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Article

Synthesis of 1-Amino-3-oxo-2,7-naphthyridines via Smiles Rearrangement: A New Approach in the Field of Chemistry of Heterocyclic Compounds

by
Samvel N. Sirakanyan
1,*,
Domenico Spinelli
2,*,
Athina Geronikaki
3,
Luca Zuppiroli
4,
Riccardo Zuppiroli
4,
Victor G. Kartsev
5,
Elmira K. Hakobyan
1,
Hasmik A. Yegoryan
1 and
Anush A. Hovakimyan
1
1
Scientific Technological Center of Organic and Pharmaceutical Chemistry of National Academy of Science of Republic of Armenia, Institute of Fine Organic Chemistry of A.L.Mnjoyan, Ave. Azatutyan 26, Yerevan 0014, Armenia
2
Dipartimento di Chimica G. Ciamician, Alma Mater Studiorum-Università di Bologna, Via F. Selmi 2, 40126 Bologna, Italy
3
School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
4
Department of Industrial Chemistry ‘Toso Montanari’, Alma Mater Studiorum-Università di Bologna, Viale del Risorgimento 4, 40136 Bologna, Italy
5
InterBioScreen, 119019 Moscow, Russia
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(11), 5904; https://doi.org/10.3390/ijms23115904
Submission received: 13 April 2022 / Revised: 17 May 2022 / Accepted: 19 May 2022 / Published: 25 May 2022
(This article belongs to the Collection Feature Papers in 'Physical Chemistry and Chemical Physics')
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Abstract

:
In this paper we describe an efficient method for the synthesis of new heterocyclic systems: furo[2,3-c]-2,7-naphthyridines 6, as well as a new method for the preparation of 1,3-diamino-2,7-naphthyridines 11. For the first time, a Smiles rearrangement was carried out in the 2,7-naphthyridine series, thus gaining the opportunity to synthesize 1-amino-3-oxo-2,7-naphthyridines 4, which are the starting compounds for obtaining furo[2,3-c]-2,7-naphthyridines. The cyclization of alkoxyacetamides 9 proceeds via two different processes: the expected formation of furo[2,3-c]-2,7-naphthyridines 10 and the ‘unexpected’ formation of 1,3-diamino-2,7-naphthyridines 11 (via a Smiles type rearrangement).

1. Introduction

2,7-Naphthyridine derivatives are interesting compounds in the field of heterocyclic chemistry due to some of their interesting biological activities, as evidenced by recent reviews [1,2,3]. Literature data shows that some 2,7-naphthyridine derivatives are potent and selective 3-phosphoinositide-dependent Kinase-1 [4], PDE5 [5], c-Kit/VEGFR-2 Kinase [6] inhibitors, while pyrazolo[3,4-c]-2,7-naphthyridines are bombesin receptor subtype-(3BRS-3) agonists [7].
Moreover, the literature has reported patents on the biological activity of 1-oxo-2,7-naphthyridines, showing that some derivatives of the latter are physiologically active compounds and provide anti-inflammatory and analgesic action and can be used as therapeutic agents for treatment of inflammatory immune diseases and chronic inflammations [8,9].
In our previous investigations on 2,7-naphthyridine derivatives, we have been able to synthesize some tricyclic heterocyclic systems, namely: isomeric 1,2,4-triazolo-2,7-naphthyridines I [10,11], pyrazolo[3,4-c]-2,7-naphthyridines II [12,13,14] and thieno[2,3-c]-2,7-naphthyridines III [15,16] as well as new heterocyclic systems based on these systems [13,14,15,16] (Figure 1).
Some of these investigations revealed that bicyclic 1,3-dihydroxy-2,7-naphthyridines can show antiarrhythmic activity [17], while tricyclic pyrazolo[3,4-c]-2,7-naphthyridines and triazolo[3,4-a]- as some triazolo[5,1-a]-2,7-naphthyridines displayed high neurotropic activity [10,12].
Furthermore, it is well known that fused derivatives of furo[2,3-b]pyridine show high biological activity [18,19,20,21,22,23,24]. Along this line we have previously synthesized several condensed furo[2,3-b]pyridines based on the cyclopenta[c]pyridines, 5,6,7,8-tetrahydroisoquinolines and pyrano[3,4-c]pyridines, obtaining compounds with neurotropic [25,26], antimicrobial [27], antitumor [28] and potent antiviral [29] activities.
Taking into account the abovementioned results, that are very interesting from both the chemical and the biological point of view, we think that it would be useful to combine these two heterocyclic systems into one molecule (Figure 1, compounds IV), as a ‘nice’ precondition for further interesting research. Until recently all our attempts to synthesize furo[2,3-c]-2,7-naphthyridines IV have failed and it is only in this study that we have been able to solve this problem by using the Smiles rearrangement. It should also be noted, that the furo[2,3-c]-2,7-naphthyridine IV system is currently not known in the literature.

2. Results and Discussion

For the synthesis of the targeted compounds we used, as a starting compound, 1,3-dichloro-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile (1) [16]. Its reaction with cyclic amines (pyrrolidine and azepane), in mild reaction conditions led to the formation of 1-amino-3-chloro-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridines 2a,b [16]. In turn, compounds 2a,b reacted with 2-mercaptoethanol giving the corresponding 1-amino-3-[(2-hydroxyethyl)thio]-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitriles 3a,b (Scheme 1) in high yields.
In a following step, compounds 3 under the action of sodium hydroxide in ethanol underwent a Smiles rearrangement [30,31,32] leading to the formation of 1-amino-7-isopropyl-3-oxo-2,3,5,6,7,8-hexahydro-2,7-naphthyridine-4-carbonitriles 4a,b in quite high yields (Scheme 1).
In compounds 4 a lactam–lactim (NH/OH) tautomerism is possible, via the proton-migration of a hydrogen atom between the two basic centers. The IR spectroscopic data strongly show that 1-amino-3-oxo-2,7-naphthyridines 4a,b in the solid state exist only in the lactam 4 (NH) tautomeric form: showing carbonyl group absorptions at 1636–1638 cm−1, nitrile groups at 2208–2210 cm−1, and NH in the region 3222–3226 cm−1. Interestingly, in solution the situation changes, as confirmed by NMR spectra, where the presence of the proton of NH group at 10.53–10.86 ppm was observed (see Supplementary Materials). Moreover, by further alkylation of 1-amino-3-oxo-2,7-naphthyridines 4a,b in basic conditions, the corresponding O-alkylated derivatives were obtained in high yields (Schemes 3 and 4).
It should be mentioned that the literature reports similar S→O [33,34,35] and S→N [36,37,38,39] type Smiles rearrangement. The possible mechanism of formation of compounds 4 is presented in Scheme 2. It is known that the cleavage product—thiirane—is formed in the reaction mixture and may polymerize under the basic conditions [33,34].
Then, for the synthesis of the targeted new heterocyclic systems, furo[2,3-c]-2,7-naphthyridines 7 (X = O), the obtained 3-oxo-2,7-naphthyridines 4a,b were alkylated by ethyl chloroacetate in basic conditions. The synthesized O-alkylated compounds 5a,b underwent cyclization in the presence of sodium ethoxide giving the fused furo[2,3-c]-2,7-naphthyridines 7a,b (Scheme 3).
A further confirmation of the structure of furo[2,3-c]-2,7-naphthyridines 7 is given by the fact that the S-alkylated compounds 6 gave the corresponding thieno[2,3-c]-2,7-naphthyridines 8. In fact, in a first step 3-chloro-2,7-naphthyridines 2a,b were alkylated with ethyl 2-mercaptoacetate and then the obtained intermediate S-alkylated derivatives 6a,b were cyclized into the relevant thieno[2,3-c]-2,7-naphthyridines 8a,b (Scheme 3).
The structure of compounds 7 and 8 were confirmed by NMR, IR and MS spectroscopy and by elemental analysis (see Supplementary Materials).
In addition, it was interesting to compare the physico-chemical properties of these two classes of compounds. Thus, furo[2,3-c]-2,7-naphthyridines 7 have a very higher solubility and lower melting point compared with thieno[2,3-c]-2,7-naphthyridines 8. Moreover, compounds 7 and 8 showed different 1H NMR data: the singlet signal of the NH2 group in compounds 7a,b were observed at 5.58 and 5.62 ppm, while in 8a,b the same proton signal was shifted to a weaker field at 6.47 and 6.50 ppm. Signals of the remaining protons of these compounds differ slightly between themselves (Figure 2).
In order to increase the scope of furo[2,3-c]-2,7-naphthyridines, the obtained 3-oxo-2,7-naphthyridines 4 were alkylated by various other alkyl halides under basic conditions. The corresponding O-alkylated derivatives of 2,7-naphthyridine 9a–p were obtained in high yields (75–89%, Scheme 4, Table 1). In the 1H NMR spectra of compounds 9a–p the singlet signals of the OCH2CO and NH groups were present at 4.69–4.92 ppm and 8.04–10.13 ppm, respectively (see Supplementary Materials). The IR spectra also confirmed their structures, namely that they showed the absorption bands of nitrile group at 2201–2208 cm−1, of carbonyl group at 1662–1698 cm−1, and of NH group at 3166–3352 cm−1.
Moreover, to gain another way for obtaining the furo[2,3-c]-2,7-naphthyridines 7, we refluxed the alkoxyacetamides 9 with sodium ethoxide in ethanol, following a route of reaction similar to that reported in Scheme 3 for compounds 7. Indeed, in this instance, different courses for the reaction were observed, depending on the structure of compounds 9 (Scheme 4).
Thus, it was observed that amides deriving from cyclic (pyrrolidine and piperidine) 9a,b,h or from aromatic amines 9c–g,i–l gave only the expected aminoamides of furo[2,3-c]-2,7-naphthyridine 10a–l in very good yields (70–83%). Therefore, it seems that in these cases only the activated CH2 group, which by the action of sodium ethoxide gave the relevant nucleophile CH−, was able to attack the nitrile group with formation of the condensed furan derivatives 10, via an intramolecular nucleophilic addition (ANi).
In contrast, the amides deriving from non-aromatic primary amines 9m–o (benzylamine or 2-furylmethylamine) furnished only the 1,3-diamino-2,7-naphthyridines 11a–c again in good yields (71–74%). Thus, in these cases a Smiles type rearrangement occurred. Finally it must be remarked that in the instance of compound 9p with primary amine [(1-methyl-2-phenylethyl)amine] no reaction occurred. This can be explained by the fact that, as is known, Smiles type rearrangements take place through the formation of a spiro-intermediate oxazolidinone ring (that is, a ‘Meisenheimer’ complex), the formation of which in this case is impossible due to the presence of the methyl near the NH group.
Such O→N Smiles type rearrangement was deeply investigated by us in the case of cycloalka[c]pyridine and pyrano[3,4-c]pyridine systems [40].
Concerning the structure of furo[2,3-c]-2,7-naphthyridines 10a–l and of 1,3-diamino-2,7-naphthyridines 11a–c, the first and most important information about their structure was given by IR spectra. In fact, the IR of the furo[2,3-c]-2,7-naphthyridines 10 showed the bands of the carbonyl group of the amide (1616–1654 cm−1) as well as of the NH2 group (3271–3488 cm−1), while the absorption bands of the nitrile group, characteristic of the initial compounds 9 and also confirmed by the 13C NMR spectrum, disappeared. Further, in the 1H NMR spectra of compounds 10a–l the protons of the NH2 group at C-1 were observed at 5.61–5.83 ppm, whereas the signals of the OCH2CO group of starting 9a–l were absent (see Supplementary Materials).
The IR spectra of compounds 11 still showed the characteristic absorption bands of nitrile group at 2186–2199 cm−1, thus indicating that the cyclization process did not occur, as confirmed also by the 13C NMR spectrum. In the 1H NMR spectra of compounds 11 the protons of the NH group at 6.40–6.60 ppm were observed, while the signals of the OCH2CO group were absent. The 13C NMR spectra also confirmed their structure (see Supplementary Materials).
The structure of compounds 10 and 11 was confirmed also by the MS spectroscopy.
Finally to gain a definitive confirmation of the structures of compounds 11, their synthesis from the 3-chloro-2,7-naphthyridines 2a,b was performed (Scheme 4).
It must be remembered, that the observed Smiles type rearrangement represents a new and effective method for the synthesis of 1,3-diamino-2,7-naphthyridines 11.

