Experimental Section - 研究對合成熔融，線性和角雜環可溶性小分子庫的支持，新的癌症治療

General Procedure for the Synthesis of Ionic Liquid (IL) bound 1c.

N N Cl OH

MW, 100⁰ C, 3 min

N NCl^- OH +

1a 1b

NaBF4, CH3CN r.t. 48 h

N N OH

BF₄ -+

A mixture of 1-Methylimidazole 1a (1.0 g, 12.2 mmol) and 2-Chloroethanol (0.975 g, 12.2 mmol) was placed in a 10 mL microwave vial, and the vial was then irradiated for 3 min at 100^o C. After the reaction was cooled to ambient temperature, the formed viscous solid was successively washed with ether (20 mL×3), and then dried under vacuum for 6 h. The hydroxyl-functionalized ionic liquid 1b was obtained as white crystals (1.85 g, 94

%). ¹H NMR (300 MHz, D2O): δ 3.79(s, 3H), 3.82 (t, J = 3.7 Hz, 2H), 4.20 (t, J = 4.0 Hz, 2H), 7.34 (s, 1H), 7.39 (s, 1H), 8.64 (s, 1H).

NaBF₄ (2.5 g, 22.8 mmol) and dry acetonitrile (50 mL) was stirred at room temperature for 48 h under nitrogen. The so formed white precipitate was filtered off and washed with acetonitrile (30 mL×3). Concentration of combined filtrates gave product 1c as light yellow oil (2.39 g, 98%). ¹H NMR (300 MHz, acetone-d6): δ 3.94(t, J = 5.1 Hz, 2H), 4.04 (s, 3H), 4.42 (t, J = 5.1 Hz, 2H), 7.66 (s, 1H), 7.70 (s, 1H), 8.91 (s, 1H); MS (FAB):

m/z 127 (M⁺);

General Procedure for the Synthesis of Ionic Liquid (IL) bound Boc-L-tryptophan (3).

NHBoc O H O

N N BF₄

Boc-L-tryptophan 2 (0.76 g, 2.52 mmol), 1-Methyl-3-ethyl imidazolium tetrafluoroborate 1 (0.40 g, 1.87 mmol) and N, N’-dimethylamino pyridine (DMAP) (0.005 g) are placed in a dry, nitrogen-purged 100 mL round-bottom flask containing dry CH3CN (15 mL). To the mixtures were added dropwise N, N’-dicyclohexylcarbodiimide (DCC) (0.54 g, 2.62 mmol) dissolved in dry CH2Cl2 (5 mL) for a period of 5 minutes. The reaction mixtures were stirred for another 15 minutes at room temperature. Then this O-acylation reaction was carried out in a tube using microwave radiation at 40 w (80 °C, 1 bar) for 12 minutes.

After the completion of the reaction, the insoluble DCU byproduct was allowed to settle, and the reaction mixtures were filtered and washed with CH₃CN (50 mLҳ3). The solvent was evaporated, and the residue was again precipitated with cold ether which was filtered through fritted funnel to remove any unreacted acid and DCC, finally collected and dried under vacuum gave product 3 as pale white solid (1.18 g, 95%).

General Procedure for the Preparation Ionic Liquid (IL) bound Tetrahydro-β-carboline (4).

NH O

O N N

BF4

4 R₂ R₁

H +

Ionic Liquid bound Boc-L-tryptophan 3 (1.30 g, 2.60 mmol) was dissolved in 20 % TFA (4 mL) in H₂O-IPA (1:1, 16 mL). The mixtures were irradiated in a pressurized microwave reactor at 40 w (80 °C, 2 bar) for 10 minutes. After Boc protective group was removed, various aldehydes or ketones (5 mmol) were added to the reaction mixtures.

Then the reaction mixtures were further irradiated in a microwave oven at 40 w (80 °C, 2 bar) for 10 minutes with aldehydes and power 70 w (130 ^oC, 9 bar) for 20 minutes with ketones in one pot manner. After completion of the reaction time, the solvent was evaporated under reduced pressure. The residue was dissolved in acetonitrile, dried over anhydrous MgSO₄and precipitated with cold ether and filtered through a fritted funnel to remove any unreacted aldehydes or ketones used in the Pictet-Spenger reaction. Finally the product obtained is the ionic liquid supported tetrahydro-β-carboline derivatives 4.

Procedure for the Synthesis of Tetracyclic tetrahydro-β-carboline Derivatives (6).

N N O

X R₃ H

X = O or S 6

The tricyclic tetrahydro-β-carboline Derivatives 4 (1.0 mmol) was dissolved in H2O-IPA (1:1, 10 mL) mixtures and treated with substituted isocyanates or isothiocyanates (1.8 mmol) in triethylamine (0.30g, 3.0 mmol). The reaction mixtures was kept into microwave synthesis apparatus and irradiated at 40 w (80 °C, 2 bar) for 12 minutes. After the completion of the reaction time, TLC was checked which indicates the complete release of the targeted compound from ionic liquid support. Then mix solvents were removed under reduced pressure. The residue was dissolved in acetontrile again, dried over anhydrous MgSO4 andprecipitated with cold ether which was then filtered through

fritted funnel and the residue was repeatedly washed with ether (50 mLҳ3). The combined filtrate were subjected to evaporation to obtain the crude compounds 6 and was checked by crude HPLC for crude purity with UV detection at λ=254nm (column:Sphereclone 5μ Si (250 x 4.6 mm);gradient: 35 % ethyl acetate in hexane; flow rate: 1 (mL/min). The crude mixtures were further purified by column chromatography and eluted with ethyl acetate: hexane (1:9) to afford the final compounds in 75-95 % yields and 72-94 % purities.

General procedure for the synthesis of ionic liquid (IL) bound 4-bromomethyl-3-nitrobenzene carboxylates 8.

