Advances in Chemistry
Volume 2017 (2017), Article ID 8147421, 7 pages
https://doi.org/10.1155/2017/8147421

Research Article

Flow and Microwave Induced Pellizzari Reactions: Synthesis of Heterocyclic Analogues of the Benzoxazepine Antipsychotic Agents Loxapine and JL-13

Nadeesha Ranasinghe,¹ Enrico Mongeau,¹ Gengyang Yuan,¹ Zachary Minden,¹ Scott Waldron,¹ Christopher Patrick Jr.,¹ Farid Fouad,² Sabiha Kappera,² and Graham B. Jones1,3

¹Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA
²Department of Chemistry, Kent State University, East Liverpool, OH 43920, USA
³Clinical and Translational Science Institute, Tufts University Medical Center, 800 Washington Street, Boston, MA 02111, USA

Correspondence should be addressed to Graham B. Jones; graham.jones@tufts.edu

Received 15 May 2017; Revised 28 September 2017; Accepted 9 October 2017; Published 4 December 2017

Academic Editor: Thierry Besson

Copyright © 2017 Nadeesha Ranasinghe et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

An expeditious route to fused triazolo-pyrido benzoxazepines has been developed using flow and microwave-mediated cyclization chemistry. A range of substituted aryl hydrazides are coupled with a core chloroimine in good to excellent yield via a Pellizzari type process, producing 1,2,4-triazolo-pyrido [,-b] [,] benzoxazepines with structural similarity to known antipsychotic agents. Modifications allow for strategically functionalized derivatives, and installation of a fluoro group for use in PET imaging is also demonstrated. Given the affinity of the tricyclic core for 5-HT and dopamine receptors, the derivatives are expected to find utility in CNS research.

1. Introduction

Heterocyclic derivatives of the benzodiazepine and benzoxazepine class are of considerable interest in medicinal chemistry due to their pharmacologic and metabolic profiles [1, 2]. Prominent examples include the anxiolytic Alprazolam (Xanax®), Loxapine, and the atypical antipsychotic JL13, which has been investigated as a next-generation clozapine analogue [3–5]. One of the pharmacologic targets of the agents is the receptor, and a number of heterocyclic analogues demonstrate high affinity including Asenapine which despite its altered geometry compares favorably to traditional agents Loxapine and Clozapine [6] (see Scheme 1). Given promising preclinical data reported for JL13 [7–9], we elected to study the potential of additional heterocyclic variants which might be readily accessible using efficient coupling strategies and which also highlights the benefits of green chemistry approaches [10, 11]. Given the functional flexibility of the triazole group and its presence in a number of pharmacologically active molecules [12], we sought to investigate use of the Pellizzari method [13], which relies on one pot coupling, and closure of imino chlorides with substituted hydrazides.

Scheme 1

2. Results and Discussion

For initial studies we designed a series of hybrid triazole-benzoxazepine mimics of Loxapine and JL13, investigating the benefit of microwave and flow-mediated Pellizzari reactions as green approaches to these classes. A chloropyridyl amide substrate 1 was firstly prepared by condensation of 2-chloro nicotinoyl chloride with 2-amino phenol (DIPEA, 94%). This was subjected to microwave accelerated base-mediated intramolecular closure to form 2 (Scheme 2) with KOtBu (90%) preferable to both NaOH (72%) and NaH (59%) with a 5 min irradiation. The cyclic amide was converted to the corresponding chloroimine, allowing us to probe the key triazole forming reaction to produce 3 (All new compounds were fully characterized by appropriate spectroscopic and analytical techniques.). A range of aryl hydrazide substrates were probed under thermal, microwave, and flow conditions at 100 mg scale and the results are summarized in Table 1.

Table 1: Intramolecular cyclization to form triazolo benzoxepines 3 (% isolated yield).