3. Materials and Methods

1H and 13C NMR spectra were recorded in DMSO-d6/CCl4 (1/3) solution (300 MHz for 1H and 75 MHz for 13C, respectively) on a Mercury 300VX spectrometer (Varian Inc., Palo Alto, CA, USA). Chemical shifts were reported as δ (parts per million) relative to TMS as internal standard. The IR spectra were recorded on a Nicolet Avatar 330-FT-IR spectrophotometer (Thermo Nicolet, Madison, CA, USA) in Vaseline, νmax in cm–1. MS spectra were recorded on Waters Q-Tof (Waters, Manchester, UK). Melting points were determined on an MP450 melting point apparatus. Elemental analyses were performed on an Elemental Analyzer Euro EA 3000. Compounds 1 [16] and 2a [16] have already been described.

3.1. Procedure for the Synthesis of Compound 2b

A mixture of compound 1 (2.70 g, 10 mmol), of hexamethyleneimine (1.24 mL, 11 mmol) and of triethylamine (1.53 mL, 11 mmol) in absolute ethanol (50 mL) was refluxed for 5 h. After cooling, water (50 mL) was added and the resulting crystals were filtered off, washed with water, dried, and recrystallized from ethanol.
1-Azepan-1-yl-3-chloro-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile (2b). Colorless solid; yield 87%, mp 137–139 °C; IR ν/cm–1: 2210 (C≡N). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.09 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.56–1.65 (m, 4H, C6H12N), 1.77–1.86 (m, 4H, C6H12N), 2.70–2.78 (m, 2H, NCH2CH2), 2.82–2.92 (m, 3H, NCH2CH2, CH(CH3)2), 3.43 (br s, 2H, NCH2), 3.56–3.62 (m, 4H, N(CH2)2); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.02, 26.25, 27.86, 29.31, 44.00, 49.42, 50.96, 53.28, 97.62, 114.45, 116.65, 147.36, 150.09, 159.13. Anal. calcd. for C18H25ClN4: C 64.95; H 7.57; N 16.83%. Found: C 65.33; H 7.77; N 17.09%.

3.2. General Procedure for the Synthesis of Compounds 3a,b

To a stirred suspension of compound 2 (10 mmol) and potassium carbonate (2.76 g, 20 mmol) in absolute DMF (50 mL) the 2-mercaptoethanol (0.84 mL, 12 mmol) was added and the reaction mixture was stirred at 85–100 °C for 15 h. Cooling water was then added (50 mL). The resulting crystals were filtered off, washed with water, dried and recrystallized from ethanol.
3-[(2-Hydroxyethyl)thio]-7-isopropyl-1-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile (3a). Yellow solid; yield 77%, mp 131–133 °C; IR ν/cm–1: 3143 (OH), 2202 (C≡N). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.08 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.92–1.98 (m, 4H, C4H8N), 2.66–2.71 (m, 2H, NCH2CH2), 2.74–2.80 (m, 2H, NCH2CH2), 2.87 (sp, J = 6.5 Hz, 1H, CH(CH3)2), 3.22 (t, J = 6.8 Hz, 2H, SCH2), 3.54 (s, 2H, NCH2), 3.60 (q, J = 6.7 Hz, 2H, SCH2CH2), 3.61–3.67 (m, 4H, N(CH2)2), 4.55 (t, J = 5.7 Hz, 1H, OH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.03, 24.99, 28.75, 31.56, 44.03, 48.61, 49.38, 53.35, 60.28, 73.52, 112.39, 115.56, 147.53, 156.63, 157.25. Anal. calcd. for C18H26N4OS: C 62.39; H 7.56; N 16.17%. Found: C 62.72; H 7.73; N 16.39%.
1-Azepan-1-yl-3-[(2-hydroxyethyl)thio]-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile (3b). Light yellow solid; yield 74%, mp 151–153 °C; IR ν/cm–1: 3125 (OH), 2202 (C≡N). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.07 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.56–1.65 (m, 4H, C6H12N), 1.77–1.87 (m, 4H, C6H12N), 2.67–2.73 (m, 2H, NCH2CH2), 2.77–2.95 (m, 3H, NCH2CH2, CH(CH3)2), 3.23 (t, J = 6.8 Hz, 2H, SCH2), 3.39 (br s, 2H, NCH2), 3.56–3.64 (m, 6H, SCH2CH2, N(CH2)2), 4.57 (t, J = 5.6 Hz, 1H, OH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.11, 26.44, 28.18, 28.91, 31.59, 44.33, 49.53, 50.72, 53.32, 60.23, 77.02, 113.66, 115.36, 148.42, 156.84, 158.98. Anal. calcd. for C20H30N4OS: C 64.13; H 8.07; N 14.96%. Found: C 64.48; H 8.26; N 15.20%.

3.3. General Procedure for the Synthesis of Compounds 4a,b

Aqueous solution of sodium hydroxide (50%, 8 g, 100 mmol) was added to a solution of compound 3 (10 mmol) in absolute ethanol (50 mL) and the mixture was refluxed for 15 h. After cooling, the water was added and the mixture was filtered off to remove white precipitate of the thiirane polymer. The filtrate was neutralized with HCl and the formed crystals of compound 4 were filtered off, washed with water and recrystallized from ethanol.
7-Isopropyl-3-oxo-1-pyrrolidin-1-yl-2,3,5,6,7,8-hexahydro-2,7-naphthyridine-4-carbonitrile (4a). Yellow solid; yield 79%, mp 222–223 °C; IR ν/cm–1: 3226 (NH), 2208 (C≡N), 1638 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.07 (d, J = 6.6 Hz, 6H, CH(CH3)2), 1.91–1.97 (m, 4H, 2CH2, C6H12N), 2.62–2.68 (m, 2H, NCH2CH2), 2.72–2.78 (m, 2H, NCH2CH2), 2.82 (sp, J = 6.6 Hz, 1H, CH(CH3)2), 3.46 (s, 2H, NCH2), 3.53–3.60 (m, 4H, N(CH2)2), 10.53 (br, 1H, NH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.07, 24.99, 29.19, 44.05, 48.62, 49.67, 53.37, 82.23, 105.16, 116.38, 151.57, 155.06, 161.14. Anal. calcd. for C16H22N4O: C 67.11; H 7.74; N 19.56%. Found: C 67.42; H 7.89; N 19.77%. ESI HRMS [C16H22O1N4+H+] Calculated: 287.1871. Found: 287.1873.
1-Azepan-1-yl-7-isopropyl-3-oxo-2,3,5,6,7,8-hexahydro-2,7-naphthyridine-4-carbonitrile (4b). Cream solid; yield 81%, mp 208–210 °C; IR ν/cm–1: 3222 (NH), 2210 (C≡N), 1636 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.08 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.58–1.66 (m, 4H, C6H12N), 1.74–1.83 (m, 4H, C6H12N), 2.66–2.72 (m, 2H, NCH2CH2), 2.77–2.99 (m, 3H, NCH2CH2, CH(CH3)2), 3.34 (s, 2H, NCH2), 3.45–3.51 (m, 4H, N(CH2)2), 10.86 (br, 1H, NH). 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.10, 26.48, 28.09, 29.08, 44.46, 48.98, 51.19, 53.34, 108.45, 115.78, 151.71, 158.23, 161.10. Anal. calcd. for C18H26N4O: C 68.76; H 8.33; N 17.82%. Found: C 69.13; H 8.51; N 18.07%. ESI HRMS C18H26O1N4+H+] Calculated: 315.2184. Found: 315.2186.

