Discovery of imidazo[1,2-a]-, [1,2,4]triazolo[4,3-a]-, and [1,2,4]triazolo[1,5-a]pyridine-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5

Abstract

Based on a hypothesis that an intramolecular hydrogen bond was present in our lead series of picolinamide mGlu₅ NAMs, we reasoned that an inactive nicotinamide series could be modified through introduction of a fused heterocyclic core to generate potent mGlu₅ NAMs. In this Letter, we describe the synthesis and evaluation of compounds that demonstrate the viability of that approach. Selected analogs were profiled in a variety of in vitro assays, and two compounds were evaluated in rat pharmacokinetic studies and a mouse model of obsessive-compulsive disorder. Ancillary pharmacology screening revealed that members of this series exhibited moderate inhibition of the dopamine transporter (DAT), and SAR was developed that expanded the selectivity for mGlu₅ versus DAT.

Keywords: Central nervous system (CNS); G-protein coupled receptor (GPCR); Heterocycle; Metabotropic glutamate receptor subtype 5 (mGlu(5)); Negative allosteric modulator (NAM).

Figure 1

Picolinamide mGlu₅ NAM clinical candidate VU0424238 (1) and related analog VU0424222 (2) and inactive nicotinamide analogs 3 and 4

Figure 2

The fused heterocycle approach to a new series of mGlu₅ NAMs

Figure 3

Marble burying assay results with 31 (A) and 51 (B); all compounds were delivered via intraperitoneal (IP) dosing and formulated in 10% polysorbate 80 in sterile water; male Harlan CD-1 mice; n ≥ 6 per treatment group; 15 min pre-treatment; 30 min burying time; *, p < 0.05 versus vehicle control group, Dunnett’s test; bars denote marbles buried.

Scheme 1

Reagents and conditions: (a) K₂S₂O₈, H₂SO₄, 0 °C to r.t., 54%; (b) 3-fluoro-5-hydroxypyridine, K₂CO₃, DMF, 91%; (c) H₂ (1 atm.), Raney Ni, MeOH, 95%; (d) ClCH₂CHO, K₂CO₃, ⁱPrOH, microwave, 170 °C, 20 min., 65%; (e) Zn(CN)₂, Pd(PPh₃)₄, DMF, microwave, 140 °C, 15 min., 81%; (f) 2N NaOH (aq.), dioxane, sealed tube, 100 °C, 18 h., 99%; (g) substituted 2-aminopyridine, POCl₃, pyridine, −15 °C, 61% (R = 6-F), 42% (R = 6-Me), 36% (R = 5-F), 55% (R = 5-Me), 60% (R = 5-OMe).

Scheme 2

Reagents and conditions: (a) HF·pyridine, NaNO₃, 0 °C, 91% (8→18), 84% (17→19); (b) H₂NNH₂, EtOH, microwave, 120 °C, 15 min., 99% (18→20) 97% (19→21); (c) RC(OEt)₃, microwave, 180 °C, 20 min., 94% (20→22), 46% (20→23), 76% (21→24); (d) Zn(CN)₂, Pd(PPh₃)₄, DMF, microwave, 140 °C, 15 min., 90% (22→25), 92% (23→26), 21% (24→27); (e) 2N NaOH (aq.), dioxane, sealed tube, 100 °C, 18 h., 37% (25→28), 92% (26→29), 99% (27→30); (f) 5-fluoro-2-aminopyridine, POCl₃, pyridine, −15 °C, 49% (28→31), 45% (29→32), 83% (30→33).

Scheme 3

Reagents and conditions: (a) Me₂NCR(OMe)₂, ⁱPrOH, reflux, then NH₂OH·HCl, 50 °C; (b) (F₃CCO)₂O, THF, 0 °C to r.t., 99% (8→39), 45% (8→40), 95% (17→41), 99% (34→42); (c) Zn(CN)₂, Pd(PPh₃)₄, DMF, microwave, 140 °C, 15 min., 81% (39→43), 78% (40→44), 42% (41→45), 50% (42→46); (d) 2N NaOH (aq.), dioxane, sealed tube, 100 °C, 18 h., 46% (43→47), 89% (44→48), 99% (45→49), 99% (46→50); (e) 5-fluoro-2-aminopyridine, POCl₃, pyridine, −15 °C, 37% (47→51), 62% (48→52), 59% (48→53), 15% (50→54).

Scheme 4

Reagents and conditions: (a) Pd(OAc)₂, 1,3-bis(diphenylphosphino) propane, NEt₃, MeOH, CO (60 psi), 60 °C, 48% (55→58), 69% (56→59), 83% (57→60); (b) 1N NaOH (aq.), dioxane, 99% (58→61), 97% (59→62), 99% (60→63); (c) 5-fluoro-2-aminopyridine, POCl₃, pyridine, −15 °C, 50% (61→64), 51% (62→65), 94% (63→66).

Scheme 5

Reagents and conditions: (a) Pd(OAc)₂, 1,3-bis(diphenylphosphino) propane, NEt₃, MeOH, CO (60 psi), 60 °C, 98%; (b) MeSO₃H, CHCl₃, 63%; (c) PhN(SO₂CF₃)₂, NEt₃, DMF, CH₂Cl₂, 0 °C, 99%; (d) Zn(CN)₂, Pd(PPh₃)₄, DMF, microwave, 140 °C, 15 min., 59%; (e) 1N NaOH (aq.), dioxane, 99% (71→72), 99% (74→75); (f) 5-fluoro-2-aminopyridine, POCl₃, pyridine, −15 °C, 46% (72→73), 50% (75→76); (g) ClCF₂CO₂Na, K₂CO₃, DMF, 95 °C, 18 h, 16%.