Entry
3
Ar

1
3a
Ph
38
54
57

2
3b
2-Cl-C₆H₄
48
86
78

3
3c
4-Cl-C₆H₄
66
96
84

4
3d
2-OH-C₆H₄
29
89
>99

5
3e
4-OH-C₆H₄
41
67
72

6
3f
3-OMe-C₆H₄
28
92
82

7
3g
3-pyridyl
57
84
98

8
3h
2-F-C₆H₄
25
88
>99

9
3i
3-F-C₆H₄
32
83
85

10
3j
4-Me-C₆H₄
39
98
88

11
3k
3-NO₂-C₆H₄
17
81
85

12
3l
3-Cl-C₆H₄
44
80
—

-BuOH, , 118°C, 6 h;  W, 200°C, -BuOH 15 min. pumps of the reactor were set to flow at equal rates (2 μl/min) at 190°C with a solution of 5-chlorobenzo[b]pyrido[,-f][,]oxazepine (0.04 M) and hydrazide (0.04 M) in -BuOH with residence time of 2.5 min. Experiments represent .

Scheme 2: MW and flow based synthesis of triazolo-pyrido-benzoxazepines.

Though moderate conversion was observed within 6 h of conventional thermolysis, the MW methods allowed very high yields of product within 15 mins with n-butanol being the most effective solvent. Essentially comparable, flow-mediated reactions (conducted using a Chemtrix Labtrix S1 system equipped with T-mixer) in some cases produced even higher yields, a presumed consequence of improved mixing interactions [14].

Given literature reports citing the importance of both basic amino functionality and a hydrophobic substituent (e.g., chloroaryl group) for optimal receptor binding [15, 16], a more elaborate substrate 5 was also prepared from hydrazide 4 (readily available from m-chloro-o-toluic acid), leading to the target compound in 87% yield (see Scheme 3). Given the impressive results with the MW Pellizzari reaction, a second family of analogues were prepared which contain the chloroaryl functionality on the parent tricyclic ring system. Amide 6 (prepared from 2-chloro nicotinoyl chloride and 2-amino-4-chloro phenol) was subjected to base induced oxepane formation and subsequent chlorination to give 7 in good yield (Scheme 4). Microwave induced Pellizzari reactions were conducted with various hydrazides to give substituted analogues 8.

Scheme 3

Scheme 4: Modification of core for MW Pellizzari route to chlorinated series.

A range of decorated analogues 9–16 were produced in good to excellent yield (see Scheme 6), which, coupled with those depicted in Table 1, will allow insightful structure-activity studies to be performed with binding assays against key receptors (, , D₁, D₂, and D4.2 being of importance, with the /D₂ ratio especially significant) [17]. In a preliminary assay, compound 5 showed a of 16 μM against , which bodes well for in depth assays [18]. Finally, and with a potential view to studying biodistribution of these ligands via in vivo imaging methods, proof of principal was demonstrated for installation of a fluoro group via nucleophilic displacement. Following extensive optimization of parameters (temp, time, and stoichiometry), nitroarene 17 was subjected to MW induced fluorodenitration to give 18 in good yield within 15 mins at 140°C using 2 equivalents of TBAF in DMSO (Scheme 5) [19]. Given the half-life of its emitting sister ¹⁸F isotope (~120 mins) this rapid transformation is compatible with late stage labeling for PET imaging.

Scheme 5: MW induced fluorodenitration.

Scheme 6

3. Conclusions

Both MW and flow based Pellizzari reactions were effective and efficient for the production of new classes of substituted triazolo-pyrido fused benzoxazepines. The route provides access to compounds which may be useful probes of the 5-HT and dopamine receptors, based on similarity to known antipsychotic agents. A specimen compound shows measurable affinity for one of the receptor subtypes and derivatization of the core via nucleophilic fluorination provides a means to utilize the class in PET imaging studies. A comprehensive screening of these agents will be reported in due course.

Appendix

A. General Experimental Procedures

All solvents were of reagent or anhydrous grade quality and purchased from Sigma-Aldrich, Alfa Aesar, or Fisher Scientific. All reagents were purchased from Sigma-Aldrich, Alfa Aesar, Fisher Scientific, or Oakwood Chemical, unless otherwise stated. All deuterated solvents were purchased from Cambridge isotopes. Analytical thin-layer chromatography (TLC) was performed on precoated glass-backed plates (EMD TLC Silica gel 60 F₂₅₄) and visualized using a UV lamp (254 nm) and potassium permanganate stain. Silica gel for manual flash chromatography was high purity grade 40–63 μm pore size and purchased from Sigma-Aldrich. Yields refer to purified and spectroscopically pure compounds. Unless otherwise noted, compounds were recrystallized from toluene-hexanes. ¹H NMR (400 MHz, DMSO-d6) and ¹³C NMR (100 MHz, DMSO-d6) spectra were obtained with a Varian instrument.

