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. 2017 Jan 18;8(2):261-265.
doi: 10.1021/acsmedchemlett.6b00487. eCollection 2017 Feb 9.

Novel 2-Substituted 7-Azaindole and 7-Azaindazole Analogues as Potential Antiviral Agents for the Treatment of Influenza

Upul K Bandarage  1 , Michael P Clark  1 , Emanuele Perola  1 , Huai Gao  1 , Marc D Jacobs  1 , Alice Tsai  1 , Jeffery Gillespie  1 , Joseph M Kennedy  1 , François Maltais  1 , Mark W Ledeboer  1 , Ioana Davies  1 , Wenxin Gu  1 , Randal A Byrn  1 , Kwame Nti Addae  1 , Hamilton Bennett  1 , Joshua R Leeman  1 , Steven M Jones  1 , Colleen O'Brien  1 , Christine Memmott  1 , Youssef Bennani  1 , Paul S Charifson  1
Affiliations

Novel 2-Substituted 7-Azaindole and 7-Azaindazole Analogues as Potential Antiviral Agents for the Treatment of Influenza

Upul K Bandarage et al. ACS Med Chem Lett. .

Abstract

JNJ-63623872 (2) is a first-in-class, orally bioavailable compound that offers significant potential for the treatment of pandemic and seasonal influenza. Early lead optimization efforts in our 7-azaindole series focused on 1,3-diaminocyclohexyl amide and urea substitutions on the pyrimidine-7-azaindole motif. In this work, we explored two strategies to eliminate observed aldehyde oxidase (AO)-mediated metabolism at the 2-position of these 7-azaindole analogues. Substitution at the 2-position of the azaindole ring generated somewhat less potent analogues, but reduced AO-mediated metabolism. Incorporation of a ring nitrogen generated 7-azaindazole analogues that were equipotent to the parent 2-H-7-azaindole, but surprisingly, did not appear to improve AO-mediated metabolism. Overall, we identified multiple 2-substituted 7-azaindole analogues with enhanced AO stability and we present data for one such compound (12) that demonstrate a favorable oral pharmacokinetic profile in rodents. These analogues have the potential to be further developed as anti-influenza agents for the treatment of influenza.

Keywords: 7-azaindole; Influenza; PB2 subunit; aldehyde oxidase; metabolic stability.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Inhibitors of influenza virus: NA inhibitor oseltamivir (1), 2, and azaindole screening hit 3.
Figure 2
Figure 2
Potent anti-influenza compounds and primary metabolite (5).
Scheme 1
Scheme 1. Synthesis of Compound 12
Reagents and conditions: (a) HC≡CHCH2OTHP, Pd(PPh3)2Cl2, CuI, THF, Et3N, 80 °C, 1 h, 82%; (b) t-BuOK, THF, 85 °C, 2 h, 64%; (c) NIS, DMF, DCM, RT, 1 h, 99%;(d) i. NaH, THF, RT, 30 min; ii. PhSO2Cl, 1 h, 97%; (e) bis(pinacolato)diboron, PdCl2(dppf)·DCM, KOAc, DMF, 85 °C, 3 h, 60%; (f) i. 14, Pd(PPh3)4, THF, aq. Na2CO3, 80 °C, 18 h; ii. TFA, MeOH, H2O, 1 h, 80%; (g) 4 N HCl, 1,4-dioxane, CH3CN, 65 °C, 1 h, 68%.
Scheme 2
Scheme 2. Synthesis of Compound 14
Reagents and conditions: (a) i. ethyl (1R,3S)-3-aminocyclohexanecarboxylate, THF, reflux, 18 h, 92%; ii. LiOH, THF, water, 95 °C, 1 h, 97%; (b) DPPA, Et3N, pyrrolidine, Et3N, THF, RT, 85 °C, 2 h, 85%.
Scheme 3
Scheme 3. Synthesis of Compounds 19, 20, and 21
Reagents and conditions: (a) (COCl)2, DMSO, Et3N,-78 °C, 2 h, 86%; (b) i. Na2HPO4, NaClO2, 2-butene, t-BuOH, RT, 18 h, 88% ii. 4 N HCl, 1,4-dioxane, CH3CN, 65 °C, 1 h, 68%; (c) i. NH2OH, EtOH, reflux, 3 h; ii. 4 N HCl, 1,4-dioxane, CH3CN, 65 °C, 1 h, 68%; (d) i. CH3MgBr, THF, RT, 1 h; ii. 4 N HCl, 1,4-dioxane, CH3CN, 65 °C, 1 h, 68%.
Scheme 4
Scheme 4. Synthesis of Compound 23
Reagents and conditions: (a) NIS, DCM, RT, 100 °C, 2 h, 80%; (b) trityl chloride, K2CO3, DMF, RT, 18 h, 81%; (c) bis(pinacolato)diboron, PdCl2(dppf).DCM, KOAc, DMF, 95 °C, 1 h, 100%; (d) 14, Pd2(dba)3, X-Phos, K3PO4, 2-methylTHF, H2O, 120 °C, 2 h, 48%; (e) Et3SiH, 30 mol-equiv of TFA, DCM, RT, 30 min, 92%.
Figure 3
Figure 3
(A) X-ray crystal structure of 12 bound to PB2 (PDB ID: 5BUH). (B) X-ray crystal structure of 16 bound to PB2 (PBD ID: 5F79).
See this image and copyright information in PMC

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