One of the promising strategies in the creation of new pharmaceuticals is the design and synthesis of fused heterocyclic compounds. Knowledge of the spatial structure of complexes of cellular proteins and membrane receptors with ligands is an important step towards understanding the mechanisms of their functioning. Rational search and design of new drug compounds require structural information about the interactions of drug prototypes with the target protein. Researches have shown that promising pharmacophore structural fragments include pyridine and pyrimidine, which are part of various effective drugs. Pyrano[3,4-c]pyridine derivatives are mainly isolated from plants and have hypotensive [1], antipsychotic [2], and anti-inflammatory [3] effects. The pyrano[3,4-c]pyridine moiety is included in the structure of the alkaloid molecules of camptothecin, irinotecan, and topotecan, known anticancer drugs [4, 5].

Previously, methods were developed for the preparation of various derivatives of pyrano[3,4-c]pyridines [6–8]. In order to expand the synthetic possibilities of this direction, we have developed a one-pot method for the preparation of substituted pyrano[3,4-c]pyridines and synthesized pyrano[4′,3′:4,5]pyrido[2,3-d]pyrimidine derivatives— new heterocyclic system. The antitumor activity of the newly synthesized compounds was predicted in silico in order to identify new compounds with potential antitumor activity.

For the synthesis, we used 2-isopropyltetrahydro-4H-pyran-4-one 1 as the starting material [9]. The reaction of ketone 1 sequentially with malonic acid dinitrile and aryl isothiocyanates in the presence of triethylamine without isolation of intermediate compounds 2, 3 leads to 6-amino-7-aryl-8-thioxo-3,4,7,8-tetrahydro-1H-pyrano[3,4-c]pyridine-5-carbonitriles 4а–4e (Scheme 1).

Scheme
scheme 1

1.

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It is assumed that during the reaction course, (2-isopropyltetrahydro-4H-pyran-4-ylidene)malononitrile 2 is first formed, which, upon interaction with aryl isothiocyanates through the intermediate formation of adducts 3, is converted into compounds 4а–4e.

The IR spectra of compounds 4а–4e contain characteristic absorption bands in the region 2215–2220 (nitrile group), 3250–3460 (amino group), 1120– 1150 cm–1 (thionic group). In the 1H NMR spectra, the signals of the protons of the NH2 group appear as broadened singlets in the region 6.47–6.55 ppm.

In order to obtain aryl-substituted aminopyridinones 6a–6e, a one-pot synthesis method was developed, the essence of which is the preliminary preparation of methylsulfanyl derivatives 5a–5e, which were treated without isolation with a methanolic solution of potassium hydroxide. Compounds 6a–6e were isolated as a result of the subsequent nucleophilic substitution reaction (Scheme 2).

Scheme
scheme 2

2.

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The IR spectra of compounds 6a–6e contain absorption bands of the carbonyl group at 1660–1665 cm–1 and there are no absorption bands of the thioxo group observed in the spectra of compounds 4а–4e. In the 1H NMR spectra, the signals of the protons of the NH2 group appear as singlets at 6.24–6.47 ppm.

The presence of vicinal located amino and nitrile groups in compounds 6a–6e allowed the condensation of compounds 6a–e with formamide to form substituted 1-aminopyrano[4′,3′:4,5]pyrido[2,3-d]pyrimidine-6-ones 7a–7e (Scheme 3).

Scheme
scheme 3

3.

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The IR spectra of compounds 7a–7e contain absorption bands of the amino group in the region 3353–3418 cm–1 and no absorption bands of the nitrile group. The 1H NMR spectra contain signals of the NH2 group protons in the diapason 6.86–7.13 ppm and singlet signals of the pyrimidine ring protons in the region of 7.94–8.05 ppm.