A.1. Synthesis of 5-Chlorobenzo[b]pyrido[3,2-f][1,4]oxazepine

A mixture of amide, benzo[b]pyrido[3,2-f][1,]oxazepine-5(6H)-one (2, 1.08 g, 5.08 mmol), phosphorous oxychloride (1.42 mL, 15.26 mmol), and N,N-dimethylaniline (2.57 mL, 20.32 mmol) in dry toluene (10 mL) was heated at reflux for 2 h. The reaction mixture was cooled to ambient temperature and excess solvents were evaporated under reduced pressure. The resulting residue was dissolved in THF (20 ml) and Na₂CO₃ (30 mL of 2 M solution) and heated at 80°C for 1 h. The reaction mixture was cooled to ambient temperature and THF was removed under reduced pressure. The resulting aqueous layer was extracted with EtOAc ( ml). The combined organic layers were washed with brine ( ml) and dried over MgSO₄ and solvents were evaporated. The resulting residue was purified by column chromatography using 5% MeOH in dichloromethane to afford the title compound (1.09 g, 93%) as a light green solid m.p. 141.9–142.7°C; ¹H NMR: δ 8.49 (dd, = 5.2, 8 Hz, 1H), 8.26 (dd, = 2, 7.2 Hz, 1H), 7.45 (dd, = 5.2, 8 Hz, 1H), 7.33 (d, 8 Hz, 1H), 7.24–7.14 (m, 3H) ppm; ¹³C NMR: δ 164.4, 162.3, 152.4, 148.1, 142.4, 130.5, 126.3, 125.3, 122.5, 121.8, 121.7, 120.0 ppm. HRMS calc. for C₁₂H₇ClN₂O: 230.0246 obs: 230.0244.

A.1.1. General Procedure for Synthesis of 3 in MW

5-Chlorobenzo[b]pyrido[3,2-f][1,]oxazepine (0.14 g, 0.61 mmol, 1 eq) and hydrazide (0.61 mmol, 1 eq) were dissolved in 1-butanol (3 mL) in a 10 mL glass microwave tube. The vial was capped with a CEM corp. PL cap (SP1318A) and stirred in the cavity of a CEM Discover® Lab Mate reactor set at 200°C for 15 min (300 W, 250 psi). The contents of the tube were poured onto crushed ice/cold water (30 mL) and extracted with EtOAc ( mL). The combined organic layers were washed with brine (1 × 25 mL) and dried over MgSO₄. Removal of solvents under reduced pressure followed by silica gel chromatography (CH₂Cl₂, with 1–10% MeOH gradient) afforded the corresponding adduct 3.

A.1.2. General Procedure for Synthesis of 3 in Flow [20, 21]

Synthesis was performed using a ChemTrix Labtrix S1 flow chemistry reactor containing a T-mixer [14]. Syringe A was loaded with a 0.04 M solution of 5-chlorobenzo[b]pyrido[3,2-f][1,]oxazepine in -butanol and syringe B was loaded with a 0.04 M solution of corresponding hydrazide in -butanol. Syringes A and B were pumped through a 10 μL glass microreactor heated to 190°C with a combined flow rate of 4 μL/min. The output collected was poured over crushed ice/cold water (20 mL) and extracted with EtOAc ( mL). The combined organic layers were washed with brine (1 × 20 mL) and dried over MgSO₄. The solvents were removed under reduced pressure and the crude product was purified by silica gel chromatography (CH₂Cl₂, with 1–10% MeOH gradient).

