Synthesis of 4-Substituted Chlorophthalazines, Dihydrobenzoazepinediones, 2-Pyrazolylbenzoic Acid, and 2-Pyrazolylbenzohydrazide via 3-Substituted 3-Hydroxyisoindolin-1-ones

Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones <b>9b</b>, <b>9i</b>–<b>9am</b>. Many of these hydroxyisoindolinones are converted to chlorophthalazines <b>1b</b>–<b>1v</b> via reaction with hydrazine, followed by chlorination with POCl₃. We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) provided dihydrobenzoazepinediones <b>15a</b>–<b>15c</b> via the proposed ring expansion of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids <b>16a</b>–<b>16d</b> and 2-pyrazolyl benzohydrazides <b>17a</b>–<b>17g</b> rather than the expected alkynyl phthalazinones

Synthesis of 4-Substituted Chlorophthalazines, Dihydrobenzoazepinediones, 2-Pyrazolylbenzoic Acid, and 2-Pyrazolylbenzohydrazide via 3-Substituted 3-Hydroxyisoindolin-1-ones

Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones <b>9b</b>, <b>9i</b>–<b>9am</b>. Many of these hydroxyisoindolinones are converted to chlorophthalazines <b>1b</b>–<b>1v</b> via reaction with hydrazine, followed by chlorination with POCl₃. We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) provided dihydrobenzoazepinediones <b>15a</b>–<b>15c</b> via the proposed ring expansion of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids <b>16a</b>–<b>16d</b> and 2-pyrazolyl benzohydrazides <b>17a</b>–<b>17g</b> rather than the expected alkynyl phthalazinones

Synthesis of 4-Substituted Chlorophthalazines, Dihydrobenzoazepinediones, 2-Pyrazolylbenzoic Acid, and 2-Pyrazolylbenzohydrazide via 3-Substituted 3-Hydroxyisoindolin-1-ones

Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones <b>9b</b>, <b>9i</b>–<b>9am</b>. Many of these hydroxyisoindolinones are converted to chlorophthalazines <b>1b</b>–<b>1v</b> via reaction with hydrazine, followed by chlorination with POCl₃. We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) provided dihydrobenzoazepinediones <b>15a</b>–<b>15c</b> via the proposed ring expansion of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids <b>16a</b>–<b>16d</b> and 2-pyrazolyl benzohydrazides <b>17a</b>–<b>17g</b> rather than the expected alkynyl phthalazinones

Synthesis of 4-Substituted Chlorophthalazines, Dihydrobenzoazepinediones, 2-Pyrazolylbenzoic Acid, and 2-Pyrazolylbenzohydrazide via 3-Substituted 3-Hydroxyisoindolin-1-ones

Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones <b>9b</b>, <b>9i</b>–<b>9am</b>. Many of these hydroxyisoindolinones are converted to chlorophthalazines <b>1b</b>–<b>1v</b> via reaction with hydrazine, followed by chlorination with POCl₃. We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) provided dihydrobenzoazepinediones <b>15a</b>–<b>15c</b> via the proposed ring expansion of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids <b>16a</b>–<b>16d</b> and 2-pyrazolyl benzohydrazides <b>17a</b>–<b>17g</b> rather than the expected alkynyl phthalazinones

Synthesis of 4-Substituted Chlorophthalazines, Dihydrobenzoazepinediones, 2-Pyrazolylbenzoic Acid, and 2-Pyrazolylbenzohydrazide via 3-Substituted 3-Hydroxyisoindolin-1-ones

Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones <b>9b</b>, <b>9i</b>–<b>9am</b>. Many of these hydroxyisoindolinones are converted to chlorophthalazines <b>1b</b>–<b>1v</b> via reaction with hydrazine, followed by chlorination with POCl₃. We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) provided dihydrobenzoazepinediones <b>15a</b>–<b>15c</b> via the proposed ring expansion of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids <b>16a</b>–<b>16d</b> and 2-pyrazolyl benzohydrazides <b>17a</b>–<b>17g</b> rather than the expected alkynyl phthalazinones

The Discovery and Hit-to-Lead Optimization of Tricyclic Sulfonamides as Potent and Efficacious Potentiators of Glycine Receptors

Current pain therapeutics suffer from undesirable psychotropic and sedative side effects, as well as abuse potential. Glycine receptors (GlyRs) are inhibitory ligand-gated ion channels expressed in nerves of the spinal dorsal horn, where their activation is believed to reduce transmission of painful stimuli. Herein, we describe the identification and hit-to-lead optimization of a novel class of tricyclic sulfonamides as allosteric GlyR potentiators. Initial optimization of high-throughput screening (HTS) hit <b>1</b> led to the identification of <b>3</b>, which demonstrated ex vivo potentiation of glycine-activated current in mouse dorsal horn neurons from spinal cord slices. Further improvement of potency and pharmacokinetics produced in vivo proof-of-concept tool molecule <b>20</b> (AM-1488), which reversed tactile allodynia in a mouse spared-nerve injury (SNI) model. Additional structural optimization provided highly potent potentiator <b>32</b> (AM-3607), which was cocrystallized with human GlyRα3_cryst to afford the first described potentiator-bound X-ray cocrystal structure within this class of ligand-gated ion channels (LGICs)