The synthesis and preclinical characterization of novel 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4H-triazolo[4,5-c]pyridines, methyl substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines, and several other series lead to the identification of a series of 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are selective P2X7 antagonists with potency at the rodent and human P2X7 ion channels. These novel P2X7 antagonists have suitable physicochemical properties, and several analogs have an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing. Improvements in metabolic stability led to the identification of JNJ-54175446 (14) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein.

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An efficient synthesis of compound 1 featuring a novel sequential Friedel-Crafts alkylation strategy to construct the 4-aryl-tetrahydroisoquinoline core structure has been developed. Resolution with (D/L)-di-p-toluoyl-tartaric acid is utilized to provide the enantiomerically pure material. Overall, the route is concise and amenable for large-scale synthesis. IntroductionSelective serotonin reuptake inhibitors (SSRIs) represent a very important class of antidepressant drugs; for example, Prozac and Zoloft, both SSRIs, are among the most commonly prescribed drugs for depression. However, SSRIs do not treat some of common symptoms associated with depression such as cognitive impairment and fatigue, even as mood improves. 1 Histamine H 3 inhibitors, in contrast, have been shown to improve cognition and increase wakefulness in preclinical pharmacology experiments. 2 With the expectation that a serotonin reuptake inhibitor with histamine H 3 activity may improve efficacy for the treatment of depression, a series of dual serotonin reuptake inhibitors/histamine H 3 antagonists were designed in our laboratories. 3 These compounds share the common structural feature of a 4-aryl-tetrahydroisoquinoline core tethered with a H 3 pharmacophore side chain. Among the analogs prepared, compound 1 has high affinity for both the histamine H 3 receptor and the serotonin reuptake transporter; good selectivity against a panel of over 50 receptors, ion channels and transporters; and favorable pharmacokinetic properties including good oral bioavailability and high exposure and receptor occupancy in the rat brain. A practical synthesis to provide multigram quantities of 1 was needed for further pharmacological evaluation. The initial discovery route (Scheme

Two enantioselective syntheses of the fused benzazepine dopamine D 1 antagonist (6aS,13bR)-11-chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-5H-benzo[d]naphth[2,1-b]azepin-12-ol (1) are described in which the starting material is (+)-L-homophenylalanine (6). In the first approach, methyl (2S)-(1,2,3,4-tetrahydro-1-oxo-2-naphthalenyl)carbamate (5) is prepared by intramolecular Friedel-Crafts cyclization of N-carbomethoxy (+)-L-homophenylalanine (9). Subsequent alkylation of 5 with (4-chloro-3-methoxyphenyl)magnesium bromide, deoxygenation with Et 3 SiH, reduction, alkylation, and epimerization yields (+)- trans-(1R,2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-1,2,3,4-tetrahydro-N-methyl-2-naphthalenamine (2), a key intermediate in the previouslydescribed route to 1 (Draper, R. W.; Hou, D.; Iyer, R.; Lee, G. M.; Liang, J. T.; Mas, J. L.; Tormos, W.; Vater, E. J.; Gu 1nter, F.; Mergelsberg, I.; Scherer, D. Org. Process Res. DeW. 1998, 2, XXXXX). A complementary route to 2 is also described in which arylation of an N-protected, carboxyl-activated (+)-L-homophenylalanine affords (2S)-1-(4-chloro-3-methoxyphenyl)-2-(methoxycarbamoyl)-4-phenyl-1-butanone (26). Reduction of the latter compound followed by an acid-catalyzed, diastereoselective cyclization affords (+)-(1R,2S)-[1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]carbamate (16), which is reduced and alkylated as before to produce 2.

Several novel enantioselective syntheses of the dopamine D 1 antagonist (6aS,13bR)-11-chloro-6,6a,7,8,9,13b-hexahydro-7methyl-5H-benzo[d]naphth[2,1-b]azepin-12-ol (2) are described in which the key intermediate was 1-(2,2-dimethoxyethyl)-1methyl-1a,2,3,7b-tetrahydro-1H-naphth[1,2-b]aziridinium salt (20). The latter species was prepared either from 1-(2,2dimethoxyethyl)-1a,2,3,7b-tetrahydro-1H-naphth[1,2-b]azirine (18) by methylation or from the tertiary amino alcohols 1-[(2,2-dimethoxyethyl)methylamino]-1,2,3,4-tetrahydro-2naphthalenol (23) or 2-[(2,2-dimethoxyethyl)methylamino]-1,2,3,4-tetrahydro-1-naphthalenol (24) by tosylation and in situ ring closure. Regioselective trapping of 20 with Grignard reagent (4-chloro-3-methoxyphenyl)magnesium bromide (10) then afforded the trans amine 1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-1,2,3,4-tetrahydro-N-methyl-2-naphthalenamine (22), which was cyclized to give 11-chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-12-methoxy-5H-benzo[d]naphth[2,1-b]azepine (9), a known precursor of 2. Several enantioselective syntheses, including a Jacobsen epoxidation route, a de noWo synthesis from L-homophenylalanine, and a classical salt resolution sequence, were developed for the preparation of the key intermediates in chiral form.