Studies in silico were carried out to predict the antitumor activity of the newly synthesized compounds. To carry out the procedure in silico for predicting possible targets, the online resource Swiss Target Prediction was used. The applying of this resource makes it possible to predict the most probable protein targets for small molecules. The prediction is based on the reverse screening methodology using descriptors that estimate the similarity coefficient at the 2D/3D level [11]. The SMAILES files were generated and canonized as working formats of molecular models of the studied compounds. A potential targets search for each compound was carried out. At the first stage, 100 top targets were selected from 3068 targets and 5.8×105 interaction options. The maximum number of targets was for compounds 4e and 7e, while the minimum number was for compound 6d. As a result of the primary selection, 408 targets for 6 studied compounds were obtained (Table 1). At the second stage of the search for possible targets using the probability criterion for finding structural similarity of compounds with a value of ≥ 0.65 for the Tanimoto coefficient (2D) and ≥0.85 for the Manhattan distance (3D), 15 top targets were selected. As a result of the secondary selection, the number of targets was 86 (Table 1).

Table 1. Number of selected targets for test compounds
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Using a database of therapeutically significant targets, the results of the involvement of the studied targets in the pathogenesis of tumor formation were obtained. As a result of the selection, the number of target samples was 58 for 6 test compounds.

Important in the process of searching and developing biologically active compounds with therapeutic significance is the determination of the conjugation of targets in metabolic pathways and the identification of key target proteins. This approach makes it possible to use targeted screening of a number of test compounds to evaluate patterns of cellular response to ligands. To identify potential targets included in the list of those responsible for tumor formation, the Therapeutic Target Database (TTD) [12] was used, which includes information on 1308 clinically proven targets [13]. The functional and physical association of the selected targets was performed on the basis of the String Protein resource [14]. Statistical analysis of the results of the study was carried out on the basis of the complex application of standard statistical methods using the MS Excel program. Data clustering was carried out on the basis of the K-means method.

To determine protein associations at the functional and physical conjugation level in the metabolic pathways that regulate tumor formation, a protein conjugation map was obtained (Fig. 1), selected on the basis of TTD results.

Fig. 1.
figure 1

Map of physical and functional conjugation of selected target proteins for 6 compounds. (Solid lines) direct conjugation, (dotted lines) indirect associations.

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The obtained results indicate that 28 out of 58 targets have conjugation with an average coefficient of 0.93 (Table 2). At the same time, the statistical value of contingency P-value is 1.81. This means that in the sample, the studied proteins interact with each other more often than with a random set of targets of the same size and distribution degree taken from the genome [15].

Table 2. List and contingency values of selected targets for 6 test compounds
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For a more detailed analysis, a sample clustering procedure was carried out based on the K-means method (Fig. 2). The obtained results of clustering indicate that the selected targets form 5 clusters. The largest cluster is formed as a result of conjugation of 10 proteins (AR, EGF, EPHB1, FYN, IGF1R, LCK, MET, PDPK1, SRC, SYK). The second cluster contains the FLT4 and KDR proteins. The third cluster includes 2 proteins (PSEN1, PSEN2). Proteins HDAC1, HDAC2, HDAC3, TTK create the fourth cluster on the contingency map. The last cluster is formed with the involvement of CDC25A, CDK2, CDK9, JAK3 proteins. There is no functional association of EDNRA, KIF11, NRG4, PLK1, PRKCG, ROCK2 proteins with other proteins in the sample.

Fig. 2.
figure 2

The constructed adjacency graph between compounds and their targets involved in the pathogenesis of tumor formation (visualization is presented based on the calculation of graph weights).

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Verification of the involvement of targets in the pathogenesis of tumor formation was carried out on the basis of the results of contingency maps. Of the 28 proteins, 14 key proteins included in the pathogenesis of tumor formation were selected using the metabolic maps of the KEGG database [16].

Figure 2 shows the constructed graph using the Graph Online resource [17], where the compound–target–disease relationship is visualized. The values of the degree of vertices were also calculated, which determine the contingency of the compounds to the predicted and selected proteins included in the list of targets involved in the pathogenesis of tumor generation.

The obtained results indicate that the maximum amount of target proteins falls on compound 7e with 10 targets, and the minimum number of targets is on compound 7d (2 targets). One of the key proteins is the EGF protein with a degree of conjugation of 7. The minimum value of the conjugation degree is for HDAC3, PRKCG, and SYK proteins.