A.2. 5-Chlorobenzo[b]pyrido[3,2-f][1,4]oxazepine

To a cooled solution of 2 (1.08 g, 5.08 mmol) in dry toluene (10 mL) POCl₃ was added (1.42 mL, 15.26 mmol) in a 50 mL round bottom flask under an atmosphere of argon followed by N,N-dimethylaniline (2.57 mL, 20.32 mmol). After refluxing for 2 h the mixture was concentrated under reduced pressure to remove excess POCl₃ and N,N-dimethylaniline. The resulting mixture was dissolved in THF (20 mL) and Na₂CO₃ (30 mL of a 2 M solution) and heated at 80°C. After 1 h the mixture was cooled to room temperature and THF was removed under reduced pressure. The resulting aqueous layer was extracted to EtOAc ( mL) and the combined organic layers were washed with brine ( mL), dried over MgSO₄, and concentrated in vacuo. The residue was purified using silica gel chromatography (5% MeOH in CH₂Cl₂) to afford 5-chlorobenzo[b]pyrido[3,2-f][1,]oxazepine as a light green solid (1.09 g, 93%). mp: 141.9–142.7°C; ¹H NMR: ppm 8.49 (dd, = 8, 5.2 Hz, 1H), 8.26 (d, = 7.2 Hz, 1H), 7.45 (dd, = 7.8, 4.8 Hz, 1H), 7.33 (d, = 7.2 Hz, 1H), 7.24–7.14 (m, 3H) ¹³C NMR: ppm 164.4, 162.2, 152.3, 148.0, 142.3, 130.5, 130.3, 126.3, 125.5, 122.4, 121.8, 119.9 MS (ESI+), C₁₂H₈ClN₂O (M + H)⁺ calcd: 231.03 obsd: 232.0.

A.2.1. Synthesis of 5 from Hydrazide 4

Compound 4 (0.615 mmol, 0.14 g) and 5-chlorobenzo[b]pyrido[3,2-f][1,]oxazepine (0.615 mmol, 0.14 g) were dissolved in 3 mL of n-BuOH in a 10 mL glass microwave vial and subjected to MW irradiation at 200°C for 15 min. The resulting mixture was concentrated in vacuo and purified by silica gel chromatography (1% MeOH in CH₂Cl₂) to afford 5 as a pale yellow solid (0.21 g, 87%). m.p. 140–143°C ¹H NMR: ppm 8.58 (dd, = 7.7, 1.8 Hz, 1H), 8.48 (dd, = 4.8, 1.8 Hz, 1H), 7.61 (d, = 8 Hz, 1H), 7.45–7.39 (m, 4H), 7.33–7.31 (m, 1H), 7.01 (t, = 7.7 Hz, 1H), 6.82 (d, = 8 Hz, 1H), 3.89 (s, 2H), 2.25 (s, 6H); ¹³C NMR: ppm 158.9, 158.3, 151.0, 133.6, 133.5, 132.0, 131.9, 131.6, 131.5, 131.2, 130.8, 130.3, 130.2, 130.1, 126.5, 124.6, 124.0, 122.9, 60.7, 45.4; HRMS (ESI+), C₂₂H₁₉ClN₅O (M + H)⁺ calc: 404.1278 obs: 404.1282.

A.3. Spectroscopic Data [See Supplemental Information for ¹³C Assignments]

See Supplemental Information for ¹³C assignments in Supplementary Material available online at https://doi.org/10.1155/2017/8147421.

3a (R=Ph): m.p. 246–247°C; ¹H NMR: ppm 8.59 (d, = 7.2 Hz, 1H), 8.48–8.47 (m, 1H), 7.96–7.95 (m, 1H), 7.64 (d, = 7.6 Hz, 2H), 7.53–7.45 (m, 3H), 7.40–7.38 (m, 2H), 7.05 (t, = 7.7 Hz, 1H), 6.87 (d, = 8 Hz, 1H); ¹³C NMR: ppm 161.6, 153.9, 151.0, 133.0, 131.0, 130.8, 130.3, 129.3, 129.2, 126.8, 126.4, 125.9, 124.4, 124.2, 122.9, 122.0, 118.6, 115.2, 114.9; HRMS (ESI+), C₁₉H₁₃N₄O (M + H)⁺ calc: 313.1089 obs: 313. 1092.

3b (R=o-ClC₆H₅): m.p. 241–244°C; ¹H NMR: ppm 8.57 (d, = 7.2 Hz, 1H), 8.48 (d, = 4.4 Hz, 1H), 7.77 (d, = 4.4 Hz, 1H), 7.62 (d, = 8.1 Hz, 1H), 7.52–7.34 (m, 5H), 7.00 (t, = 8 Hz, 1H), 6.74 (d, = 8 Hz, 1H); ¹³C NMR: ppm 162.0, 161.8, 151.1, 150.5, 150.3, 139.6, 134.2, 132.7, 132.3, 130.6, 130.3, 127.8, 127.6, 126.8, 126.5, 124.2, 123.5, 122.8, 115.3; HRMS (ESI+), C₁₉H₁₂ClN₄O (M + H)⁺ calc: 347.0700 obs: 347.0694.