NO₂ Br O

8 N + NBF4

4-Bromometyl 3-nitro benzoic acid 7 (0.63 g, 2.43 mmol), 1-methyl-3-ethyl imidazolium tetrafluoroborate 1c (0.40 g, 1.87 mmol) and N, N’-dimethylamino pyridine (DMAP) (0.005 g) are placed in a dry, nitrogen-purged 100 mL round-bottom flask containing dry CH3CN (15 mL). N, N’-dicyclohexylcarbodiimide (DCC) (0.54 g, 2.62 mmol) dissolved in dry CH₂Cl₂(5 mL) was added drop wise to the mixtures for a period of 5 minutes. The reaction mixtures were stirred for another 15 minutes at room temperature. Then this O-acylation reaction was carried out in a sealed vessel using microwave radiation at (75 °C, 1 bar) for 12 minutes. After the completion of the reaction, the reaction mixtures were allowed to settle, and the insoluble dicylohexyl urea (DCU) was filtered off and washed with CH₃CN (50 mLҳ3). The solvent was evaporated, and the residue so left was precipitated with cold ether, filtered through fritted funnel dried under vacuum, gave product 8 as pale white solid. ¹H NMR (300 MHz, acetone-d6) d, J = 5.1 Hz,

2H), 4.04 (s, 3H), 4.42 t, J = 5.1 Hz, 2H), 7.66 (s, 1H), 7.70 (s, 1H), 8.91 (s, 1H); ¹³ C-NMR (75 MHz, CDCl3) δ 163.8, 148.7, 137.9, 137.8, 134.7, 133.8, 131.5, 126.5, 124.5, 123.5, 64.4, 48.9, 36.2; MS (FAB): m/z^

General procedure for the preparation ionic liquid (IL) bound 4-((substituted amino) methyl)-3-nitrobenzene carboxylates.

NO₂ HN O

R₁ 9

N +NBF4

Ionic liquid bound 4-bromomethyl-3-nitrobenzene carboxylates 8 (1.0 g, 2.19 mmol) in acetonitrile (15 mL) as treated with various primary amines (1.5 equiv). The reaction mixtures were irradiated in a pressurized microwave reactor at 80 °C, 0 w 1 bar for 5 minutes to complete reaction and the reaction mixtures was evaporated washed with cold ether (75 mL), dried to obtain the ionic liquid (IL) bound 4-((substituted amino)methyl)-3-nitrobenzene carboxylates 9.

General procedure for the preparation ionic liquid (IL) bound 3-amino-4-((substituted amino) methyl) benzene carboxylates 10.

NH₂ HN O

R₁ 10

N + NBF4

To a solution of 8 in methanol (15 mL), 10 % Pd/C ( 5 equiv) and ammonium formate ( 7 equiv) were added. The crude mixtures were stirred for 5 min for complete reduction of

O O

N HN R₃

R₁ 12 BF₄

N + N

nitro group. The reaction mixtures were filtered through filter paper to remove 10 % Pd/C.

The solvent was evaporated to dryness. Acetonitrile (10 mL) was added to salt out ammonium formate to obtain the ionic liquid (IL) bound 3-Amino-4-((substituted amino) methyl) benzene carboxylates 10.

General procedure for the preparation ionic liquid (IL) bound dihydro (11) and tetrahydro quinazolin derivatives 12.

O O

N H

R₁ R₂

11 BF₄

N + N

To a stirred solution of ionic liquid (IL) bound 3-amino-4-((substituted amino) methyl) benzene carboxylates 5 in dry CH₃CN (20 mL), N, N’-dicyclohexylcarbodiimide (DCC) (0.54 g, 2.62 mmol, 1 equiv) as activating agent and various isothiocyanates (1.05 mmol, 5.0 equiv) were added. The reaction mixture was sealed and exposed under pressured microwave irradiation at 80 ^oC for 10 minutes. Upon completion of the irradiation time, the insoluble DCU was allowed to settle, and the reaction mixtures were filtered and washed with CH₃CN (50 mLҳ3). The crude product mixtures were purified by precipitation with cold ether and dried to obtain the conjugate 11 in high purity. In case of tetrahydroquinazoline derivatives 12, various aldehydes (3 equiv) were added to the stirred solution of IL-conjugates 5 in dry CH₃CN (20 mL). The reaction mixtures was sealed and irradiated under pressured microwave irradiation at 80 ^oC for 10 minutes.

Upon completion of the irradiation time, the crude product mixtures were purified by precipitation with cold ether and dried to obtain the conjugate 12 in high purity.

NH N

N O

S O

General procedure for the cleavage of ionic liquid (IL) bound substituted dihydro and tetrahydro quinazolin derivatives 13a-n.

O O

N H

N R₁

R₂ O O

N HN R₃

13a-n

To a solution of conjugates 11 and 12 in methanol (20 mL), NaOMe (100 mg) was added and sealed. The reaction mixture was irradiated under pressured microwave irradiation at 80 ^oC for 12 minutes. After completion of the reaction, the crude product was precipitated with excess of cold ether (100 mL), the ionic liquid was filtered off and subjected to rota-vapor. The residue was dried under vacuum, and subjected to crude HPLC analysis with UV detection at λ=254 nm (column: Sphereclone 5μ Si (250 x 4.6 mm); gradient: 35 %

ethyl acetate in hexane; flow rate: 1 mL/min.). The residue was dissolved in dichloromethane (5 mL) and again subjected to rotavapor. The slurry obtained was loaded on silica gel column and eluted with a mixture of ethyl acetate and hexane (1:4) to get the title compounds 13a-n in good yields.

(11aS)-2-(Furan-2-ylmethyl)-5,5-dimethyl-3-thioxo-2,3,5,6,11,11a-hexahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indol-1-one (6a).

NH N

N O

1H NMR (300 MHz, CDCl3) δ 8.01 (s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.40-7.38 (m, 2H), 7.28-7.19 (m, 2H), 6.46 (d, J = 3.2 Hz, 1H), 6.35 (dd, J =7.3, 3.2 Hz, 1H), 5.14 (s, 2H), 4.33 (dd, J = 11.4, 4.4 Hz, 1H), 3.45 (dd, J = 15.0, 4.4 Hz, 1H), 2.87 (dd, J = 15.0, 11.4 Hz, 1H), 2.30 (s, 3H), 1.98 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 179.8, 171.7, 149.5, 142.8, 139.4, 136.6, 126.3, 123.2, 120.7, 118.8, 111.6, 110.9, 110.0, 105.6, 60.2, 60.0, 37.7, 29.5, 24.1, 22.9 ppm; MS (ESI): m/z 366 (MH⁺); HRMS (ESI) calcd for:

C₂₀H₁₉N₃O₂SNa: m/z 388.1096; Found: 388.1098 (M+Na); [α]_D²⁵₌-4.5 (c = 0.2, CHCl₃);

IR(KBr): 3338, 3027, 2923, 1730, 1596, 1446 cm^-1.