3.4. General Procedure for the Synthesis of Compounds 5a,b and 6a,b

To a suspension of compound 4/2 (10 mmol) and potassium carbonate (2.76 g, 20 mmol) in absolute DMF (50 mL) ethyl chloroacetate (1.28 mL, 12 mmol) or ethyl 2-mercaptoacetate (1.32 mL, 12 mmol) was added dropwise under stirring. The reaction mixture was maintained at 75–80 °C for 3 h, then cooled to room temperature, and poured onto ice water. The resulting crystals were filtered off, washed with water, dried, and recrystallized from ethanol.
Ethyl [(4-cyano-7-isopropyl-1-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)oxy]acetate (5a). Light yellow solid; yield 73%, mp 98–100 °C; IR ν/cm–1: 2205 (C≡N), 1747 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.09 (d, J = 6.4 Hz, 6H, CH(CH3)2), 1.26 (t, J = 7.1 Hz, 3H, CH2CH3), 1.89–1.95 (m, 4H, C4H8N), 2.64–2.74 (m, 2H, NCH2CH2), 2.78–2.91 (m, 3H, NCH2CH2, CH(CH3)2), 3.52–3.60 (m, 6H, N(CH2)2, NCH2), 4.16 (q, J = 7.1 Hz, 2H, CH2CH3), 4.78 (s, 2H, OCH2); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 13.76, 18.02, 24.90, 28.98, 43.92, 48.58, 49.17, 53.35, 59.83, 61.91, 81.35, 110.13, 114.84, 149.78, 156.21, 159.80, 167.50. Anal. calcd. for C20H28N4O3: C 64.49; H 7.58; N 15.04%. Found: C 64.83; H 7.74; N 15.28%.
Ethyl [(1-azepan-1-yl-4-cyano-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)oxy]acetate (5b). Light yellow solid; yield 83%, mp 102–104 °C; IR ν/cm–1: 2204 (C≡N), 1745 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.08 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.26 (t, J = 7.1 Hz, 3H, CH2CH3), 1.53–1.61 (m, 4H, C6H12N), 1.72–1.81 (m, 4H, C6H12N), 2.71 (t, J = 5.9 Hz, 2H, NCH2CH2), 2.79–2.89 (m, 3H, NCH2CH2, CH(CH3)2), 3.40 (s, 2H, NCH2), 3.49–3.54 (m, 4H, N(CH2)2), 4.15 (q, J = 7.1 Hz, 2H, CH2CH3), 4.81 (s, 2H, OCH2); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 13.71, 18.10, 26.22, 28.06, 29.16, 44.17, 49.56, 50.67, 53.32, 59.92, 61.77, 82.87, 111.35, 114.61, 150.70, 158.27, 159.41, 167.42. Anal. calcd. for C22H32N4O3: C 65.97; H 8.05; N 13.99%. Found: C 66.36; H 8.25; N 14.26%.
Ethyl [(4-cyano-7-isopropyl-1-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)thio]acetate (6a). Yellow solid; yield 76%, mp 114–116 °C; IR ν/cm–1: 2198 (C≡N), 1737 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.08 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.26 (t, J = 7.1 Hz, 3H, CH2CH3), 1.92–1.98 (m, 4H, C4H8N), 2.70 (t, J = 5.9 Hz, 2H, NCH2CH2), 2.76–2.92 (m, 3H, NCH2CH2, CH(CH3)2), 3.55 (s, 2H, NCH2), 3.58–3.64 (m, 4H, N(CH2)2), 3.91 (s, 2H, SCH2), 4.12 (q, J = 7.1 Hz, 2H, CH2CH3); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 13.67, 18.00, 24.91, 28.74, 29.17, 31.11, 43.90, 48.60, 49.32, 49.59, 53.32, 60.36, 93.60, 112.88, 115.21, 147.61, 155.69, 156.62, 167.82. Anal. calcd. for C20H28N4O2S: C 61.83; H 7.26; N 14.42%. Found: C 62.15; H 7.43; N 14.65%.
Ethyl [(1-azepan-1-yl-4-cyano-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)thio]acetate (6b). Light yellow solid; yield 74%, mp 103–105 °C; IR ν/cm–1: 2198 (C≡N), 1749 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.08 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.26 (t, J = 7.1 Hz, 3H, CH2CH3), 1.58–1.63 (m, 4H, C6H12N), 1.76–1.85 (m, 4H, C6H12N), 2.71 (t, J = 5.9 Hz, 2H, NCH2CH2), 2.80–2.88 (m, 3H, NCH2CH2, CH(CH3)2), 3.40 (s, 2H, NCH2), 3.54–3.59 (m, 4H, N(CH2)2), 3.94 (s, 2H, SCH2), 4.12 (q, J = 7.1 Hz, 2H, CH2CH3); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 13.67, 18.08, 26.44, 28.11, 28.90, 30.97, 44.21, 49.53, 50.64, 53.30, 60.40, 60.43, 95.02, 114.28, 114.97, 148.60, 155.16, 159.07, 167.71. Anal. calcd. for C22H32N4O2S: C 63.43; H 7.74; N 13.45%. Found: C 63.83; H 7.95; N 13.73%.

3.5. General Procedure for the Synthesis of Compounds 7a,b and 8a,b

To a solution of sodium ethoxide [0.25 g (11 mmol) in absolute ethanol (30 mL)] was added compound 5/6 (10 mmol). The mixture was refluxed for 1 h, cooled, and poured onto ice. The formed crystals were filtered off, washed with water, dried, and recrystallized from ethanol.
Ethyl 1-amino-7-isopropyl-5-pyrrolidin-1-yl-6,7,8,9-tetrahydrofuro[2,3-c]-2,7-naphthyridine-2-carboxylate (7a). Cream solid; yield 71%, mp 138–140 °C; IR ν/cm–1: 3503, 3381 (NH2), 1663 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.12 (d, J = 6.3 Hz, 6H, CH(CH3)2), 1.38 (t, J = 7.1 Hz, 3H, CH2CH3), 1.92–1.98 (m, 4H, C4H8N), 2.75–2.95 (m, 3H, NCH2CH2, CH(CH3)2), 3.15–3.22 (m, 2H, NCH2CH2), 3.49–3.56 (m, 4H, N(CH2)2), 3.57 (s, 2H, NCH2), 4.27 (q, J = 7.1 Hz, 2H, CH2CH3), 5.58 (s, 2H, NH2); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 14.25, 17.85, 25.05, 26.50, 44.12, 48.81, 49.65, 53.90, 58.34, 102.45, 104.47, 119.98, 140.71, 140.96, 157.62, 157.73, 160.25. Anal. calcd. for C20H28N4O3: C 64.49; H 7.58; N 15.04%. Found: C 64.85; H 7.76; N 15.29%. ESI HRMS [C20H28O3N4+H+] Calculated: 373.2239. Found: 373.2241.
Ethyl 1-amino-5-azepan-1-yl-7-isopropyl-6,7,8,9-tetrahydrofuro[2,3-c]-2,7-naphthyridine-2-carboxylate (7b). Yellow solid; yield 69%, mp 147–149 °C; IR ν/cm–1: 3456, 3362 (NH2), 1676 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.11 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.38 (t, J = 7.1 Hz, 3H, CH2CH3), 1.63–1.69 (m, 4H, C6H12N), 1.78–1.86 (m, 4H, C6H12N), 2.77 (t, J = 5.8 Hz, 2H, NCH2CH2), 2.87 (sp, J = 6.5 Hz, 1H, CH(CH3)2), 3.20 (t, J = 5.5 Hz, 2H, NCH2CH2), 3.44 (s, 2H, NCH2), 3.44–3.48 (m, 4H, N(CH2)2), 4.28 (q, J = 7.1 Hz, 2H, CH2CH3), 5.62 (s, 2H, NH2); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 14.24, 18.15, 26.37, 27.18, 28.35, 44.66, 49.61, 51.84, 53.41, 58.42, 103.95, 116.16, 120.36, 140.50, 141.89, 157.11, 160.32, 160.39. Anal. calcd. for C22H32N4O3: C 65.97; H 8.05; N 13.99%. Found: C 66.28; H 8.20; N 14.21%.
Ethyl 1-amino-7-isopropyl-5-pyrrolidin-1-yl-6,7,8,9-tetrahydrothieno[2,3-c]-2,7-naphthyridine-2-carboxylate (8a). Light yellow solid; yield 90%, mp 180–182 °C; IR ν/cm–1: 3441, 3335 (NH2), 1655 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.11 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.36 (t, J = 7.1 Hz, 3H, CH2CH3), 1.92–1.98 (m, 4H, C4H8N), 2.75 (t, J = 5.8 Hz, 2H, NCH2CH2), 2.86 (sp, J = 6.5 Hz, 1H, CH(CH3)2), 3.26 (t, J = 5.9 Hz, 2H, NCH2CH2), 3.50–3.57 (m, 4H, N(CH2)2), 3.52 (s, 2H, NCH2), 4.24 (q, J = 7.1 Hz, 2H, CH2CH3), 6.47 (s, 2H, NH2); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 14.19, 18.17, 25.04, 27.63, 44.65, 49.57, 49.63, 53.35, 58.59, 90.91, 115.58, 115.98, 141.69, 150.50, 157.94, 157.98, 164.62. Anal. calcd. for C20H28N4O2S: C 61.83; H 7.26; N 14.42%. Found: C 62.18; H 7.43; N 14.66%. ESI HRMS [C20H28O2N4S1+H+] Calculated: 389.2011. Found: 389.2013.
Ethyl 1-amino-5-azepan-1-yl-7-isopropyl-6,7,8,9-tetrahydrothieno[2,3-c]-2,7-naphthyridine-2-carboxylate (8b). Light yellow solid; yield 89%, mp 162–164 °C; IR ν/cm–1: 3473, 3340 (NH2), 1659 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.12 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.36 (t, J = 7.1 Hz, 3H, CH2CH3), 1.65–1.72 (m, 4H, C6H12N), 1.77–1.86 (m, 4H, C6H12N), 2.77 (t, J = 5.8 Hz, 2H, NCH2CH2), 2.86 (sp, J = 6.5 Hz, 1H, CH(CH3)2), 3.29 (t, J = 5.6 Hz, 2H, NCH2CH2), 3.44 (s, 2H, NCH2), 3.43–3.49 (m, 4H, N(CH2)2), 4.25 (q, J = 7.1 Hz, 2H, CH2CH3), 6.50 (s, 2H, NH2); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 14.17, 18.19, 26.44, 26.50, 27.63, 28.43, 28.48, 45.04, 49.63, 52.01, 53.32, 58.72, 91.93, 117.18, 117.79, 142.25, 150.25, 157.39, 160.98, 164.62. Anal. calcd. for C22H32N4O2S: C 63.43; H 7.74; N 13.45%. Found: C 63.82; H 7.94; N 13.73%.