Thus, we have developed one-pot methods for the preparation of previously undescribed 6-amino-7-aryl-3-isopropyl-8-thioxo(oxo)pyrano[3,4-c]pyridines based on 2-isopropyltetrahydro-4H-pyran-4-one. The reaction of 3-amino-2-arylpyridin-1-ones with formamide leads to a new heterocyclic system, aminopyrano[4′,3′:4,5]pyrido[2,3-d]pyrimidinone. As a result of experiments in silico, it was found that the studied compounds can exhibit an antitumor action at the level of a modulating effect when interacting with selected targets involved in the pathogenesis of certain types of oncological diseases. The obtained compounds can be considered as promising objects for the development of new drugs with antitumor activity.

EXPERIMENTAL

Commercial reagents from Fluka (Germany), Aldrich, and Sigma (USA) were used in experiments. Solvents were purified according to standard procedures.

IR spectra were recorded on a Nicolet Avatar 330 FT-IR spectrometer (USA) in vaseline oil. 1Н and 13С NMR spectra were obtained on a Mercury 300 Vx device (USA) with operating frequencies of 300 and 75.462 MHz, respectively, internal standard—TMS. The DEPT method was used to assign signals in the 1H and 13C NMR spectra. Elemental analysis was performed on an Elemental Analyzer Euro EA 3000 instrument (Germany). Melting points were determined on a Boetius heating bench (Germany).

General procedure for synthesis of 6-amino-7-aryl-3-isopropyl-8-thioxopyrano[3,4-c]pyridine-5-carbonitriles 4а–4e. A mixture of 2-isopropyltetrahydro-4H-pyran-4-one 1 (1.42 g, 10 mmol), malononitrile (0.66 g, 10 mmol), aryl isothiocyanate (10 mmol) and triethylamine (2 mL) was stirred at 35°C for 5 h. After cooling, the crystalline precipitate was filtered off, washed with methanol, and dried. The IR spectra of compounds 4а–4е contain bands at 3250–3460 (NH2), 2215–2220 (CN), and 1120–1150 cm–1 (C=S).

6-Amino-3-isopropyl-8-thioxo-7-phenyl-3,4,7,8-tetrahydro-1H-pyrano[3,4-c]pyridine-5-carbonitrile (4a). Yield 2.31 g (71%), mp 267–268°С. 1H NMR spectrum (DMSO-d6), δ, ppm: 1.03 d (3H, CHCH3, J 6.8 Hz), 1.04 d (3H, CHCH3, J 6.8 Hz), 1.86 octet (1H, CHCH3, J 6.8 Hz), 2.48–2.65 m (2H, C4H2), 3.22–3.27 m (1H, C3H), 4.26 d. t (1H, OCH2, J 15.7, 1.8 Hz), 4.72 d (1H, OCH2, J 15.7 Hz), 6.48 br. s (2H, NH2), 7.12–7.19 m (2H, CHAr), 7.54–7.67 m (3H, CHAr). Found, %׃ C 66.57; H 5.79; N 12.82; S 9.76. C18H19N3OS. Calculated, %: C 66.43; H 5.88; N 12.91; S 9.85.

6-Amino-3-isopropyl-7-(2-methoxyphenyl)-8-thioxo-3,4,7,8-tetrahydro-1H-pyrano[3,4-c]pyridine-5-carbonitrile (4b). Yield 2.49 g (70%), mp 269–270°С. 1H NMR spectrum (DMSO-d6), δ, ppm: 1.02 d [3H, CH(CH3), J 6.6 Hz], 1.04 d [3H, CH(CH3), J 6.6 Hz], 1.82 d. septets (1H, CHCH3, J 7.7, 6.6 Hz), 2.40–2.65 m (2H, C4H2), 3.22–3.35 m (1H, C3H), 3.81 s (3H, OCH3), 4.17 d. t (1H, OCHH, J 15.6, 1.9 Hz), 4.68 d (1H, OCHH, J 15.6 Hz),6.47 br. s (2H, NH2), 7.01–7.05 m (1H, CHAr), 7.08–7.19 m (2H, CHAr), 7.43–7.51 m (1H, CHAr). 13С NMR spectrum (DMSO-d6), δС, ppm: 17.8 (CH3), 17.9 (CH3), 29.3 (CH2), 31.9 (CH), 55.3 (OCH3), 67.2 (OCH2), 77.1 (OCH), 78.1 (C5), 113.0 (CHAr), 115.2 (C≡N), 121.3 (CHAr), 123.8 (NCAr), 125.5 (CHAr), 128.9 (C8a), 130.7 (CHAr), 142.3 (C4a), 153.8 (C6), 154.0 (CAr), 178.0 (C=S). Found, %: C 64.35; H 5.88; N 11.73; S 9.18. C19H21N3O2S. Calculated, %: C 64.20; H 5.95; N 11.82; S 9.02.