(11aS)-2-butyl-5,5-dimethyl-3-thioxo-2,3,5,6,11,11a-hexahydro-1H- imidazo[1',5':1,6]pyrido[3,4-b]indol-1-one (6b).

1H NMR (300 MHz, CDCl3) δ 7.92 (s, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.28-7.17 (m, 2H), 4.28 (dd, J = 11.4, 4.4 Hz, 1H), 3.90 (t, J = 7.5 Hz, 2H), 3.45 (dd, J = 15.0, 4.4 Hz, 1H), 2.84 (dd, J = 15.0, 11.4 Hz, 1H), 2.31 (s, 3H), 1.99 (s, 3H), 1.74-1.68 (m, 2H), 1.45-1.37 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 180.7, 172.1, 139.6, 136.5, 126.4, 123.2, 120.7, 118.8, 111.5, 105.8, 60.0, 59.8, 41.3, 30.1, 29.6, 24.1, 23.0, 20.5, 14.2 ppm; MS (ESI): m/z 342 (MH⁺); HRMS (ESI) calcd for C19H23N3OSNa: m/z 364.1459; Found: 364.1456 (M+Na); [α]D 25

= -24.6 (c = 0.1, CHCl₃); IR(KBr): 3349, 1720, 1627, 1436 cm^-1.

NH N

N O

O NH

N N O

(11aS)-2-benzyl-5,5-dimethyl-5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione (6c).

1H NMR (300 MHz, CDCl₃) δ 8.26 (s, 1H), 7.53 (d, J = 7.4 Hz, 1H), 7.48-7.46 (m, 2H), 7.39-7.31 (m, 4H), 7.28-7.16 (m, 2H), 4.74 (s, 2H), 4.27 (dd, J = 11.4, 4.6 Hz, 1H), 3.90 (dd, J = 14.9, 4.6 Hz, 1H), 2.83 (dd, J = 14.9, 11.4 Hz, 1H), 2.04 (s, 3H), 1.75 (s, 3H);

13C NMR (75 MHz, CDCl3) δ 172.0, 154.7, 139.0, 136.6, 136.5, 129.7, 129.1, 129.0, 128.3, 127.8, 126.7, 122.9, 120.5, 118.8, 111.5, 105.8, 56.7, 55.9, 42.6, 28.6, 26.5, 23.3 ppm; MS (FAB): m/z 360 (MH+); HRMS (ESI) calcd for C₂₂H₂₁N₃O₂Na: m/z 382.1531;

Found: 382.1535 (M+Na); [α]D 25

= -28.8 (c = 0.05, CHCl3); IR(KBr): 3330, 2923, 1760, 1702, 1596, 1448 cm^-1.

(11aS)-2-butyl-5,5-dimethyl-5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione (6d).

1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.28-7.15 (m, 2H), 4.25 (dd, J = 11.4, 4.4 Hz, 1H), 3.58 (t, J = 7.2 Hz, 2H), 3.40 (dd, J = 14.9, 4.4 Hz, 1H), 2.83 (dd, J = 14.9, 11.4 Hz, 1H), 2.06 (s, 3H), 1.77 (s, 3H), 1.70-1.65 (m, 2H), 1.43-1.35 (m, 2H), 0.97 (t, J = 7.1 Hz, 3H);¹³C NMR (75 MHz,

NH N

N O

O O

N N O

CDCl3) δ 172.3, 155.1, 139.1, 136.6, 126.6, 123.0, 120.5, 118.8, 111.5, 105.9, 56.4, 55.8, 38.9, 30.7, 28.7, 26.5, 23.3, 20.5, 14.1 ppm; MS (ESI): m/z 326 (MH⁺); HRMS (ESI) calcd for C19H23N3O2Na: m/z 348.1688; Found: 348.1685 (M+Na); [α]D 25

= -35.5 (c = 0.15, CHCl₃); IR (KBr): 3338, 2960, 1762, 1702, 1454 cm^-1.

(11a'S)-2'-(4-ethoxyphenyl)-11',11a'-dihydrospiro[cyclohexane-1,5'-imidazo[1',5':1,6]pyrido[3,4-b]indole]-1',3'(2'H,6'H)-dione (6e).

1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.46-7.33 (m, 3H), 7.46-7.17 (m, 2H), 6.99 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 4.46 (dd, J = 11.2, 4.8 Hz, 1H), 4.07 (q, J = 7.0 Hz, 2H), 3.49 (dd, J = 15.1, 4.8 Hz, 1H), 2.98 (dd, J = 15.1, 11.2 Hz, 1H), 2.41 (m, 1H), 2.11-1.94 (m, 2H), 1.94-1.65 (m, 7H), 1.45 (t, J = 7.0 Hz, 3H); ¹³C NMR (75 MHz, CDCl3) δ 171.6, 159.0, 154.1, 139.7, 136.1, 128.2, 126.2, 124.5, 123.0, 122.9, 120.5, 118.6, 115.3, 115.2, 111.6, 106.3, 64.1, 59.6, 55.6, 35.8, 33.8, 24.6, 24.1, 24.0, 23.9, 15.2 ppm; MS (ESI): m/z 430 (MH⁺); HRMS (ESI): calcd for C26H27N3O3Na: m/z 452.1950; Found: 452.1947 (M+Na); [α]D 25

= -93.0 (c = 0.14, CHCl₃); IR (KBr): 3413, 2933, 1766, 1710, 1512 cm^-1.

(11a'S)-2'-benzyl-11',11a'-dihydrospiro[cyclohexane-1,5'-imidazo[1',5':1,6]pyrido[3,4-b]indole]-1',3'(2'H,6'H)-dione (6f).

NH N

N O

1H NMR (300 MHz, CDCl₃) δ 8.44 (s, 1H), 7.55 (d, J = 7.3 Hz, 1H), 7.48 (d, J = 6.8 Hz, 2H), 7.42-7.30 (m, 4H), 7.28-7.17 (m, 2H), 4.78 (d, J = 14.6 Hz, 1H), 4.72 (d, J = 14.6 Hz, 1H), 4.34 (dd, J = 11.1, 4.7 Hz, 1H), 3.41 (dd, J = 15.0, 4.7 Hz, 1H), 2.86 (dd, J = 15.0, 11.1 Hz, 1H), 2.33 (m, 1H), 2.10-1.97 (m, 2H), 1.84-1.73 (m, 7H); ¹³C NMR (75 MHz, CDCl3) δ 172.3, 154.7, 139.6, 136.7, 136.0, 129.2, 129.0, 128.9, 128.3, 127.7, 126.2, 122.9, 120.6, 118.7, 111.6, 106.4, 59.4, 56.7, 45.1, 42.6, 36.0, 33.8, 32.3, 24.7, 23.9 ppm; MS (ESI): m/z 400 (MH⁺); HRMS (ESI): calcd for C25H25N3O2Na: m/z 422.1844; Found: 422.1846 (M+Na); [α]_D²⁵₌-113.7 (c = 0.13, CHCl₃); IR (KBr): 3417, 2925, 1762, 1704, 1600, 1492, 1452 cm^-1.