3.6. General Procedure for the Synthesis of Compounds 9a–p

To a stirred suspension of compound 4 (1 mmol) and potassium carbonate (0.28 g, 2 mmol) in absolute DMF (25 mL) the corresponding alkyl chloride (1.2 mmol) was added. The reaction mixture was maintained at 75–80 °C for 3 h. Then the reaction mixture was cooled at room temperature, and water was added (50 mL). The resulting crystals were filtered off, washed with water, dried and recrystallized from ethanol.
7-Isopropyl-3-(2-oxo-2-pyrrolidin-1-ylethoxy)-1-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile (9a). Milky solid; yield 75%, mp 178–180 °C; IR ν/cm–1: 2202 (C≡N), 1665 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.10 (d, J = 6.0 Hz, 6H, CH(CH3)2), 1.79–2.04 (m, 8H, 4CH2, C4H8N), 2.64–2.95 (m, 5H, NCH2CH2, CH(CH3)2), 3.37 (t, J = 6.8 Hz, 2H, NCH2), 3.50 (t, J = 6.8 Hz, 2H, NCH2), 3.53–3.60 (m, 6H, C4H8N, 8-CH2), 4.82 (s, 2H, OCH2); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 17.97, 23.31, 24.91, 25.70, 28.90, 43.93, 44.72, 45.21, 48.48, 48.50, 49.08, 53.43, 63.41, 81.21, 115.11, 149.5, 156.24, 160.13, 164.79. Anal. calcd. for C22H31N5O2: C 66.47; H 7.86; N 17.62%. Found: C 66.80; H 8.02; N 17.87%.
7-Isopropyl-3-(2-oxo-2-piperidin-1-ylethoxy)-1-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile (9b). Colorless solid; yield 80%, mp 164–166 °C; IR ν/cm–1: 2201 (C≡N), 1671 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.09 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.46–1.71 (m, 6H, C5H10N), 1.90–1.95 (m, 4H, C4H8N), 2.66–2.91 (m, 5H, NCH2CH2, CH(CH3)2), 3.40–3.47 (m, 2H, NCH2), 3.54–3.61 (m, 8H, 2N(CH2)2, C4H8N, C5H10N), 4.92 (s, 2H, OCH2); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.02, 23.96, 24.91, 24.99, 25.02, 25.76, 28.92, 41.98, 42.02, 43.98, 44.88, 44.90, 48.54, 49.20, 53.39, 63.11, 81.33, 109.66, 115.12, 149.51, 156.27, 160.15, 164.45. Anal. calcd. for C23H33N5O2: C 67.12; H 8.08; N 17.02%. Found: C 67.49; H 8.27; N 17.29%.
2-[(4-Cyano-7-isopropyl-1-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)oxy]-N-phenylacetamide (9c). Cream solid; yield 78%, mp 227–229 °C; IR ν/cm–1: 3251 (NH), 2208 (C≡N), 1686 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.07 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.79–1.88 (m, 4H, C4H8N), 2.68 (t, J = 5.7 Hz, 2H, NCH2CH2), 2.79–2.93 (m, 3H, NCH2CH2, CH(CH3)2), 3.51–3.58 (m, 6H, NCH2, N(CH2)2), 4.80 (s, 2H, OCH2), 6.95–7.02 (m, 1H, Ph), 7.19–7.26 (m, 2H, Ph), 7.54–7.59 (m, 2H, Ph), 9.68 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.03, 24.86, 28.98, 44.00, 48.56, 49.26, 53.37, 64.50, 81.23, 109.88, 115.35, 119.00, 122.60, 127.90, 138.37, 149.48, 156.37, 160.14, 165.62. Anal. calcd. for C24H29N5O2: C 68.71; H 6.97; N 16.69%. Found: C 69.03; H 7.12; N 16.92%.
2-[(4-Cyano-7-isopropyl-1-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)oxy]-N-(3-methylphenyl)acetamide (9d). Colorless solid; yield 83%, mp 222–224 °C; IR ν/cm–1: 3235, 3184 (NH), 2205 (C≡N), 1683 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.08 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.81–1.88 (m, 4H, C4H8N), 2.31 (s, 3H, CH3), 2.67–2.72 (m, 2H, NCH2CH2), 2.81–2.93 (m, 3H, NCH2CH2, CH(CH3)2), 3.52–3.59 (m, 6H, NCH2, N(CH2)2), 4.79 (s, 2H, OCH2), 6.75–6.81 (m, 1H, C6H4), 7.06–7.15 (m, 1H, C6H4), 7.30–7.35 (m, 1H, C6H4), 7.39–7.41 (m, 1H, C6H4), 9.54 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.01, 20.97, 24.86, 28.92, 43.99, 48.53, 49.26, 53.41, 64.49, 81.25, 104.45, 115.32, 116.19, 119.61, 123.40, 127.75, 137.15, 138.21, 149.44, 156.36, 160.13, 165.50. Anal. calcd. for C25H31N5O2: C 69.26; H 7.21; N 16.15%. Found: C 69.62; H 7.39; N 16.40%.
N-(3-Chlorophenyl)-2-[(4-cyano-7-isopropyl-1-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)oxy]acetamide (9e). Cream solid; yield 76%, mp 206–208 °C; IR ν/cm–1: 3259, 3193 (NH), 2208 (C≡N), 1674 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.07 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.80–1.88 (m, 4H, C4H8N), 2.68 (t, J = 5.8 Hz, 2H, NCH2CH2), 2.82 (t, J = 6.0 Hz, 2H, NCH2CH2), 2.84 (sp, J = 6.5 Hz, 1H, CH(CH3)2), 3.50–3.57 (m, 4H, N(CH2)2), 3.55 (s, 2H, NCH2), 4.79 (s, 2H, OCH2), 6.95–7.00 (m, 1H, C6H4), 7.20 (t, J = 8.1 Hz, 1H, C6H4), 7.46–7.50 (m, 1H, C6H4), 7.72 (t, J = 2.0 Hz, 1H, C6H4), 9.93 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.02, 24.85, 28.99, 43.99, 48.56, 49.26, 53.36, 64.53, 81.25, 109.95, 115.32, 117.12, 118.83, 122.39, 129.16, 133.13, 139.80, 149.51, 156.33, 160.07, 166.07. Anal. calcd. for C24H28ClN5O2: C 63.50; H 6.22; N 15.43%. Found: C 63.83; H 6.38; N 15.67%.
2-[(4-Cyano-7-isopropyl-1-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)oxy]-N-(3-methoxyphenyl)acetamide (9f). Cream solid; yield 82%, mp 195–197 °C; IR ν/cm–1: 3264, 3205 (NH), 2205 (C≡N), 1673 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.07 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.80–1.89 (m, 4H, C4H8N), 2.68 (t, J = 5.9 Hz, 2H, NCH2CH2), 2.82 (t, J = 6.0 Hz, 2H, NCH2CH2), 2.84 (sp, J = 6.5 Hz, 1H, CH(CH3)2), 3.51–3.58 (m, 6H, NCH2, N(CH2)2), 3.76 (s, 3H, OCH3), 4.79 (s, 2H, OCH2), 6.51–6.55 (m, 1H, C6H4), 7.04–7.14 (m, 2H, C6H4), 7.28–7.30 (m, 1H, C6H4), 9.67 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.03, 24.87, 28.99, 44.00, 48.58, 49.26, 53.36, 54.35, 64.51, 81.23, 104.71, 108.47, 109.89, 111.20, 115.34, 128.54, 139.50, 149.48, 156.37, 159.20, 160.14, 165.66. Anal. calcd. for C25H31N5O3: C 66.79; H 6.95; N 15.58%. Found: C 67.17; H 7.14; N 15.85%.
2-[(4-Cyano-7-isopropyl-1-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)oxy]-N-(4-ethoxyphenyl)acetamide (9g). Colorless solid; yield 77%, mp 184–186 °C; IR ν/cm–1: 3238, 3188 (NH), 2203 (C≡N), 1680 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.08 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.38 (t, J = 6.9 Hz, 3H, OCH2CH3), 1.82–1.89 (m, 4H, C4H8N), 2.55–2.72 (m, 2H, NCH2CH2), 2.79–2.89 (m, 3H, NCH2CH2, CH(CH3)2), 3.52–3.59 (m, 6H, NCH2, N(CH2)2), 3.97 (q, J = 6.9 Hz, 2H, OCH2CH3), 4.77 (s, 2H, OCH2), 6.72–6.78 (m, 2H, C6H4), 7.42–7.48 (m, 2H, C6H4), 9.46 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 14.38, 18.02, 24.88, 28.98, 43.99, 48.58, 49.27, 53.37, 62.53, 64.49, 81.30, 109.90, 113.68, 115.34, 120.44, 131.33, 149.47, 154.34, 156.37, 160.14, 165.10. Anal. calcd. for C26H33N5O3: C 67.36; H 7.18; N 15.11%. Found: C 67.68; H 7.33; N 15.34%.
1-Azepan-1-yl-7-isopropyl-3-(2-oxo-2-pyrrolidin-1-ylethoxy)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile (9h). Light yellow solid; yield 75%, mp 173–175 °C; IR ν/cm–1: 2208 (C≡N), 1673 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.08 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.53–1.60 (m, 4H, C6H12N), 1.71–1.80 (m, 4H, C6H12N), 1.80–1.89 (m, 2H, C4H8N), 1.94–2.04 (m, 2H, C4H8N), 2.70 (br t, J = 5.9 Hz, 2H, NCH2CH2), 2.79–2.89 (m, 3H, NCH2CH2, CH(CH3)2), 3.36 (t, J = 6.9 Hz, 2H, NCH2, C4H8N), 3.39 (s, 2H, NCH2), 3.44–3.55 (m, 6H, N(CH2)2, NCH2), 4.84 (s, 2H, OCH2); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.12, 23.30, 25.70, 26.18, 28.09, 29.16, 44.24, 44.47, 45.21, 49.56, 50.68, 53.33, 63.30, 82.82, 110.95, 114.94, 150.45, 158.22, 159.84, 164.59. Anal. calcd. for C24H35N5O2: C 67.73; H 8.29; N 16.46%. Found: C 68.13; H 8.50; N 16.75%.
