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (II-C), or a pharmaceutically acceptable salt thereof: wherein R1, m, R2, R3 and R5 are as disclosed with respect to Formula (I) herein. In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (II-D), or a pharmaceutically acceptable salt thereof: wherein R1, m, R2, R3 and R5 are as disclosed with respect to Formula (I) herein. In certain embodiments, the compound is a compound of Formula (III), or a pharmaceutically acceptable salt thereof: wherein Ring A, R1, m, Ra and R5 are as disclosed herein for Formula (I) or Formulae (II-A), (II-B), (II-C) and (II-D); X and Y are each independently O, NR7 or S;x is 1 or 2;each of R6a and R6b is independently H, halo, C1-4 alkyl, or C1-4 haloalkyl; or R6a and R6b taken together with the atoms to which they are attached combine to form carbonyl (C═O), C3-6 spirocyclic-cycloalkyl, or a 3-6 membered spirocyclic heterocyclyl comprising one or more O, N or S heteroatoms; wherein each hydrogen atom in cycloalkyl and heterocyclyl is optionally substitut