(11a'S)-2'-butyl-11',11a'-dihydrospiro[cyclohexane-1,5'-imidazo[1',5':1,6]pyrido[3,4-b]indole]-1',3'(2'H,6'H)-dione (6g).

1H NMR (300 MHz, CDCl₃) δ 8.47 (s, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.28-7.15 (m, 2H), 4.30 (dd, J = 11.2, 4.9 Hz, 1H), 3.58 (t, J = 7.1 Hz, 2H), 3.40 (dd, J = 15.0, 4.9 Hz, 1H), 2.85 (dd, J = 15.0, 11.2, Hz, 1H), 2.37 (m, 1H), 2.13-1.98 (m, 2H), 1.90-1.68 (m, 7H), 1.80-1.65 (m, 2H), 1.42-1.35 (m, 2H) 0.98 (t, J = 6.2 Hz, 3H);

13C NMR (75 MHz, CDCl3): δ 172.6, 154.9, 139.7, 136.1, 126.3, 122.8, 120.5, 118.6, 111.6, 106.4, 59.2, 56.6, 56.5, 38.9, 36.1, 33.8, 30.7, 24.7, 24.0, 23.9, 20.5, 14.2 ppm;

MS (ESI): m/z 366 (MH⁺); HRMS (ESI) calcd for C22H27N3O2Na: m/z 388.2001; Found:

NH N

N O

O O

NH N

N O

388.2003 (M+Na); [α]D 25

= -232.0 (c = 0.2, CHCl3); IR ( KBr): 3413, 2933, 1766, 1710, 1512 cm^-1.

(5R,11aS)-5-(1,3-benzodioxol-5-yl)-2-(2-methylpropyl)-3-thioxo-2,3,5,6,11,11a-hexahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indol-1-one (6h).

1H NMR (300 MHz, CDCl3) δ 7.90 (s, 1H), 7.56 (d, J = 7.3 Hz, 1H), 7.33-7.17 (m, 3H), 7.01 (dd, J = 7.9, 1.7 Hz, 1H), 6.96 (m, 1H), 6.78 (d, J = 7.9 Hz, 1H), 5.95 (dd, J = 5.1, 1.2 Hz, 2H), 4.42 (dd, J = 11.2, 5.8 Hz, 1H), 3.68 (dd, J = 7.3, 3.1 Hz, 2H), 3.54 (dd, J = 15.1, 5.8 Hz, 1H), 2.93 (dd, J = 15.1, 11.2 Hz, 1H), 2.30 (sept, J = 7.0 Hz, 1H), 0.96 (d, J

= 7.0 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 181.3, 173.9, 148.5, 137.0, 132.4, 131.3, 126.3, 123.4, 123.1, 120.7, 118.9, 111.6, 110.9, 109.3, 108.9, 107.9, 101.8, 55.9,

55.4, 48.9, 27.5, 24.4, 20.5, 20.4 ppm; MS (EI): m/z 433 (M⁺); HRMS (ESI) calcd for C₂₄H₂₃N₃O₃SNa: m/z 456.1358; Found: 456.1355 (M+Na); [α]_D²⁵₌-75.3 (c = 0.2 , CHCl3); IR (KBr): 3357, 2960, 1737, 1637, 1457 cm^-1.

(5R,11aS)-2-benzyl-5-butyl-5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione (6i)

NH N

N O

S O

1H NMR (300 MHz, CDCl3) δ 8.15 (s, 1H), 7.50-7.44 (m, 3H), 7.38-7.30 (m, 4H), 7.24-7.13 (m, 2H), 5.27 (t, J = 7.2 Hz, 1H), 4.77 (d, J = 14.6 Hz, 1H), 4.72 (d, J = 14.6 Hz, 1H), 4.34 (dd, J = 11.0, 5.7 Hz, 1H), 3.40 (dd, J = 15.3, 5.7 Hz, 1H), 2.76 (dd, J = 15.3, 11.0 Hz, 1H), 2.01 (m, 1H), 1.78 (m, 1H), 1.44-1.32 (m, 4H), 0.90 (t, J = 6.8 Hz, 3H);

13C NMR (75 MHz, CDCl3) δ 173.3, 155.7, 136.7, 136.5, 133.0, 129.2, 128.9, 128.3, 126.6, 122.9, 120.5, 118.6, 111.5, 106.3, 54.3, 49.1, 42.8, 36.2, 28.2, 23.9, 23.1, 14.4 ppm; MS (ESI): m/z 388 (MH⁺); HRMS (ESI): calcd for C₂₄H₂₅N₃O₂Na: m/z 410.1844;

Found: 410.1842 (M+Na); [α]D 25

= -72.4 (c = 0.1, CHCl3); IR ( KBr): 3324, 2923, 1764, 1706, 1450 cm^-1.

(5R,11aS)-5-butyl-2-(furan-2-ylmethyl)-3-thioxo-2,3,5,6,11,11a-hexahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indol-1-one (6j).

1H NMR (300 MHz, CDCl3) δ 8.11 (s, 1H), 7.42-7.38 (m, 2H), 7.24-7.13 (m, 3H), 6.48 (dd, J = 6.6, 3.2 Hz, 1H), 6.36 (dd, J = 6.6, 3.2 Hz, 1H), 5.88 (t, J = 6.0 Hz 1H), 5.17 (s, 2H), 4.40 (dd, J = 12.0, 6.0 Hz, 1H), 3.29 (dd, J = 15.0, 6.0 Hz, 1H), 2.46 (dd, J = 15.0, 12.0 Hz, 1H), 2.16 (m, 1H), 1.89 (m, 1H), 1.46-1.32 (m, 4H), 0.91 (t, J = 6.0 Hz, 3H);

13C NMR (75 MHz, CDCl3) δ 180.7, 173.4, 149.3, 142.8, 136.7, 132.4, 126.3, 123.0, 120.5, 118.6, 111.3, 110.9, 110.0, 106.1, 57.1, 53.1, 38.2, 35.0, 27.9, 23.7, 23.2, 14.3 ppm; MS (ESI): m/z 394 (MH⁺); HRMS (ESI) calcd for C₂₂H₂₃N₃O₂SNa: m/z 416.1409;

NH N

N O

NH N

N O

Found: 416.1405 (M+Na); [α]D 25

= -166.1 (c = 0.2, CHCl3); IR ( KBr): 3399, 2931, 1747, 1623, 1463 cm^-1.