6-Amino-3-isopropyl-7-(3-methoxyphenyl)-8-thioxo-3,4,7,8-tetrahydro-1H-pyrano[3,4-c]pyridine-5-carbonitrile (4c). Yield 2.56 g (72%), mp 244–245°С. 1H NMR spectrum (DMSO-d6), δ, ppm: 1.03 d [3H, CH(CH3), J 6.6 Hz], 1.05 d [3H, CH(CH3), J 6.6Hz], 1.83 d. septets (1H, CHCH3, J 7.7, 6.6 Hz), 2.42–2.64 m (2H, C4H2), 3.21–3.30 m (1H, C3H), 3.84 s (3H, OCH3), 4.18 d. t (1H, OCHH, J 15.6, 1.9 Hz), 4.70 d (1H, OCHH, J 15.6 Hz), 6.53 br. s (2H, NH2), 6.68–6.73 m (2H, CHAr), 7.00–7.06 m (1H, CHAr), 7.44–7.52 m (1H, CHAr). 13C NMR spectrum (DMSO-d6), δС, ppm: 17.9 (2CH3), 29.3 (CH2), 32.0 (CH), 54.9 (OCH3), 67.2 (OCH2), 77.1 (OCH), 78.4 (C5), 113.3 (C8a), 115.1 (C≡N), 115.2 (CHAr), 119.6 (CHAr), 124.1 (CHAr),130.6 (CHAr), 138.4 (NCAr), 142.3 (C4a), 153.8 (C6), 160.7 (CAr), 178.1 (C=S). Found, %: C 64.08; H 6.03; N 11.93; S 9.16. C19H21N3O2S. Calculated, %: C 64.20; H 5.95; N 11.82; S 9.02.

6-Amino-3-isopropyl-7-(4-methoxyphenyl)-8-thioxo-3,4,7,8-tetrahydro-1H-pyrano[3,4-c]pyridine-5-carbonitrile (4d). Yield 2.52 g (71%), mp 252–253°С. 1H NMR spectrum (DMSO-d6), δ, ppm: 1.04 d [6H, CH(CH3)2, J 6.6 Hz], 1.83 d. septets (1H, CHCH3, J 7.7, 6.6 Hz), 2.44–2.62 m (2H, C4H2), 3.21–3.34 m (1H, C3H), 3.87 s (3H, OCH3), 4.18 d. t (1H, OCHH, J 15.7, 1.8 Hz), 4.68 d (1H, OCHH, J 15.7 Hz), 6.47 br. s (2H, NH2), 7.01–7.17 m (4H, CHAr). Found, %: C 66.27; H 5.86; N 11.75; S 8.96. C19H21N3O2S. Calculated, %: C 64.20; H 5.95; N 11.82; S 9.02.

6-Amino-7-(4-chlorophenyl)-3-isopropyl-8-thioxo-3,4,7,8-tetrahydro-1H-pyrano[3,4-c]pyridine-5-carbonitrile (4e). Yield 2.66 g (74%), mp 249–250°С. 1H NMR spectrum (DMSO-d6), δ, ppm: 1.05 d [6H, CH(CH3)2, J 6.6 Hz], 1.83 d. septets (1H, CHCH3, J 7.7, 6.6 Hz), 2.47–2.61 m (2H, C4H2), 3.21–3.32 m (1H, C3H), 4.19 d. t (1H, OCHH, J 15.8, 2.3 Hz), 4.72 d (1H, OCHH, J 15.8 Hz), 6.55 br. s (2H, NH2), 7.09–7.18 m (2H, CHAr), 7.52–7.60 m (2H, CHAr). Found, %: C 60.21; H 5.12; Cl 9.97; N 11.52; S 8.78. C18H18ClN3OS. Calculated, %: C 60.07; H 5.04; Cl 9.85; N 11.68; S 8.91.