2-[(1-Azepan-1-yl-4-cyano-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)oxy]-N-(3-methylphenyl)acetamide (9i). Colorless solid; yield 81%, mp 183–185 °C; IR ν/cm–1: 3286, 3166 (NH), 2205 (C≡N), 1677 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.08 (d, J = 6.6 Hz, 6H, CH(CH3)2), 1.46–1.54 (m, 4H, C6H12N), 1.67–1.77 (m, 4H, C6H12N), 2.32 (s, 3H, CH3), 2.71 (br t, J = 5.9 Hz, 2H, NCH2CH2), 2.79–2.90 (m, 3H, NCH2CH2, CH(CH3)2), 3.39 (m, 2H, NCH2), 3.47–3.57 (m, 4H, N(CH2)2), 4.80 (s, 2H, OCH2), 6.77–6.81 (m, 1H, C6H4), 7.06–7.12 (m, 1H, C6H4), 7.30–7.35 (m, 1H, C6H4), 7.38–7.41 (m, 1H, C6H4), 9.55 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.11, 20.97, 26.27, 28.04, 29.19, 44.27, 49.58, 50.69, 53.35, 64.37, 82.82, 111.09, 115.09, 116.14, 119.57, 123.39, 127.73, 137.11, 138.21, 150.40, 158.44, 159.78, 165.31. Anal. calcd. for C27H35N5O2: C 70.25; H 7.64; N 15.17%. Found: C 70.61; H 7.82; N 15.42%.
2-[(1-Azepan-1-yl-4-cyano-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)oxy]-N-(4-methylphenyl)acetamide (9j). Colorless solid; yield 84%, mp 202–204 °C; IR ν/cm–1: 3245, 3187 (NH), 2208 (C≡N), 1683 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.08 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.46–1.54 (m, 4H, C6H12N), 1.67–1.77 (m, 4H, C6H12N), 2.29 (s, 3H, CH3), 2.71 (t, J = 5.5 Hz, 2H, NCH2CH2), 2.79–2.91 (m, 3H, NCH2CH2, CH(CH3)2), 3.39 (s, 2H, NCH2), 3.47–3.53 (m, 4H, N(CH2)2), 4.80 (s, 2H, OCH2), 6.99–7.04 (m, 2H, C6H4), 7.40–7.46 (m, 2H, C6H4), 9.57 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.10, 20.27, 26.25, 28.03, 29.15, 29.18, 44.26, 49.54, 49.56, 49.59, 50.66, 53.35, 64.34, 82.77, 111.05, 115.10, 118.97, 128.36, 131.49, 135.80, 150.37, 158.42, 159.80, 165.15. Anal. calcd. for C27H35N5O2: C 70.25; H 7.64; N 15.17%. Found: C 70.64; H 7.85; N 15.44%.
2-[(1-Azepan-1-yl-4-cyano-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)oxy]-N-(3-methoxyphenyl)acetamide (9k). Colorless solid; yield 89%, mp 170–172 °C; IR ν/cm–1: 3327, 3274 (NH), 2206 (C≡N), 1674 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.07 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.45–1.54 (m, 4H, C6H12N), 1.67–1.76 (m, 4H, C6H12N), 2.71 (t, J = 5.8 Hz, 2H, NCH2CH2), 2.79–2.91 (m, 3H, NCH2CH2, CH(CH3)2), 3.39 (s, 2H, NCH2), 3.47–3.53 (m, 4H, N(CH2)2), 3.75 (s, 3H, OCH3), 4.81 (s, 2H, OCH2), 6.50–6.55 (m, 1H, 4-CH, C6H4), 7.03–7.13 (m, 2H, 5,6-CH, C6H4), 7.28–7.31 (m, 1H, 2-CH, C6H4), 9.68 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.11, 26.27, 28.04, 29.19, 44.26, 49.59, 50.67, 53.35, 54.32, 64.35, 82.76, 104.65, 108.46, 111.08, 111.14, 115.11, 128.51, 139.49, 150.40, 158.43, 159.17, 159.80, 165.47. Anal. calcd. for C27H35N5O3: C 67.90; H 7.39; N 14.66%. Found: C 68.23; H 7.55; N 14.90%.
N-(4-Acetylphenyl)-2-[(1-azepan-1-yl-4-cyano-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)oxy]acetamide (9l). Light yellow solid; yield 76%, mp 198–200 °C; IR ν/cm–1: 3277, 3192 (NH), 2206 (C≡N), 1690, 1680 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.07 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.44–1.51 (m, 4H, C6H12N), 1.65–1.74 (m, 4H, C6H12N), 2.51 (s, 3H, COCH3), 2.71 (t, J = 5.7 Hz, 2H, NCH2CH2), 2.78–2.91 (m, 3H, NCH2CH2, CH(CH3)2), 3.39 (s, 2H, NCH2), 3.45–3.51 (m, 4H, N(CH2)2), 4.85 (s, 2H, OCH2), 7.68–7.73 (m, 2H, C6H4), 7.82–7.87 (m, 2H, C6H4), 10.13 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.10, 25.64, 26.23, 28.02, 29.20, 44.25, 49.60, 50.63, 53.34, 64.36, 82.77, 111.13, 115.07, 118.12, 128.70, 131.50, 142.70, 150.47, 158.37, 159.74, 166.10, 194.55. Anal. calcd. for C28H35N5O3: C 68.69; H 7.21; N 14.30%. Found: C 69.04; H 7.39; N 14.56%.
N-Benzyl-2-[(4-cyano-7-isopropyl-1-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)oxy]acetamide (9m). Colorless solid; yield 80%, mp 173–175 °C; IR ν/cm–1: 3352 (NH), 2205 (C≡N), 1698 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.09 (d, J = 6.6 Hz, 6H, CH(CH3)2), 1.81–1.90 (m, 4H, C5H8N), 2.69 (t, J = 5.6 Hz, 2H, NCH2CH2), 2.78–2.91 (m, 3H, NCH2CH2, CH(CH3)2), 3.48–3.55 (m, 4H, N(CH2)2), 3.57 (s, 2H, NCH2), 4.31 (d, J = 6.0 Hz, 2H, NHCH2), 4.70 (s, 2H, OCH2), 7.13–7.26 (m, 5H, Ph), 8.05 (t, J = 6.0 Hz, 1H, NH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.03, 24.87, 28.99, 41.72, 43.99, 48.57, 49.19, 53.36, 64.23, 81.42, 109.84, 115.31, 126.03, 127.01, 127.48, 138.97, 149.47, 156.30, 160.03, 166.96. Anal. calcd. for C25H31N5O2: C 69.26; H 7.21; N 16.15%. Found: C 69.64; H 7.42; N 16.43%. ESI HRMS [C25H31O2N5+Na+] Calculated: 456.2375. Found: 456.2377.
2-[(1-Azepan-1-yl-4-cyano-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)oxy]-N-benzylacetamide (9n). Colorless solid; yield 83%, mp 150–152 °C; IR ν/cm–1: 3197 (NH), 2206 (C≡N), 1675 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.09 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.52–1.59 (m, 4H, C6H12N), 1.71–1.80 (m, 4H, C6H12N), 2.72 (t, J = 5.9 Hz, 2H, NCH2CH2), 2.81–2.90 (m, 3H, NCH2CH2, CH(CH3)2), 3.40 (s, 2H, NCH2), 3.46–3.51 (m, 4H, N(CH2)2), 4.31 (d, J = 5.9 Hz, 2H, CH2Ph), 4.72 (s, 2H, OCH2), 7.13–7.28 (m, 5H, Ph), 8.08 (t, J = 5.9 Hz, 1H, NH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.14, 26.27, 28.09, 29.19, 41.75, 44.34, 49.52, 50.67, 53.36, 64.18, 82.89, 111.06, 115.10, 126.08, 126.99, 127.55, 138.89, 150.40, 158.44, 159.66, 166.82. Anal. calcd. for C27H35N5O2: C 70.25; H 7.64; N 15.17%. Found: C 70.65; H 7.86; N 15.47%. ESI HRMS [C27H35O2N5+Na+] Calculated: 484.2688. Found: 484.2689.
2-[(1-Azepan-1-yl-4-cyano-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)oxy]-N-(2-furylmethyl)acetamide (9o). Light yellow solid; yield 77%, mp 154–156 °C; 152 oC; IR ν/cm–1: 3288, 3189 (NH), 2206 (C≡N), 1678 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.09 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.53–1.59 (m, 4H, C6H12N), 1.72–1.80 (m, 4H, C6H12N), 2.71 (t, J = 5.9 Hz, 2H, NCH2CH2), 2.80–2.90 (m, 3H, NCH2CH2, CH(CH3)2), 3.40 (s, 2H, NCH2), 3.48–3.53 (m, 4H, N(CH2)2), 4.30 (d, J = 5.7 Hz, 2H, NHCH2), 4.69 (s, 2H, OCH2), 6.14 (d, J = 3.1 Hz, 1H, 4-CHfur), 6.28 (dd, J = 3.1, 1.9 Hz, 1H, 3-CHfur), 7.36 (d, J = 1.5 Hz, 1H, 5-CHfur), 8.04 (t, J = 5.7 Hz, 1H, NH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.12, 26.28, 28.09, 29.18, 35.03, 44.30, 49.54, 50.67, 53.34, 63.98, 82.84, 106.29, 109.73, 111.04, 115.06, 140.90, 150.38, 151.81, 158.43, 159.65, 166.73. Anal. calcd. for C25H33N5O3: C 66.50; H 7.37; N 15.51%. Found: C 66.82; H 7.54; N 15.75%. ESI HRMS [C25H33O3N5+Na+] Calculated: 474.2481. Found: 474.2482.
2-[(1-Azepan-1-yl-4-cyano-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)oxy]-N-(1-methyl-2-phenylethyl)acetamide (9p). Colorless solid; yield 79%, mp 164–166 °C; IR ν/cm–1: 3306 (NH), 2207 (C≡N), 1662 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.07 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.10 (d, J = 5.4 Hz, 3H, CHCH3), 1.53–1.59 (m, 4H, C6H12N), 1.73–1.81 (m, 4H, C6H12N), 2.55–2.92 (m, 7H, NCH2CH2, CH(CH3)2, CH2Ph), 3.40 (s, 2H, NCH2), 3.47–3.52 (m, 4H, N(CH2)2), 3.97–4.11 (m, 1H, NHCH), 4.54–4.66 (m, 2H, OCH2), 7.07–7.26 (m, 6H, NH, Ph); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.10, 19.42, 26.28, 28.09, 29.19, 41.76, 44.32, 45.60, 49.52, 50.72, 53.38, 64.09, 82.77, 111.14, 115.05, 125.39, 127.55, 128.60, 138.13, 150.38, 158.46, 159.59, 165.88. Anal. calcd. for C29H39N5O2: C 71.13; H 8.03; N 14.30%. Found: C 71.51; H 8.24; N 14.59%.