(5R,11aS)-5-butyl-2-phenyl-5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione (6k).

1H NMR (300 MHz, CDCl₃) δ 8.04 (s, 1H), 7.55-7.49 (m, 5H), 7.41-7.33 (m, 3H), 7.22 (m, 1H), 5.38 (t, J = 5.6 Hz, 1H), 4.50 (dd, J = 10.9, 5.7 Hz, 1H), 3.51 (dd, J = 15.0, 5.7 Hz, 1H), 2.97 (dd, J = 15.0, 10.9 Hz, 1H), 2.08 (m, 1H), 1.85 (m, 1H), 1.58-1.26 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 172.4, 154.8, 136.7, 132.9, 132.0, 129.6, 129.5, 128.6, 126.7, 126.5, 123.0, 120.8, 120.6, 120.5, 118.6, 111.5, 106.3 54.3, 49.3, 36.1, 28.2, 23.1, 14.4 ppm; MS (ESI): m/z 374 (MH⁺); HRMS (ESI) calcd for C23H23N3O2Na: m/z 396.1688; Found: 396.1691 (M+Na); [α]D 25

= -72.4 (c = 0.05, CHCl3); IR (KBr): 3318, 2923, 1714, 1596, 1492, 1444 cm^-1.

(5R,11aS)-5-butyl-2-(4-fluorophenyl)-3-thioxo-2,3,5,6,11,11a-hexahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indol-1-one (6l).

NH N

N O

1H NMR (300 MHz, CDCl3) δ 8.16 (s, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.38-7.40 (m, 3H), 7.28-7.18 (m, 4H), 5.98 (t, J = 5.5 Hz, 1H), 4.64 (dd, J = 11.0, 5.9 Hz, 1H), 3.53 (dd, J = 15.2, 5.9 Hz, 1H), 2.98 (dd, J = 15.2, 11.0 Hz, 1H), 2.26 (m, 1H), 1.94 (m, 1H), 1.50-1.41 (m, 4H), 0.94 (t, J = 7.0 Hz, 3H) ; ¹³C NMR (75 MHz, CDCl₃) δ 182.2, 173.3, 136.9, 132.7, 130.9, 130.7, 128.2, 128.1, 126.4, 123.1, 120.6, 118.6, 117.0, 116.8, 116.5, 111.6, 105.9 57.7, 53.5, 34.9, 28.0, 23.3, 14.4 ppm; MS (ESI): m/z 408 (MH⁺); HRMS (ESI) calcd for C₂₃H₂₂FN₃OSNa: m/z 430.1365; Found: 430.1362 (M+Na); [α]_D²⁵₌ -108.9 (c = 0.2, CHCl3); IR (KBr): 3357, 2923, 1743, 1598, 1454 cm^-1.

(5R,11aS)-5-butyl-2-(2-methylpropyl)-3-thioxo-2,3,5,6,11,11a-hexahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indol-1-one (6m).

1H NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.36 (dd, J = 7.8, 3.0 Hz, 1H), 7.28-7.14 (m, 2H), 5.90 (t, J = 5.4 Hz, 1H), 4.42 (dd, J =12.0, 5.9 Hz, 1H), 3.76 (d, J = 7.3 Hz, 2H), 3.39 (dd, J =15.0, 5.9 Hz, 1H), 2.66 (dd, J =15.0, 12.0 Hz, 1H), 2.37 (m, 1H), 2.20 (m, 1H), 1.90 (m, 1H), 1.50-1.30 (m, 4H), 0.99-0.94 (m, 6H), 0.90 (t, J = 6.7 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 181.9, 174.3, 136.8, 132.9, 126.5, 123.0, 120.6, 118.6, 111.5, 106.2, 57.1, 53.0, 48.9, 35.1, 28.0, 27.8, 24.2, 23.5, 20.5, 20.4, 14.4 ppm; MS (ESI): m/z 370 (MH⁺); HRMS (ESI): calcd for C21H27N3OSNa: m/z 392.1772;

Found: 392.1771 (M+Na); [α]_D²⁵₌-71.9 (c = 0.2, CHCl₃); IR (KBr): 3399, 2931, 1747, 1623, 1463 cm^-1.

NH N

N O

(11a'S)-2'-butyl-3'-thioxo-2',3',11',11a'-tetrahydrospiro[cyclopentane-1,5'-imidazo[1',5':1,6]pyrido[3,4-b]indol]-1'(6'H)-one (6n).

1H NMR (300 MHz, CDCl₃) δ 7.81 (s, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.39 (dd, J = 7.8, 0.9 Hz, 1H), 7.25-7.16 (m, 2H), 4.29 (dd, J = 11.5, 4.5 Hz, 1H), 3.92 (t, J = 7.5 Hz, 2H), 3.44 (dd, J = 14.9, 4.5 Hz, 1H), 2.85 (dd, J = 14.9, 11.5 Hz, 1H), 2.78 (m, 1H), 2.58 (m, 1H), 2.42 (m, 1H), 2.24 (m, 1H), 2.01-1.90 (m, 4H), 1.73-1.67 (m, 2H), 1.47-1.37 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H); ¹³C NMR (75 MHz, CDCl3) δ 179.8, 172.2, 141.3, 136.7, 126.1, 123.0, 120.7, 118.7, 111.5, 105.3, 69.2, 61.5, 41.2, 38.8, 38.0, 30.2, 28.8, 26.8, 23.1, 20.5, 14.2 ppm; MS (ESI): m/z 368 (MH⁺); HRMS (ESI) calcd for C21H25N3OSNa:

m/z 390.1616; Found: 390.1618 (M+Na); [α]_D²⁵₌-6.5 (c = 0.2, CHCl₃); IR (KBr): 3401, 2923, 1728, 1596, 1490, 1444 cm^-1.