3c (R=p-ClC₆H₅): m.p. 236–238°C; ¹H NMR: ppm 8.60 (d, = 7.2 Hz, 1H), 8.50 (d, = 4.4 Hz, 1H), 7.67 (d, = 8.1 Hz, 1H), 7.60 (d, = 8.8 Hz, 2H), 7.46–7.40 (m, 4H), 7.10 (t, = 7.7 Hz, 1H), 6.88 (d, = 8 Hz, 1H); ¹³C NMR: ppm 152.7, 151.1, 147.5, 146.2, 141.4, 139.8, 137.1, 136.4, 132.8, 130.5, 129.6, 126.5, 125.3, 124.3, 123.1, 116.3, 115.1; HRMS (ESI+), C₁₉H₁₂N₄ClO (M + H)⁺ calc: 347.0700 obs: 347.0706.

3e (R=pOHC₆H₅): m.p. 264-265°C; ¹H NMR: ppm 8.61 (d, = 7.3 Hz, 1H), 8.50 (d, = 4.4 Hz, 1H), 8.10 (d, = 8 Hz, 1H), 7.51 (d, = 8 Hz, 2H), 7.42 (d, = 8.1 Hz, 2H), 7.10 (t, = 7.2 Hz, 1H), 6.95–6.93 (m, 3H), 6.69 (bs, 1H); ¹³C NMR: ppm 202.6, 161.7, 161.3, 152.0, 151.6, 150.1, 141.0, 131.3, 131.2, 131.1, 130.85, 128.5, 126.5, 124.0, 123.9, 121.4, 116.5; HRMS (ESI+), C₁₉H₁₃N₄O₂ (M + H)⁺ calc: 329.1039 obs: 329.1038.

3f (R=mOCH₃C₆H₅): m.p. 255-256°C; ¹H NMR: ppm 8.54 (d, = 8 Hz, 1H), 8.43 (d, = 7.2 Hz, 1H), 7.61–7.59 (m, 1H), 7.37–7.32 (m, 3H), 7.19 (s, 1H), 7.10–7.08 (m, 1H), 7.05–6.98 (m, 2H), 6.92 (d, = 8 Hz, 1H), 3.75 (s, 3H); ¹³C NMR: ppm 161.6, 160.0, 154.3, 150.8, 150.4, 130.3, 130.2, 126.3, 125.9, 127.8, 127.5, 126.3, 125.9, 124.0, 122.9, 121.6, 117.0, 115.1, 114.2, 55.6; HRMS (ESI+), C₂₀H₁₅N₄O₂ (M + H)⁺ calc: 343.1195 obs: 343.1191.

3g (R=mpyridyl): m.p. 226-227°C; ¹H NMR: ppm 8.92 (s, 1H), 8.76 (d, = 3.2 Hz, 1H), 8.61 (dd, = 8, 2.4 Hz, 1H), 8.50 (dd, = 4.8, 1.8 Hz, 1H), 8.38 (dd, = 7.7, 1.8 Hz, 1H), 8.30-8.29 (m, 1H), 7.46–7.44 (m, 1H), 7.31 (dd, = 7.7, 4.8 Hz, 1H), 7.21–7.19 (m, 2H), 7.08–7.06 (m, 1H). ¹³C NMR: ppm 172.6, 167.2, 161.5, 161.1, 157.3, 150.4, 146.9, 146.4, 141.5, 128.5, 126.7, 125.3, 125.2, 123.9, 123.0, 122.3, 121.2, 119.8; HRMS (ESI+), C₁₈H₁₂N₅O (M + H)⁺ calc: 314.1042 obs: 314.1042.