3.7. General Procedure for the Synthesis of Compounds 10a–l

To a solution of sodium ethoxide [0.05 g (2.2 mmol) of sodium in absolute ethanol (35 mL)] compound 5 (2 mmol) was added. The mixture was refluxed for 4 h, cooled, and poured onto water. The formed crystals were filtered off, washed with water, dried and recrystallized from ethanol.
7-Isopropyl-5-pyrrolidin-1-yl-2-(pyrrolidin-1-ylcarbonyl)-6,7,8,9-tetrahydrofuro[2,3-c]-2,7-naphthyridin-1-amine (10a). Milky solid; yield 77%, mp 250–252 °C; IR ν/cm–1: 3449, 3347 (NH2), 1619 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.13 (d, J = 6.3 Hz, 6H, CH(CH3)2), 1.91–1.98 (m, 8H, 4CH2, C4H8N), 2.72–2.93 (m, 3H, NCH2CH2, CH(CH3)2), 3.17–3.25 (m, 2H, NCH2CH2), 3.45–3.58 (m, 8H, 2(NCH2)2), 3.74 (br, 2H, NCH2), 5.64 (s, 2H, NH2); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.04, 25.02, 26.90, 44.38, 46.08, 46.16, 49.17, 49.71, 53.57, 103.30, 113.98, 123.61, 138.57, 140.75, 156.44, 157.13, 160.32. Anal. calcd. for C22H31N5O2: C 66.47; H 7.84; N 17.62%. Found: C 66.83; H 8.06; N 17.89%. ESI HRMS [C22H31O2N5+H+] Calculated: 398.2556. Found: 398.2557.
7-Isopropyl-2-(piperidin-1-ylcarbonyl)-5-pyrrolidin-1-yl-6,7,8,9-tetrahydrofuro[2,3-c]-2,7-naphthyridin-1-amine (10b). Light yellow solid; yield 71%, mp 179–181 °C; IR ν/cm–1: 3427, 3306 (NH2), 1615 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.11 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.60–1.74 (m, 6H, C5H10N), 1.91–1.97 (m, 4H, C4H8N), 2.76 (t, J = 5.9 Hz, 2H, NCH2CH2), 2.88 (sp, J = 6.5 Hz, 1H, CH(CH3)2), 3.19 (t, J = 5.8 Hz, 2H, NCH2CH2), 3.47–3.54 (m, 4H, N(CH2)2, C5H10N), 3.53 (s, 2H, NCH2), 3.74–3.79 (m, 4H, N(CH2)2, C4H8N), 5.67 (s, 2H, NH2); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.13, 24.49, 25.00, 25.89, 27.05, 44.45, 49.34, 49.38, 49.72, 53.43, 103.15, 114.34, 123.02, 139.74, 140.80, 156.06, 157.35, 160.70. Anal. calcd. for C23H33N5O2: C 67.12; H 8.08; N 17.02%. Found: C 67.45; H 8.24; N 17.27%.
1-Amino-7-isopropyl-N-phenyl-5-pyrrolidin-1-yl-6,7,8,9-tetrahydrofuro[2,3-c]-2,7-naphthyridine-2-carboxamide (10c). Cream solid; yield 73%, mp 196–198 °C; IR ν/cm–1: 3464, 3403, 3315 (NH, NH2), 1647 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.12 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.91–1.99 (m, 4H, C4H8N), 2.77 (t, J = 5.8 Hz, 2H, NCH2CH2), 2.89 (sp, J = 6.5 Hz, 1H, CH(CH3)2), 3.21 (t, J = 5.5 Hz, 2H, NCH2CH2), 3.47–3.54 (m, 4H, N(CH2)2), 3.55 (s, 2H, NCH2), 5.67 (s, 2H, NH2), 6.92–6.98 (m, 1H, Ph), 7.18–7.25 (m, 2H, Ph), 7.78–7.83 (m, 2H, Ph), 9.25 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.16, 25.07, 27.10, 44.41, 49.38, 49.78, 53.51, 103.72, 114.28, 119.53, 121.88, 122.64, 127.66, 138.44, 139.14, 141.34, 156.65, 157.29, 159.25. Anal. calcd. for C24H29N5O2: C 68.71; H 6.97; N 16.69%. Found: C 69.10; H 7.17; N 16.97%. ESI HRMS [C24H29O2N5+H+] Calculeted: 420.2399. Found: 420.2400.
1-Amino-7-isopropyl-N-(3-methylphenyl)-5-pyrrolidin-1-yl-6,7,8,9-tetrahydrofuro[2,3-c]-2,7-naphthyridine-2-carboxamide (10d). Colorless solid; yield 70%, mp 108–110 °C; IR ν/cm–1: 3457, 3413, 3332 (NH, NH2), 1637 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.12 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.90–1.97 (m, 4H, C4H8N), 2.32 (s, 3H, CH3), 2.77 (t, J = 5.4 Hz, 2H, NCH2CH2), 2.91 (sp, J = 6.5 Hz, 1H, CH(CH3)2), 3.20 (t, J = 5.5 Hz, 2H, NCH2CH2), 3.48–3.52 (m, 4H, N(CH2)2), 3.58 (s, 2H, NCH2), 5.64 (s, 2H, NH2), 6.74–6.80 (m, 1H, C6H4), 7.04–7.13 (m, 1H, C6H4), 7.54–7.59 (m, 1H, C6H4), 7.63–7.68 (m, 1H, C6H4), 9.10 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.15, 21.08, 25.04, 27.11, 44.40, 49.38, 49.76, 53.47, 103.74, 114.32, 116.66, 120.09, 122.64, 122.68, 127.52, 136.77, 138.33, 138.93, 141.31, 156.58, 157.26, 159.16. Anal. calcd. for C25H31N5O2: C 69.26; H 7.21; N 16.15%. Found: C 69.57; H 7.38; N 16.39%. ESI HRMS [C25H31O2N5+H+] Calculated: 434.2556. Found: 434.2557.
1-Amino-N-(3-chlorophenyl)-7-isopropyl-5-pyrrolidin-1-yl-6,7,8,9-tetrahydrofuro[2,3-c]-2,7-naphthyridine-2-carboxamide (10e). Light yellow solid; yield 83%, mp 202–204 °C; IR ν/cm–1: 3383, 3271 (NH, NH2), 1647 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.12 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.91–2.00 (m, 4H, C4H8N), 2.77 (t, J = 5.7 Hz, 2H, NCH2CH2), 2.88 (sp, J = 6.5 Hz, 1H, CH(CH3)2), 3.21 (t, J = 5.7 Hz, 2H, NCH2CH2), 3.47–3.54 (m, 4H, N(CH2)2), 3.56 (s, 2H, NCH2), 5.75 (s, 2H, NH2), 6.90–6.94 (m, 1H, C6H4), 7.18 (t, J = 8.1 Hz, 1H, C6H4), 7.69–7.74 (m, 1H, C6H4), 8.05 (t, J = 2.0 Hz, 1H, C6H4), 9.57 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.13, 25.05, 27.09, 44.36, 49.35, 49.77, 53.48, 103.51, 114.26, 117.59, 119.20, 121.43, 122.29, 128.75, 132.80, 139.05, 140.73, 141.41, 156.79, 157.38, 159.28. Anal. calcd. for C24H28ClN5O2: C 63.50; H 6.22; N 15.43%. Found: C 63.87; H 6.41; N 15.70%. ESI HRMS [C24H28O2N5Cl1+H+] Calculeted: 454.2009. Found: 454.2011.
1-Amino-7-isopropyl-N-(3-methoxyphenyl)-5-pyrrolidin-1-yl-6,7,8,9-tetrahydrofuro[2,3-c]-2,7-naphthyridine-2-carboxamide (10f). Cream solid; yield 76%, mp 189–191 °C; IR ν/cm–1: 3374, 3276 (NH, NH2), 1651 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.12 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.91–1.99 (m, 4H, C4H8N), 2.77 (t, J = 5.9 Hz, 2H, NCH2CH2), 2.89 (sp, J = 6.5 Hz, 1H, CH(CH3)2), 3.21 (t, J = 5.7 Hz, 2H, NCH2CH2), 3.47–3.54 (m, 4H, N(CH2)2), 3.55 (s, 2H, NCH2), 3.78 (s, 3H, OCH3), 5.69 (s, 2H, NH2), 6.47–6.52 (m, 1H, C6H4), 7.09 (t, J = 8.1 Hz, 1H, C6H4), 7.34–7.38 (m, 1H, C6H4), 7.55 (t, J = 2.2 Hz, 1H, C6H4), 9.21 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.15, 25.05, 27.11, 44.40, 49.38, 49.76, 53.48, 54.33, 103.71, 104.91, 108.01, 111.72, 114.31, 122.58, 128.23, 138.49, 140.29, 141.35, 156.62, 157.29, 159.04, 159.22. Anal. calcd. for C25H31N5O3: C 66.79; H 6.95; N 15.58%. Found: C 67.13; H 7.11; N 15.83%. ESI HRMS [C25H31O3N5+H+] Calculated: 450.2505. Found: 450.2507.