Methyl 3-[2-(cyclohex-1-en-1-yl)ethyl]-2-(phenylamino)-3,4-dihydroquinazoline-7-carboxylate (13a)

O O H₃C

N H

1H NMR (300MHz, CDCl3) δ 7.44 (s, 1H), 7.37 (dd, J = 6.1, 1.7 Hz, 1H), 7.35-7.32 (m, 3H), 7.31 (d, J = 1.7 Hz, 1H), 7.23 (m, 1H), 7.14 (d, J = 6.1 Hz, 1H), 5.48 (m, 1H), 5.20 (s, 2H), 4.62 (brs, 1H), 3.89 (s, 3H), 3.57 (t, J = 7.4 Hz, 1H), 2.18 (t, J = 7.4 Hz, 1H),

1.98-1.88 (m, 4H), 1.62-1.50 (m, 4H).¹³C NMR (75 MHz, CDCl₃)  181.9, 167.6, 146.6, 140.0, 134.8, 131.5, 131.3, 129.2, 126.5, 126.4, 125.0, 124.5, 118.9, 116.8, 53.9, 52.5, 48.2, 35.5, 29.0, 25.6, 23.1, 22.5 ppm. MS (ESI): m/z 390 (MH⁺); HRMS (ESI) calcd for:

C24H28N3O2: m/z 390.2181. Found 390.2184; IR(KBr): 3322, 2925, 1707, 1600, 1533, 1448 cm^-1.

Methyl 3-[2-(cyclohex-1-en-1-yl)ethyl]-2-[(furan-2-ylmethyl)amino]-3,4-dihydroquinazoline-7-carboxylate (13b)

O O H₃C

N H

N O

1H NMR (300MHz, CDCl3) δ 7.36 (dd, J = 6.0, 1.1 Hz, 1H), 7.32 (dd, J = 6.0, 1.1 Hz, 1H), 7.09 (d, J = 8.9 Hz, 1H), 6.33 (t, J = 3.0 Hz, 1H), 6.30 (d, J = 3.0 Hz, 1H), 5.93 (t, J

= 3.0 Hz, 1H), 5.48 (m, 1H), 5.25 (s, 2H), 4.90 (d, J = 6.0 Hz, 2H), 3. 98 (s, 3H), 3.39 (t, J = 7.4 Hz, 2H), 2.08 (t, J = 7.4 Hz, 2H), 1.98-1.88 (m, 2H), 1.80-1.78 (m, 2H), 1.60-1.40 (m, 4H);¹³C NMR (75 MHz, CDCl3)  181.9, 151.8, 146.7, 134.9, 131.2, 131.1, 125.0, 124.9, 119.0, 116.5, 111.1, 108.9, 54.2, 52.5, 47.4, 43.8, 35.2, 28.8, 25.5, 23.0, 22.5 ppm.

MS (ESI): m/z 394 (MH⁺); HRMS (EI) calcd for: C23H27N3O2: m/z 393.2052. Found 393.2055; IR(KBr): 3337, 2927, 1704, 1633 cm^-1.

Methyl 3-[2-(cyclohex-1-en-1-yl)ethyl]-2-[(2-methylpropyl)amino]-3,4-dihydroquinazoline-7-carboxylate (13c)

O O H₃C

N H

1H NMR (300MHz, CDCl3) δ 7.34-7.28 (m, 2H), 7.09 (d, J = 7.7 Hz, 1H), 5.67 (t, J = 4.8 Hz, 1H), 5.41 (brs, 1H), 5.18 (s, 2H), 3.88 (s, 3H), 3.52 (t, J = 6.3 Hz, 2H), 3.38 (t, J = 7.7 Hz, 2H), 2.04 (t, J = 7.7 Hz, 2H), 1.97-1.88 (m, 2H), 1.89-1.83(m, 2H), 1.63-1.49 (m, 4H), 0.95 (d, J = 6.3 Hz, 6H). ¹³C-NMR (75 MHz, CDCl₃) δ 181.4, 167.6, 146.6, 134.7, 131.4, 131.3, 124.9, 124.6, 118.7, 116.6, 54.3, 54.0, 52.5, 47.3, 35.3, 28.9, 28.6, 25.6, 23.1, 22.4, 20.7 ppm. MS (ESI): m/z 370 (MH⁺) . HRMS (ESI) calcd for:

C₂₂H₃₂N₃O₂: m/z 370.2494. Found 370.2496. IR(KBr): 3324, 2925, 1710, 1631, 1529, 1438 cm^-1.

Methyl 3-cyclopentyl-2-[(furan-2-ylmethyl)amino]-3,4-dihydroquinazoline-7-carboxylate (13d)

O O H₃C

N H

N O

1H NMR (300MHz, CDCl3) δ 7.39 ( dd, J = 7.9, 1.4 Hz, 1H), 7.35 (d, J = 1.4 Hz, 1H), 7.27 (m, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.27 (dd, J = 3.1, 1.8 Hz, 1H), 6.17 (d, J = 3.1 Hz 1H), 5.74 (t, J = 4.4 Hz, 1H), 5.29 (t, J = 8.5 Hz, 1H), 4.83 (d, J = 4.8 Hz 1H), 4.62 (s, 2H), 3.95(m, 1H), 3.88 (s, 2H), 1.99-1.93 (m, 2H), 1.69-1.55 (m, 4H), 1.48-1.41 (m, 2H).

13C-NMR (75 MHz, CDCl₃) δ 182.7, 167.4, 151.3, 144.1, 142.5, 130.7, 127.7, 125.8, 120.4, 117.5, 110.8, 108.0, 61.7, 52.5, 47.2, 43.6, 29.3, 24.2 ppm. MS (ESI) m/z 354

(MH⁺). HRMS (ESI) calcd for: C20H24N3O3: m/z 354.1818 . Found 354.1815. IR(KBr):

3365, 2952, 1708, 1631, 1529, 1436 cm^-1.