3h (R=oFC₆H₅): m.p. 247–249°C; ¹H NMR: ppm 8.59 (d, = 7.2 Hz, 1H), 8.49-8.48 (m, 1H), 7.86 (t, = 7.2 Hz, 1H), 7.64-7.65 (m, 1H), 7.55 (d, = 5.1 Hz, 1H), 7.41–7.35 (m, 3H), 7.13–7.03 (m, 2H), 6.86 (d, = 8 Hz, 1H); ¹³C NMR: ppm 167.7, 156.7, 150.0, 143.7, 139.5, 137.6, 132.9, 131.8, 130.1, 126.4, 126.0, 125.1, 123.9, 123.4, 122.8, 116.6, 116.3, 115.7, 115.1; HRMS (ESI+), C₁₉H₁₂FN₄O (M + H)⁺ calc: 331.0995 obs: 331.0992.

3l (R=m-ClC₆H₅): m.p. 236-237°C ¹H NMR: ppm 8.59 (dd, = 7.7, 1.8 Hz, 1H), 8.49-8.48 (m, 1H), 7.73–7.75 (m, 1H), 7.68–7.66 (m, 1H), 7.49–7.46 (m, 3H), 7.37-7.36 (m, 2H), 7.13–7.09 (m, 1H), 6.89 (dd, = 7.8, 1.5 Hz, 1H); ¹³C NMR: ppm 151.2, 148.5, 142.7, 142.2, 132.9, 131.9, 130.9, 130.6, 130.4, 130.3, 129.3, 128.5, 127.3, 126.5, 125.7, 124.9, 124.3, 122.9, 118.9; HRMS (ESI+), C₁₉H₁₂ClN₄O (M + H)⁺ calc: 347.0700 obs: 347.0700.

10: yellow oil. ¹H NMR: ppm 8.57 (dd, = 7.7, 1.8 Hz, 1H), 8.48 (dd, = 4.8, 1.8 Hz, 1H), 7.79–7.77 (m, 1H), 7.63 (d, = 8 Hz, 1H), 7.04–7.02 (m, 1H), 6.87–6.85 (m, 1H), 3.87 (s, 2H), 2.25 (s, 6H); ¹³C NMR: ppm 159.9, 150.9, 149.2, 146.1, 135.6, 132.1, 131.9, 131.6, 126.6, 124.6, 123.9, 123.7, 115.3, 62.1, 46.4 HRMS (ESI+), C₁₆H₁₅ClN₅O (M + H)⁺ calc: 328.0965 obs: 328.0958.

12: m.p. 217–219°C; ¹H NMR: ppm 8.77–8.75 (m, 1H), 8.48–8.43 (m, 2H), 7.54 (d, = 8 Hz, 1H), 7.42–7.38 (m, 2H), 3.72 (s, 2H), 2.83–2.80 (m, 4H), 2.57–2.55 (m, 4H), 2.34 (s, 3H) ¹³C NMR: ppm 161.6, 151.6, 151.1, 150.1, 149.0, 139.9, 131.9, 129.9, 128.3, 126.1, 124.9, 123.0, 115.3, 55.1, 52.5, 51.7, 46.1; HRMS (ESI+), C₁₉H₂₀ClN₆O (M + H)⁺ calc: 383.1387 obs: 383.1391.

13: m.p 191–193°C; ¹H-NMR: δ 8.57–8.54 (m, 2H), 7.92 (dd, = 5.0, 0.8 Hz, 1H), 7.69 (d, = 8.8 Hz, 1H), 7.63–7.58 (m, 2H), 7.37 (dd, = 3.5, 0.7 Hz, 1H), 7.29 (d, = 2.4 Hz, 1H), 7.24 (dd, = 4.9, 3.8 Hz, 1H); ¹³C-NMR: δ 160.3, 151.3, 149.4, 148.7, 139.5, 130.4, 130.4, 130.0, 129.9, 128.2, 127.7, 126.4, 125.6, 124.8, 123.6, 123.6, 114.0. HRMS (ESI+), C₁₇H₉ClN₄OS (M + H)⁺ calc: 353.0263 obs: 353.0257.

14: m.p. 201–203°C; ¹H-NMR: δ 8.58–8.55 (m, 2H), 7.98 (d, = 1.1 Hz, 1H), 7.67 (d, = 8.8 Hz, 1H), 7.64–7.59 (m, 2H), 7.19 (dd, = 3.3, 0.5 Hz, 1H), 7.17 (d, = 2.5 Hz, 1H), 6.81 (dd, = 3.5, 1.8 Hz, 1H). ¹³C-NMR: δ 160.3, 151.3, 149.4, 148.3, 145.8, 140.0, 139.6, 130.3, 130.1, 127.7, 125.1, 124.6, 123.6, 119.8, 114.2, 113.9, 112.3. HRMS (ESI+), C₁₇H₉ClN₄O₂; (M + H)⁺ calc: 337.0492 obs: 337.0486.