General procedure for synthesis of 6-amino-7-aryl-3-isopropyl-8-oxopyrano[3,4-c]pyridine-5-carbonitriles 6a–e. A mixture of 10 mmol of compound 4а–4e and 1.5 g (12 mmol) of dimethyl sulfate was heated for 10 min at 100–110°C. After cooling, a solution of 1.2 g of KOH in 30 mL of methanol was added to the mixture. The mixture was refluxed for 2 h, and then 20 mL of water was added. The formed crystals were filtered off, washed with water and dried, and recrystallized from nitromethane. The IR spectra of compounds 6a–6e contain absorption bands at 3237–3442 (NH2), 2200–215 (CN), and 1660–1665 cm–1 (C=O).

6-Amino-3-isopropyl-8-oxo-7-phenyl-3,4,7,8-tetrahydro-1H-pyrano[3,4-c]pyridine-5-carbonitrile (6a). Yield 2.41 g (78%), mp 275–276°С. 1H NMR spectrum (DMSO-d6–CCl4, 1 : 3), δ, ppm: 1.02 d (3H, CHCH3, J 6.6 Hz), 1.03 d (3H, CHCH3, J 6.6 Hz), 1.81 d. septets (1H, CHCH3, J 7.7, 6.6 Hz), 2.34–2.55 m (2H, C4H2), 3.21–3.30 m (1H, C3H), 4.16 d. t (1H, OCHH, J 15.0, 2.2 Hz), 4.46 d (1H, OCHH, J 15.0 Hz), 6.27 s (2H, NH2), 7.17–7.23 m (2H, 2CHAr), 7.47–7.61 m (3H, CHAr). 13С NMR spectrum (DMSO-d6–CCl4, 1 : 3), δС, ppm: 17.8 (CH3), 17.9 (CH3), 29.0 (CH2), 32.1 (CH), 63.8 (OCH2), 70.3 (C5), 77.5 (OCH), 110.9 (C8a), 116.0 (C≡N), 128.3 (CHAr), 128.5 (CHAr), 129.0 (CHAr), 129.7 (2CHAr), 134.1 (CAr), 144.7 (C4a), 154.2 (C6), 158.1 (C=O). Found, %: C 69.74; H 6.25; N 13.42. C18H19N3O2. Calculated, %: C 69.88; H 6.19; N 13.58.

6-Amino-3-isopropyl-7-(2-methoxyphenyl)-8-oxo-3,4,7,8-tetrahydro-1H-pyrano[3,4-c]pyridine-5-carbonitrile (6b). Yield 2.58 g (76%), mp 272–273°С. 1H NMR spectrum (DMSO-d6–CCl4, 1:3), δ, ppm: 1.02 d [3H, CH(CH3), J 6.6 Hz], 1.04 d [3H, CH(CH3), J 6.6 Hz], 1.81 d. septets (1H, CHCH3, J 7.7, 6.6 Hz), 2.83–2.91 m (2H, C4H2), 3.21–3.33 m (1H, C3H), 3.84 s (3H, OCH3), 4.18 d. t (1H, OCHH, J 17.0, 2.4 Hz), 4.49 d (1H, OCHH, J 17.0 Hz), 6.28 s (2H, NH2), 7.08–7.17 m (3H, 3CHAr), 7.41–7.54 m (1H, CHAr). Found, %: C 67.08; H 6.29; N 12.47. C19H21N3O3. Calculated, %: C 67.24; H 6.24; N 12.38.

6-Amino-3-isopropyl-7-(3-methoxyphenyl)-8-oxo-3,4,7,8-tetrahydro-1H-pyrano[3,4-c]pyridine-5-carbonitrile (6c). Yield 2.68 g (79%), mp 253–254°С. 1H NMR spectrum (DMSO-d6–CCl4, 1:3), δ, ppm: 1.03 d [6H, CH(CH3)2, J 6.6 Hz], 1.80 d. septets (1H, CHCH3, J 6.6 Hz), 2.81–2.88 m (2H, C4H2), 3.23–3.34 m (1H, C3H), 3.87 s (3H, OCH3), 4.19 d. t (1H, OCHH, J 15.0, 2.2 Hz), 4.37 d (1H, OCHH, J 15.0 Hz), 6.24 s (2H, NH2), 6.68–6.79 m (2H, CHAr), 7.00–7.08 m (1H, CHAr), 7.42–7.56 m (1H, CHAr). Found, %: C 67.11; H 6.17; N 12.23. C19H21N3O3. Calculated, %: C 67.24; H 6.24; N 12.38.