Methyl 3-cyclopentyl-2-(prop-2-en-1-ylamino)-3,4-dihydroquinazoline-7-carboxylate (13e)

O O H₃C

N H

1H NMR (300MHz, CDCl3) δ 7.45 (dd, J = 7.9, 1.4 Hz 1H), 7.41 (d, J = 1.4 Hz 1H), 7.10 (d, J = 7.9 Hz, 1H), 5.84 (m, 1H), 5.44 (t, J = 5.3 Hz, 2H), 5.38 (m, 1H), 5.10-5.02 (m, 2H), 4.61 (s, 2H), 4.30 (t, J = 5.3 Hz, 2H), 3.89 (s, 3H), 2.03-1.95 (m, 2H), 1.69-1.55 (m, 4H), 1.48-1.41 (m, 2H); ¹³C-NMR (75 MHz, CDCl3) δ 182.9, 167.4, 144.0, 134.2, 130.8, 127.6, 125.7, 120.4, 117.5, 117.0, 61.8, 52.6, 49.0, 47.0, 29.3, 24.2 ppm. MS (ESI) m/z 314 (MH⁺). HRMS (ESI) calcd for: C18H24N3O2: m/z 314.1868 . Found 314.1866.

IR(KBr): 3370, 2954, 1710, 1631, 1577, 1444 cm^-1.

Methyl3-(2-methoxyethyl)-2-[(2-methylpropyl)amino]-3,4-dihydroquinazoline-7-carboxylate (13f)

O O H₃C

N H

1H NMR (300MHz, CDCl₃) δ 7.50 (t, J = 8.1, Hz 1H), 7.32-7.28 (m, 2H), 7.05 (d, J = 8.1 Hz 1H), 5.26 (s, 2H), 3.89 (s, 3H), 3.52 (t, J = 8.4 Hz, 2H), 3.45 (t, J = 5.7 Hz, 2H), 3.30 (s, 3H), 1.97-1.88 (m, 2H), 0.87 (d, J = 8.4 Hz, 6H). ¹³C-NMR (75 MHz, CDCl3) δ 184.2, 167.6, 146.8, 131.6, 131.4, 125.1, 118.6, 116.5, 72.1, 59.6, 54.9, 54.5, 52.5, 49.7, 28.4,

20.7 ppm; MS (ESI) m/z 320 (MH⁺). HRMS (ESI) calcd for: C17H26N3O3: m/z 320.1974 . Found 320.1977. IR(KBr): 3338, 2952, 1728, 1629, 1579, 1240 cm^-1.

Methyl 3-(2-methylpropyl)-2-[(2-methylpropyl)amino]-3,4-dihydroquinazoline-7-carboxylate (13g)

O O H₃C

N H

1H NMR (300MHz, CDCl₃) δ 7.32 (dd, J = 7.8, 1.5 Hz 1H), 7.29 (d, J = 1.5 Hz 1H), 7.04 (d, J = 7.8 Hz, 1H), 5.84 (m, 1H), 5.62 (t, J = 5.2 Hz, 2H), 5.22 (s, 2H), 3.87 (s, 3H), 3.51 (dd, J = 6.8, 5.2, Hz 1H 2H), 3.16(d, J = 7.6 Hz 1H), 2.06 (m, 1H), 1.93 (m, 1H), 0.91 (t, 6.8 Hz, 12H); ¹³C-NMR (75 MHz, CDCl₃) δ 182.1, 167.5, 146.5, 131.3, 131.2, 124.9, 118.9, 116.8, 55.1, 54.4, 54.3, 52.5, 28.5, 27.6, 20.9, 20.7 ppm. MS (ESI) m/z 318 (MH⁺). HRMS (ESI) calcd for: C₁₈H₂₈N₃O₂ m/z 318.2181. Found 318.2179. IR(KBr):

3370, 2954, 1710, 1631, 1577, 1444 cm^-1.

Methyl 2-[(furan-2-ylmethyl)amino]-3-(2-methylpropyl)-3,4-dihydroquinazoline-7-carboxylate (13h).

O O H₃C

N H

N O

1H NMR (300MHz, CDCl3) δ 7.35-7.28 (m, 3H), 7.04 (d, J = 7.8 Hz 1H), 6.32 (dd, , J

=3.2, 2.0 Hz, 1H), 6.27 (d, J =3.2 Hz, 1H), 5.94 (t, J = 4.6 Hz, 1H), 5.22 (s, 1H), 4.88 (d, J = 4.6 Hz, 1H), 3.90 (s, 3H), 3.15 (d, J = 7.6 Hz, 2H), 2.05-1.99 (m, 1H) 0.86 (d, J = 6.7 Hz, 6H); ¹³C-NMR (75 MHz, CDCl ) δ 181.9, 167.6, 151.2, 146.4, 142.6, 131.3, 131.2,

O O H₃C

N H

124.8, 118.9, 116.8, 110.9, 108.3, 55.0, 54.5, 52.5, 43.8, 27.5, 20.8 ppm; MS (ESI) m/z 342 (M⁺). HRMS (ESI) calcd for: C₁₉H₂₄N₃O₃ m/z 342.1818. Found 342.1817. IR(KBr):

3446, 2927, 1704, 1531, 1438 cm^-1.

Methyl 3-(2-methylpropyl)-2-(prop-2-en-1-ylamino)-3,4-dihydroquinazoline-7-carboxylate (13i)

1H NMR (300MHz, CDCl₃) δ 7.31 (dd, J = 7.7, 1.6 Hz 1H), 7.28 (d, J = 1.6 Hz 1H), 7.03 (d, J = 7.7 Hz 1H), 5.90 (m, 1H), 5.73 (t, J = 5.1 Hz, 1H), 5.19 (s, 2H), 5.15-5.11 (m, 1H), 4.34-4.30 (m, 2H), 3.85 (s, 3H), 3.16 (d, J = 7.7 Hz, 2H), 2.06 (m, 1H), 0.83 (d, J = 7.7 Hz, 6H); ¹³C-NMR (75 MHz, CDCl₃) δ 182.1, 167.6, 146.4, 134.3, 131.2, 130.8, 124.9, 118.9, 117.3, 116.8, 55.0, 54.4, 52.5, 49.2, 27.5, 20.8 ppm; MS (ESI) m/z 302 (MH⁺). HRMS (ESI) calcd for: C₁₇H₂₄N₃O₂: m/z 302.1868. Found 302.1867. IR(KBr):

3370, 2954, 1710, 1631, 1577, 1444 cm^-1.