15: m.p 221–223°C; ¹H-NMR: δ 8.58 (dd, = 7.6, 1.9 Hz, 1H), 8.46 (dd, = 4.8, 1.9 Hz, 1H), 7.57 (d, = 8.8 Hz, 1H), 7.43–7.38 (m, 3H), 7.33 (dd, = 8.7, 2.4 Hz, 1H), 6.98 (d, = 2.4 Hz, 1H), 6.73 (d, = 8.5 Hz, 2H), 4.07 (s, 2H). ¹³C-NMR: δ 161.0, 154.6, 150.7, 149.9, 149.0, 148.7, 139.6, 131.5, 130.4, 129.8, 128.8, 125.6, 125.0, 123.0, 115.2, 115.1, 115.0. HRMS (ESI+), C₁₉H₁₂ClN₅O (M + H)⁺ calc: 362.0809 obs: 362.0804.

16: m.p. 177–179°C; ¹H NMR: ppm 8.59 (dd, = 7.3, 1.5 Hz, 1H), 8.49 (dd, = 4.81, 1.8 Hz, 1H), 7.60–7.56 (m, 3H), 7.45 (d, = 8 Hz, 2H), 7.43–7.40 (m, 1H), 7.34 (dd, = 8.8, 2.9 Hz, 1H), 6.78 (d, = 2.2 Hz, 1H), 3.60 (s, 2H), 2.74–2.50 (m, 8H), 2.46 (s, 3H); ¹³C NMR: ppm 163.6, 153.5, 153.2, 145.2, 138.8, 136.3, 133.5, 133.2, 131.4, 131.1, 129.6, 128.9, 125.8, 125.3, 123.4, 122.9, 118.9, 62.3, 59.8, 54.7, 46.8; HRMS (ESI+), C₂₅H₂₄ClN₆O (M + H)⁺ calc: 459.1700 obs: 459.1701.

17: m.p. 241–243°C; ¹H NMR: ppm 8.57–8.62 (m, 1H), 8.45 (d, = 1.5 Hz, 1H), 8.38-8.37 (m, 1H), 7.97 (d, = 8.1 Hz, 1H), 7.73-7.72 (m, 1H), 7.65-7.64 (m, 1H), 7.59-7.58 (m, 1H), 7.49-7.48 (m, 1H), 7.17-7.16 (m, 1H), 7.01 (dd, = 8, 1.5 Hz, 1H), 6.86 (t, = 7.2 Hz, 1H); ¹³C NMR: ppm 157.9, 153.4, 152.6, 151.0, 150.6, 148.2, 140.3, 135.8, 133.4, 133.2, 132.4, 132.0, 131.4, 128.7, 127.3, 126.7, 125.7, 124.5, 114.8; HRMS (ESI+), C₁₉H₁₂N₅O₃ (M + H)⁺ calc: 358.0940 obs: 358.0949.

18: m.p. 251-252°C; ¹H NMR: ppm 8.57 (dd, = 7.2, 1.8 Hz, 1H), 8.37 (dd, = 8.2, 2 Hz, 1H), 7.87-7.86 (m, 1H), 7.66–7.63 (m, 1H), 7.52–7.49 (m, 1H), 7.46–7.44 (m, 2H), 7.32–7.29 (m, 1H), 7.21–7.18 (m, 2H), 6.90–6.88 (m, 1H); ¹³C NMR: ppm 167.2, 165.2, 163.3, 160.9, 153.0, 148.6, 143.1, 138.0, 131.5, 131.0, 129.6, 127.2. 127.1, 126.3, 125.4, 124.3, 122.5, 121.0, 120.8; HRMS (ESI+), C₁₉H₁₂FN₄O (M + H)⁺ calc: 331.0995 obs: 331.0992.

Conflicts of Interest

The authors report no conflicts of interest.

Acknowledgments

Graham B. Jones acknowledges financial support from the National Institutes of Health (UL1TR001064).

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