1-Amino-N-(4-ethoxyphenyl)-7-isopropyl-5-pyrrolidin-1-yl-6,7,8,9-tetrahydrofuro[2,3-c]-2,7-naphthyridine-2-carboxamide (10g). Light yellow solid; yield 70%, mp 187–189 °C; IR ν/cm–1: 3405, 3316 (NH, NH2), 1643 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.13 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.39 (t, J = 7.0 Hz, 3H, OCH2CH3), 1.92–1.98 (m, 4H, C4H8N), 2.79 (br t, J = 5.6 Hz, 2H, NCH2CH2), 2.84–2.96 (m, 1H, CH(CH3)2), 3.22 (t, J = 5.6 Hz, 2H, NCH2CH2), 3.47–3.53 (m, 4H, N(CH2)2), 3.57 (s, 2H, NCH2), 3.99 (q, J = 7.0 Hz, 2H, OCH2CH3), 5.61 (s, 2H, NH2), 6.72–6.77 (m, 2H, C6H4), 7.64–7.70 (m, 2H, C6H4), 9.15 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 14.50, 18.08, 25.07, 26.91, 44.37, 49.24, 49.77, 53.62, 62.59, 103.85, 113.53, 113.94, 120.95, 122.87, 132.13, 137.86, 141.13, 153.92, 156.57, 157.13, 159.01. Anal. calcd. for C26H33N5O3: C 67.36; H 7.18; N 15.11%. Found: C 67.76; H 7.39; N 15.40%. ESI HRMS [C26H33O3N5+H+] Calculated: 464.2661. Found: 464.2663.
5-Azepan-1-yl-7-isopropyl-2-(pyrrolidin-1-ylcarbonyl)-6,7,8,9-tetrahydrofuro[2,3-c]-2,7-naphthyridin-1-amine (10h). Yellow solid; yield 75%, mp 198–200 °C; IR ν/cm–1: 3446, 3349 (NH2), 1616 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.12 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.66–1.72 (m, 4H, 2CH2), 1.77–1.85 (m, 4H, 2CH2), 1.90–1.99 (m, 4H, 2CH2), 2.77 (t, J = 5.8 Hz, 2H, NCH2CH2), 2.87 (sp, J = 6.5 Hz, 1H, CH(CH3)2), 3.22 (t, J = 5.8 Hz, 2H, NCH2CH2), 3.38–3.43 (m, 4H, N(CH2)2, C6H12N), 3.48 (s, 2H, NCH2), 3.54–3.97 (m, 4H, N(CH2)2, C4H8N), 5.65 (s, 2H, NH2); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.15, 26.45, 27.08, 28.46, 44.84, 46.12, 49.36, 52.29, 53.40, 104.92, 116.78, 124.16, 138.26, 141.30, 156.03, 159.94, 160.32, 165.48. Anal. calcd. for C24H35N5O2: C 67.73; H 8.29; N 16.46%. Found: C 68.08; H 8.47; N 16.72%. ESI HRMS [C24H35O2N5+H+] Calculeted: 426.2869. Found: 426.2871.
1-Amino-5-azepan-1-yl-7-isopropyl-N-(3-methylphenyl)-6,7,8,9-tetrahydrofuro[2,3-c]-2,7-naphthyridine-2-carboxamide (10i). Colorless solid; yield 80%, mp 91–93 °C; IR ν/cm–1: 3398, 3304 (NH, NH2), 1654 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.13 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.66–1.72 (m, 4H, C6H12N), 1.78–1.87 (m, 4H, C6H12N), 2.34 (s, 3H, CH3), 2.80 (br t, J = 5.6 Hz, 2H, NCH2CH2), 2.83–2.95 (m, 1H, CH(CH3)2), 3.25 (t, J = 5.5 Hz, 2H, NCH2CH2), 3.41–3.46 (m, 4H, N(CH2)2), 3.50 (s, 2H, NCH2), 5.69 (s, 2H, NH2), 6.75–6.79 (m, 1H, C6H4), 7.07–7.13 (m, 1H, C6H4), 7.52–7.57 (m, 1H, C6H4), 7.64–7.66 (m, 1H, C6H4), 9.10 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.14, 21.06, 26.41, 27.07, 28.42, 44.76, 49.44, 52.09, 53.45, 105.33, 116.67, 120.11, 122.79, 123.20, 127.53, 136.78, 137.97, 138.79, 141.73, 156.16, 159.15, 159.96. Anal. calcd. for C27H35N5O2: C 70.25; H 7.64; N 15.17%. Found: C 70.63; H 7.84; N 15.44%. ESI HRMS [C27H35O2N5+H+] Calculated: 462.2869. Found: 462.2870.
1-Amino-5-azepan-1-yl-7-isopropyl-N-(4-methylphenyl)-6,7,8,9-tetrahydrofuro[2,3-c]-2,7-naphthyridine-2-carboxamide (10j). Yellow solid; yield 77%, mp 204–206 °C; IR ν/cm–1: 3485, 3397, 3316 (NH, NH2), 1647 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.13 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.65–1.73 (m, 4H, C6H12N), 1.78–1.87 (m, 4H, C6H12N), 2.31 (s, 3H, CH3), 2.79 (t, J = 5.7 Hz, 2H, NCH2CH2), 2.84–2.94 (m, 1H, CH(CH3)2), 3.24 (t, J = 5.7 Hz, 2H, NCH2CH2), 3.40–3.46 (m, 4H, N(CH2)2), 3.49 (s, 2H, NCH2), 5.67 (s, 2H, NH2), 7.00–7.05 (m, 2H, C6H4), 7.63–7.68 (m, 2H, C6H4), 9.15 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.15, 20.30, 26.41, 27.08, 28.42, 44.77, 49.46, 52.09, 53.44, 105.37, 116.60, 119.55, 123.28, 128.18, 130.81, 136.39, 137.79, 141.72, 156.13, 159.10, 159.91. Anal. calcd. for C27H35N5O2: C 70.25; H 7.64; N 15.17%. Found: C 70.56; H 7.79; N 15.40%. ESI HRMS [C27H35O2N5+H+] Calculated: 462.2869. Found: 462.2870.
1-Amino-5-azepan-1-yl-7-isopropyl-N-(3-methoxyphenyl)-6,7,8,9-tetrahydrofuro[2,3-c]-2,7-naphthyridine-2-carboxamide (10k). Colorless solid; yield 72%, mp 210–212 °C; IR ν/cm–1: 3488, 3415, 3334 (NH, NH2), 1650 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.13 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.66–1.72 (m, 4H, C6H12N), 1.79–1.87 (m, 4H, C6H12N), 2.79 (t, J = 5.9 Hz, 2H, NCH2CH2), 2.89 (sp, J = 6.5 Hz, 1H, CH(CH3)2), 3.24 (t, J = 5.7 Hz, 2H, NCH2CH2), 3.41–3.46 (m, 4H, N(CH2)2), 3.49 (s, 2H, NCH2), 3.79 (s, 3H, OCH3), 5.71 (s, 2H, NH2), 6.48–6.53 (m, 1H, C6H4), 7.07–7.13 (m, 1H, C6H4), 7.33–7.38 (m, 1H, C6H4), 7.54–7.56 (m, 1H, C6H4), 9.22 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.15, 26.40, 27.12, 28.40, 44.77, 49.48, 52.08, 53.41, 54.30, 104.93, 105.28, 108.11, 111.73, 116.62, 123.11, 128.23, 138.14, 140.15, 141.80, 156.18, 159.04, 159.21, 160.0. Anal. calcd. for C27H35N5O3: C 67.90; H 7.39; N 14.66%. Found: C 68.29; H 7.60; N 14.94%. ESI HRMS [C27H35O3N5+H+] Calculated: 478.2818. Found: 478.2816.
N-(4-Acetylphenyl)-1-amino-5-azepan-1-yl-7-isopropyl-6,7,8,9-tetrahydrofuro[2,3-c]-2,7-naphthyridine-2-carboxamide (10l). Light yellow solid; yield 81%, mp 116–118 °C; IR ν/cm–1: 3399, 3312 (NH, NH2), 1673, 1648 (C=O). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.13 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.66–1.72 (m, 4H, C6H12N), 1.79–1.87 (m, 4H, C6H12N), 2.51 (s, 3H, COCH3), 2.80 (br t, J = 5.6 Hz, 2H, NCH2CH2), 2.84–2.94 (m, 1H, CH(CH3)2), 3.25 (t, J = 5.7 Hz, 2H, NCH2CH2), 3.42–3.47 (m, 4H, N(CH2)2), 3.50 (s, 2H, NCH2), 5.83 (s, 2H, NH2), 7.81–7.86 (m, 2H, C6H4), 7.95–8.00 (m, 2H, C6H4), 9.69 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.15, 25.64, 26.42, 28.38, 44.73, 49.51, 52.02, 53.46, 105.00, 118.58, 122.83, 128.47, 130.77, 139.09, 141.97, 143.71, 156.43, 159.30, 160.20, 194.62. Anal. calcd. for C28H35N5O3: C 68.69; H 7.21; N 14.30%. Found: C 69.04; H 7.39; N 14.56%. ESI HRMS [C28H35O3N5+H+] Calculated: 490.2818. Found: 490.2819.