6-Amino-3-isopropyl-7-(4-methoxyphenyl)-8-oxo-3,4,7,8-tetrahydro-1H-pyrano[3,4-c]pyridine-5-carbonitrile (6d). Yield 2.61 g (77%), mp 354–355°С. 1H NMR spectrum (DMSO-d6–CCl4, 1 : 3), δ, ppm: 1.02 d (3H, CHCH3, J 6.6 Hz), 1.03 d (3H, CHCH3, J 6.6 Hz), 1.81 d. septets (1H, CHCH3, J 7.7, 6.6 Hz), 2.33–2.54 m (2H, C4H2), 3.20–3.29 m (1H, C3H), 3.86 s (3H, OCH3), 4.15 d. t (1H, OCHH, J 15.0, 2.2 Hz), 4.45 d (1H, OCHH, J 15.0 Hz), 6.25 s (2H, NH2), 7.01–7.13 m (4H, CHAr). 13С NMR spectrum (DMSO-d6–CCl4, 1:3), δС, ppm: 17.8 (CH3),17.9 (CH3), 29.0 (CH2), 32.0 (CH), 54.9 (OCH3), 63.8 (OCH2), 70.1 (C5), 77.5 (OCH), 110.8 (C8a), 115.0 (2CHAr), 116.1 (C≡N), 126.3 (NCAr), 129.3 (CHAr), 129.4 (CHAr), 144.5 (C4a), 154.6 (C6), 158.3 (C=O), 159.5 (CAr). Found, %: C 67.37; H 6.18; N 12.25. C19H21N3O3. Calculated, %: C 67.24; H 6.24; N 12.38.

6-Amino-7-(4-chlorophenyl)-3-isopropyl-8-oxo-3,4,7,8-tetrahydro-1H-pyrano[3,4-c]pyridine-5-carbonitrile (6e). Yield 2.58 g (75%), mp 283–284°С. 1H NMR spectrum (DMSO-d6–CCl4, 1 : 3), δ, ppm: 1.02 d (3H, CHCH3, J 6.6 Hz), 1.03 d (3H, CHCH3, J 6.6 Hz), 1.81 d. septets (1H, CHCH3, J 7.7, 6.6 Hz), 2.34–2.55 m (2H, C4H2), 3.20–3.29 m (1H, C3H), 4.16 d. t (1H, OCHH, J 15.0, 2.2 Hz), 4.46 d (1H, OCHH, J 15.0 Hz), 6.47 s (2H, NH2), 7.16–7.22 m (2H, 2CHAr), 7.51–7.57 m (2H, 2CHAr). 13С NMR spectrum (DMSO-d6–CCl4, 1:3), δС, ppm: 17.8 (CH3), 17.9 (CH3), 29.0 (CH2), 32.1 (CH), 63.8 (OCH2), 70.3 (C5), 77.5 (OCH), 110.6 (C8a), 116.0 (C≡N), 129.8 (2CHAr), 130.2 (CHAr), 130.3 (CHAr), 132.9 (NCAr), 134.2 (CAr), 144.9 (C4a), 154.2 (C6), 158.0 (C=O). Found, %: C 62.76; H 5.35; Cl 10.46; N 12.31. C18H18ClN3O2. Calculated, %: C 62.88; H 5.28; Cl 10.31; N 12.22.

General procedure for synthesis of 1-amino-5-aryl-9-isopropylpyrano[4′,3′:4,5]pyrido[2,3-d]pyrimidine-6-ones 7a–7e. A mixture of 5 mmol of compound 4а–4e and 10 mL of formamide was refluxed for 4 h. After cooling, the formed crystals were filtered off, washed with water, ethanol, and recrystallized from DMSO. The IR spectra of compounds 7a–7e contain absorption bands at 3353–3418 (NH2), 1650–1658 cm–1 (C=O).

1-Amino-9-isopropyl-5-phenyl-5,7,9,10-tetrahydro-6H-pyrano[4′,3′:4,5]pyrido[2,3-d]pyrimidine-6-one (7a). Yield 1.41 g (84%), mp 307–308°С. 1H NMR spectrum (DMSO-d6–CCl4, 1 : 3), δ, ppm: 1.06 d [6H, CH(CH3)2, J 6.7 Hz], 1.88 d. septets (1H, CHCH3, J 7.7, 6.6 Hz), 2.79–2.89 m (1H, C10HH), 3.05–3.25 m (2H, C10HH, C9H), 4.36 d. t (1H, OCHH, J 17.0, 2.4 Hz), 4.70 d (1H, OCHH, J 17.0 Hz), 6.88 s (2H, NH2), 7.06–7.13 m (2H, CHAr), 7.36–7.52 m (3H, CHAr), 7.95 s (1H, C3H). 13С NMR spectrum (DMSO-d6–CCl4, 1:3), δС, ppm: 17.7 (CH3), 18.0 (CH3), 30.1 (CH2), 31.9 (CH), 65.0 (OCH2), 77.9 (OCH), 97.4 (C10b), 124.0 (C6a), 127.1 (CHAr), 128.2 (2CHAr), 128.6 (2CHAr), 136.8 (CAr), 140.5 (C10a), 154.5 (C1), 155.3 (NCH), 159.2 (C=O), 160.4 (C4a). Found, %׃C 67.71; H 5.93; N 16.75. C19H20N4O2. Calculated, %: C 67.84; H 5.99; N 16.66.

1-Amino-9-isopropyl-5-(2-methoxyphenyl)-5,7,9,10-tetrahydro-6H-pyrano[4′,3′:4,5]pyrido[2,3-d]pyrimidine-6-one (7b). Yield 1.50 g (82%), mp 321–322°С. 1H NMR spectrum (DMSO-d6–CCl4, 1 : 3), δ, ppm: 1.03 d [6H, CH(CH3)2, J 6.6 Hz], 1.86 d. septets (1H, CHCH3, J 7.7, 6.6 Hz), 2.96–3.24 m (3H, C10H2, C9H), 3.65 s (3H, OCH3), 4.38 d. t (1H, OCHH, J 17.0, 2.4 Hz), 4.81 d (1H, OCHH, J 17.0 Hz), 6.86 s (2H, NH2), 7.03–7.16 m (1H, CHAr), 7.32–7.48 m (3H, CHAr), 8.01 s (1H, C3H). 13С NMR spectrum (DMSO-d6–CCl4, 1:3), δС, ppm: 18.0 (CH3), 18.2 (CH3), 30.4 (CH2), 31.9 (CH), 55.6 (OCH3), 68.3 (OCH2), 77.7 (OCH), 101.3 (C10b), 112.5 (CHAr), 120.8 (C6a), 129.4 (2CHAr), 129.9 (CHAr), 132.5 (CAr), 138.7 (C10a), 153.7 (C1), 156.5 (NCH), 156.5 (CAr), 159.7 (C=O), 161.2 (C4a). Found, %: C 65.66; H 5.97; N 15.13. C20H22N4O3. Calculated, %: C 65.56; H 6.05; N 15.29.