3.8. General Procedure for the Synthesis of Compounds 11a–c

 A.
The same method used for the preparation of compounds 10a–l.
 B.
A mixture of compound 2 (1 mmol) and the corresponding amine (5 mmol) was refluxed for 30 min. The reaction mixture was cooled, water (50 mL) was added, and the separated crystals were filtered off, washed with water, dried, and recrystallized from ethanol.
3-(Benzylamino)-7-isopropyl-1-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile (11a). Yellow solid; yield 72(A)/78(B)%, mp 168–170 °C; IR ν/cm–1: 3348 (NH), 2186 (C≡N). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.06 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.83–1.89 (m, 4H, C5H8N), 2.62–2.68 (m, 2H, NCH2CH2), 2.70–2.76 (m, 2H, NCH2CH2), 2.80 (sp, J = 6.4 Hz, 1H, CH(CH3)2), 3.43–3.51 (m, 4H, N(CH2)2), 3.44 (s, 2H, NCH2), 4.54 (d, J = 6.0 Hz, 2H, NHCH2), 6.52 (t, J = 6.0 Hz, 1H, NH), 7.10–7.31 (m, 5H, Ph); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.13, 24.91, 28.95, 43.88, 44.40, 48.74, 49.03, 53.36, 77.81, 105.84, 117.33, 125.68, 126.73, 127.36, 140.68, 147.87, 156.0, 157.43. Anal. calcd. for C23H29N5: C 73.57; H 7.78; N 18.65%. Found: C 73.89; H 7.94; N 18.89%. ESI HRMS [C23H29N5+H+] Calculated: 376.2501. Found: 376.2503.
1-Azepan-1-yl-3-(benzylamino)-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile (11b). Yellow solid; yield 71(A)/76(B)%, mp 127–129 °C; IR ν/cm–1: 3215 (NH), 2189 (C≡N). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.06 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.47–1.55 (m, 4H, C6H12N), 1.64–1.72 (m, 4H, C6H12N), 2.66 (t, J = 5.9 Hz, 2H, NCH2CH2), 2.72–2.84 (m, 3H, NCH2CH2, CH(CH3)2), 3.30 (s, 2H, NCH2), 3.38–3.43 (m, 4H, N(CH2)2), 4.55 (d, J = 5.9 Hz, 2H, CH2Ph), 6.60 (t, J = 5.9 Hz, 1H, NH), 7.09–7.28 (m, 5H, Ph); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.20, 26.20, 28.20, 29.15, 43.92, 44.66, 49.57, 50.64, 53.34, 79.13, 107.00, 117.09, 125.62, 126.41, 127.37, 140.54, 148.63, 155.73, 159.54. Anal. calcd. for C25H33N5: C 74.40; H 8.24; N 17.35%. Found: C 74.78; H 8.45; N 17.62%. ESI HRMS [C25H33N5+H+] Calculated: 404.2814. Found: 404.2816.
1-Azepan-1-yl-3-[(2-furylmethyl)amino]-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile (11c). Yellow solid; yield 74(A)/79(B)%, mp 113–115 °C; IR ν/cm–1: 3394 (NH), 2199 (C≡N). 1H NMR (300 MHz, DMSO-d6/CCl4, 1/3): δ 1.07 (d, J = 6.5 Hz, 6H, CH(CH3)2), 1.52–1.60 (m, 4H, C6H12N), 1.71–1.80 (m, 4H, C6H12N), 2.66 (t, J = 5.6 Hz, 2H, NCH2CH2), 2.72–2.85 (m, 3H, NCH2CH2, CH(CH3)2), 3.31 (s, 2H, NCH2), 3.46–3.52 (m, 4H, N(CH2)2), 4.52 (d, J = 5.8 Hz, 2H, NHCH2), 6.09 (dd, J = 3.2, 0.9 Hz, 1H, 4-CHfur), 6.24 (dd, J = 3.2, 1.8 Hz, 1H, 3-CHfur), 6.40 (t, J = 5.8 Hz, 1H, NH), 7.31 (dd, J = 1.8, 0.9 Hz, 1H, 5-CHfur); 13C NMR (75 MHz, DMSO-d6/CCl4, 1/3): δ 18.19, 26.26, 28.23, 29.11, 37.40, 44.64, 49.52, 50.69, 53.34, 79.43, 105.33, 107.29, 109.60, 116.90, 140.35, 148.63, 153.57, 155.42, 159.51. Anal. calcd. for C23H31N5O: C 70.20; H 7.94; N 17.80%. Found: C 70.56; H 8.13; N 18.05%. ESI HRMS [C23H31O1N5+H+] Calculated: 394.2607. Found: 394.2609.

4. Conclusions

In summary, an efficient method for the synthesis of new heterocyclic systems, furo[2,3-c]-2,7-naphthyridines 6, and a new method for the synthesis of 1,3-diamino-2,7-naphthyridines 11 were described. The studies have shown that 1-amino-3-[(2-hydroxyethyl)thio]-2,7-naphthyridines 3, obtained from the alkylation of 1-amino-3-chloro-2,7-naphthyridines 2, under the action of sodium hydroxide, could undergo Smiles rearrangement with the formation of 1-amino-3-oxo-2,7-naphthyridines 4 in high yields.
It was found that the cyclization reaction of alkoxyacetamides 9 could follow two different pathways depending on their structure. Thus, in the cases of alkoxyacetamides containing cyclic or aromatic amine fragments only the expected aminoamides of furo[2,3-c]-2,7-naphthyridine 10 were obtained. In the cases of amides deriving from non-aromatic primary amines the Smiles type rearrangement occurred with formation of 1,3-diamino-2,7-naphthyridines 11.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijms23115904/s1.

Author Contributions

Conceptualization, S.N.S., E.K.H., H.A.Y. and A.A.H. performed experiments on the synthesis of all compounds and analyze the results. L.Z. and R.Z. recorded and analyzed the MS spectra. A.G., D.S. and V.G.K. reviewed and edited the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

The work was supported by the Science Committee of RA, in the frames of the research project NO. 21AG-1D036.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Ijms 23 05904 g001 550
Figure 1. The general structures of previously I–III and new IV synthesized compounds.
Figure 1. The general structures of previously I–III and new IV synthesized compounds.
Ijms 23 05904 g001
Ijms 23 05904 sch001 550
Scheme 1. Synthesis of 1-amino-3-oxo-2,7-naphthyridines 4.
Scheme 1. Synthesis of 1-amino-3-oxo-2,7-naphthyridines 4.
Ijms 23 05904 sch001
Ijms 23 05904 sch002 550
Scheme 2. Mechanism of the rearrangement proposed for the synthesis of compounds 4.
Scheme 2. Mechanism of the rearrangement proposed for the synthesis of compounds 4.
Ijms 23 05904 sch002
Ijms 23 05904 sch003 550
Scheme 3. Synthesis of new heterocyclic compounds: furo(thieno)[2,3-c]-2,7-naphthyridines 7, 8.
Scheme 3. Synthesis of new heterocyclic compounds: furo(thieno)[2,3-c]-2,7-naphthyridines 7, 8.
Ijms 23 05904 sch003
Ijms 23 05904 g002 550
Figure 2. 1H NMR spectra of compounds 7b and 8b.
Figure 2. 1H NMR spectra of compounds 7b and 8b.
Ijms 23 05904 g002
Ijms 23 05904 sch004 550
Scheme 4. Synthesis and cyclization of alkoxyacetamides of 2,7-naphthyridines 9.
Scheme 4. Synthesis and cyclization of alkoxyacetamides of 2,7-naphthyridines 9.
Ijms 23 05904 sch004
Table
Table 1. Amino-7-isopropyl-2,7-naphthyridines 9a–p and furo[2,3-c]-2,7-naphthyridines 10a–l.
Table 1. Amino-7-isopropyl-2,7-naphthyridines 9a–p and furo[2,3-c]-2,7-naphthyridines 10a–l.
Compoundn―NR1R2Compoundn―NR1R2
9a/10a1 Ijms 23 05904 i0019i/10i3 Ijms 23 05904 i002
9b/10b1 Ijms 23 05904 i0039j/10j3 Ijms 23 05904 i004
9c/10c1 Ijms 23 05904 i0059k/10k3 Ijms 23 05904 i006
9d/10d1 Ijms 23 05904 i0079l/10l3 Ijms 23 05904 i008
9e/10e1 Ijms 23 05904 i0099m1 Ijms 23 05904 i010
9f/10f1 Ijms 23 05904 i0119n3 Ijms 23 05904 i012
9g/10g1 Ijms 23 05904 i0139o3 Ijms 23 05904 i014
9h/10h3 Ijms 23 05904 i0159p3 Ijms 23 05904 i016
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Sirakanyan, S.N.; Spinelli, D.; Geronikaki, A.; Zuppiroli, L.; Zuppiroli, R.; Kartsev, V.G.; Hakobyan, E.K.; Yegoryan, H.A.; Hovakimyan, A.A. Synthesis of 1-Amino-3-oxo-2,7-naphthyridines via Smiles Rearrangement: A New Approach in the Field of Chemistry of Heterocyclic Compounds. Int. J. Mol. Sci. 2022, 23, 5904. https://doi.org/10.3390/ijms23115904

AMA Style

Sirakanyan SN, Spinelli D, Geronikaki A, Zuppiroli L, Zuppiroli R, Kartsev VG, Hakobyan EK, Yegoryan HA, Hovakimyan AA. Synthesis of 1-Amino-3-oxo-2,7-naphthyridines via Smiles Rearrangement: A New Approach in the Field of Chemistry of Heterocyclic Compounds. International Journal of Molecular Sciences. 2022; 23(11):5904. https://doi.org/10.3390/ijms23115904

Chicago/Turabian Style

Sirakanyan, Samvel N., Domenico Spinelli, Athina Geronikaki, Luca Zuppiroli, Riccardo Zuppiroli, Victor G. Kartsev, Elmira K. Hakobyan, Hasmik A. Yegoryan, and Anush A. Hovakimyan. 2022. "Synthesis of 1-Amino-3-oxo-2,7-naphthyridines via Smiles Rearrangement: A New Approach in the Field of Chemistry of Heterocyclic Compounds" International Journal of Molecular Sciences 23, no. 11: 5904. https://doi.org/10.3390/ijms23115904

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