1-Amino-9-isopropyl-5-(3-methoxyphenyl)-5,7,9,10-tetrahydro-6H-pyrano[4′,3′:4,5]pyrido[2,3-d]pyrimidine-6-one (7c). Yield 1.56 g (85%), mp 294–295°С. 1H NMR spectrum (DMSO-d6–CCl4, 1 : 3), δ, ppm: 1.06 d [6H, CH(CH3)2, J 6.6 Hz], 1.88 d. septets (1H, CHCH3, J 7.7, 6.6 Hz), 2.78–2.88 m (1H, C10HH), 3.05–3.25 m (2H, C10HH, C9H), 3.81 s (3H, OCH3), 4.36 d. t (1H, OCHH, J 17.0, 2.5 Hz), 4.69 d (1H, OCHH, J 17.0 Hz), 6.60–6.63 m (1H, CHAr), 6.63–6.68 m (1H, CHAr), 6.88 s (2H, NH2), 6.91–6.97 m (1H, CHAr), 7.32–7.39 m (1H, CHAr), 7.96 s (1H, 3-CH). 13C NMR spectrum (DMSO-d6–CCl4, 1:3), δС, ppm: 17.7 (CH3), 18.1 (CH3), 30.1 (CH2), 31.9 (CH), 54.6 (OCH3), 64.9 (OCH2), 77.9 (OCH), 97.4 (C10b), 113.0 (CHAr), 114.3 (CHAr), 120.7 (CHAr), 123.9 (C6a), 128.8 (CHAr), 137.8 (CAr), 140.5 (C10a), 154.5 (C1), 155.3 (NCH), 159.1 (CAr), 159.5 (C=O), 160.4 (C4a). Found, %: C 65.43; H 6.11; N 15.41. C20H22N4O3. Calculated, %: C 65.56; H 6.05; N 15.29.

1-Amino-9-isopropyl-5-(4-methoxyphenyl)-5,7,9,10-tetrahydro-6H-pyrano[4′,3′:4,5]pyrido[2,3-d]pyrimidine-6-one (7d). Yield 1.54 g (84%), mp 315–316°С. 1H NMR spectrum (DMSO-d6), δ, ppm: 1.01 d [6H, CH(CH3)2, J 6.6 Hz], 1.84 d. septets (1H, CHCH3, J 7.7, 6.6 Hz), 2.77–2.87 m (1H, C10HH), 3.08–3.28 m (2H, C10HH, C9H), 3.81 s (3H, OCH3), 4.36 d. t (1H, OCHH, J 17.0, 2.4 Hz), 4.68 d (1H, OCHH, J 17.0 Hz), 6.97–7.11 m (4H, CHAr), 7.13 s (2H, NH2), 8.05 s (1H, C3H). 13C NMR spectrum (DMSO-d6), δС, ppm: 18.0 (CH3), 18.2 (CH3), 30.1 (CH2), 32.0 (CH), 55.2 (OCH3), 65.0 (OCH2), 77.9 (OCH), 97.5 (C10b), 114.0 (2CHAr), 123.8 (C6a), 129.6 (CAr), 129.8 (2CHAr), 140.8 (C10a), 155.0 (C1), 155.9 (NCH), 158.5 (C=O), 159.8 (CAr), 160.6 (C4a). Found, %: C 65.63; H 6.21; N 15.17. C20H22N4O3. Calculated, %: C 65.56; H 6.05; N 15.29.

1-Amino-5-(4-chlorophenyl)-9-isopropyl-5,7,9,10-tetrahydro-6H-pyrano[4′,3′:4,5]pyrido[2,3-d]pyrimidine-6-one (7e). Yield 1.59 g (86%), mp 324–325°С. 1H NMR spectrum (DMSO-d6–CCl4, 1 : 3), δ, ppm: 1.05 d [6H, CH(CH3)2, J 6.6 Hz], 1.87 d. septets (1H, CHCH3, J 7.7, 6.6 Hz), 2.78–2.88 m (1H, C10HH), 3.05–3.25 m (2H, C10HH, C9H), 4.35 d. t (1H, OCHH, J 17.0, 2.4 Hz), 4.69 d (1H, OCHH, J 17.0 Hz), 6.94 s (2H, NH2), 7.07–7.13 m (2H, CHAr), 7.43–7.49 m (2H, CHAr), 7.94 s (1H, C3H). 13C NMR spectrum (DMSO-d6–CCl4, 1 : 3), δС, ppm: 17.7 (CH3), 18.1 (CH3), 30.1 (CH2), 31.9 (CH), 64.9 (OCH2), 77.9 (OCH), 97.4 (C10b), 123.9 (C6a), 128.4 (2CHAr), 130.2 (2CHAr), 132.6 (CAr), 135.3 (CAr), 140.7 (C10a), 154.4 (C1), 155.3 (NCH), 159.0 (C=O), 160.4 (C4a). Found, %: C 61.46; H 5.23; Cl 9.75; N 14.98. C19H19ClN4O2. Calculated, %: C 61.54; H 5.16; Cl 9.56; N 15.11.