Methyl 3-(propan-2-yl)-2-(prop-2-en-1-ylamino)-3,4-dihydroquinazoline-7-carboxylate (13j)

O O H₃C

N H

1H NMR (300MHz, CDCl₃) δ 7.45 (d, J = 8.3, 1.4 Hz, 1H), 7.42 (d, J = 3.3 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 5.80 (m, 1H), 5.46-5.37 (m, 2H), 5.07-4.99 (m, 2H), 4.60 (s, 2H), 4.31-4.26 (m, 2H), 3.89 (s, 3H), 1.21 (s, 6H); ¹³C-NMR (75 MHz, CDCl3) δ 182.1,166.9,

143.7, 133.8, 130.5, 127.5, 125.1, 119.9, 117.1, 116.5, 52.1, 51.5, 48.5, 45.3, 19.9 ppm;

MS (ESI) m/z 288 (MH⁺). HRMS (ESI) calcd for: C₁₆H₂₂N₃O₂: m/z 288.1712. Found 288.1710. IR(KBr): 3376, 2954, 1712, 1629, 1577, 1444 cm^-1.

Methyl 3-(propan-2-yl)-2-(pyridin-3-yl)-1,2,3,4-tetrahydroquinazoline-7-carboxylate (13k)

O O H₃C

N HN

1H NMR (300MHz, CDCl3) δ 8.70 (s, 1H), 8.51 (dd, J = 4.8 Hz, 1H), 7.76 (dt, J = 6.8, 1.5 Hz, 1H), 7.34~7.22 (m, 3H), 6.93 (d, J = 7.6 Hz, 1H), 5.39 (s, 1H), 4.64 (brs, NH), 3.88 (s, 3H), 3.72 (dd, J = 36.9, 16.8 Hz, 2H), 2.97~2.87 (m, 1H), 1.18 (d, J = 6.2 Hz, 3H), 1.08 (d, J = 6.2 Hz, 3H); ¹³C-NMR (75 MHz, CDCl3) δ 167.3, 149.2, 149.0, 142.2, 138.3, 135.0, 129.2, 127.0, 125.3, 123.7, 119.0, 114.9, 68.6, 52.4, 49.9, 44.3, 22.2, 20.4 ppm. MS (ESI) m/z 311 (M⁺) HRMS (EI) calcd for: C18H21N3O2: m/z 311.1634. Found 311.1639. IR(KBr): 3394, 1706, 1297 cm^-1.

Methyl 3-isobutyl-2-phenyl-1,2,3,4-tetrahydro-7-quinazolinecarboxylate (13l)

O O

N HN

1H NMR (300 MHz, CDCl3): δ 7.65-7.43 (m, 2H), 7.38-7.28 (m, 5H), 6.94 (d, J =7.8 Hz, 1H), 5.10 (s, 1H), 4.52 (s, 1H), 3.91 (s, 3H), 3.76 (d, J = 16.7 Hz, 2H), 3.56 (d, J = 16.7 Hz, 2H), 2.41 (dd, J = 7.8, 13.8 Hz, 1H), 2.24 (dd, J = 7.0, 12.6 Hz, 1H), 1.84 (m, 1H),

0.93 (m, 6H); ¹³C NMR (75 MHz, CDCl3): 167.4, 142.7, 129.1, 128.9, 128.5, 127.8, 127.7, 127.2, 126.9, 125.2, 118.3, 114.2, 72.5, 60.0, 52.0, 49.9, 26.0, 19.0 ppm; MS (EI):

m/z 324 (M⁺); HRMS (ESI) calcd for: C19H22N2O2: m/z 324.1838; Found: 324.1833 (M+H); IR(KBr): 3386, 1706, 1502, 1295 cm^-1.

Methyl 2-phenyl-3-(thiophen-2-ylmethyl)-1,2,3,4-tetrahydroquinazoline-7-carboxylate (13m)

O O

N HN

1H NMR (300MHz, CDCl3): δ 7.53-7.50 (m, 2H), 7.38-7.26 (m, 6H), 6.98-6.92 (m, 3H), 5.21 (s, 2H), 4.55 (s, 2H), 3.89 (s, 3H), 3.87-3.82(m, 1H); ¹³C-NMR (75 MHz, CDCl3) δ 167.8, 143.3, 142.4, 142.3, 129.8, 128.9, 128.3, 128.1, 127.4, 126.9, 126.2, 125.7, 124.0, 119.0, 115.0, 71.2, 52.4, 51.7, 48.8 ppm; MS (EI) m/z 364 (M+1). HRMS (ESI) calcd for: C₂₁H₂₀N₂O₂S: m/z 364.1245. Found 364.1243. IR(KBr): 3380, 1705, 1616, 1505 cm^-1.

Methyl 2-(4-nitrophenyl)-3-(thiophen-2-ylmethyl)-1,2,3,4-tetrahydroquinazoline-7-carboxylate(13n)

N HN O

S NO₂

1H NMR (300MHz, CDCl₃): δ 8.17 (dd, J = 6.9, 2.1 Hz, 1H), 7.69(d, J = 8.7 Hz, 2H), 7.43 (d, J = 1.5 Hz, 1H), 7.39 (d, J = 1.5 Hz, 1H), 7.30 (dd, J = 7.5, 1.5 Hz, 1H), 6.98-6.91 (m, 3H), 5.23 (d, J = 2.7 Hz, 1H) 4.63 (d, J = 3.6 Hz, 1H), 4.08-3.68 (m, 5H); ¹³

C-O O H₃C

N HN

NMR (75 MHz, CDCl3) δ 167.2, 147.6, 140.8, 130.5, 129.8, 128.1, 127.8, 126.7, 126.4, 125.7, 124.3, 124.1, 123.7, 119.3, 115.0, 70.5, 69.3, 52.1, 51.7 ppm. MS(ESI) m/z 410 (M+1). HRMS (ESI) calcd for: C21H20N3O4S: m/z 410.1174. Found 410.1176. IR(KBr):

2931, 1708, 1600, 1505 cm^-1.

Methyl 2-(pyridin-3-yl)-3-(thiophen-2-ylmethyl)-1,2,3,4-tetrahydroquinazoline-7-carboxylate(13o)

1H NMR (300MHz, CDCl3) δ 8.60 (d, J = 4.8 Hz, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.78 (td, J = 7.8, 1.5 Hz, 1H), 7.45 (d, J = 1.2 Hz, 1H), 7.38 (dd, J = 7.8, 1.2 Hz, 1H), 7.29-7.23 (m, 2H), 6.95 (d, J = 7.8 Hz, 1H), 6.91 (dd, J = 5.1, 3.6 Hz, 1H), 6.82 (d, J = 3.3 Hz, 1H), 5.52 (s, 1H), 4.25 (d, J = 17.1 Hz, 1H), 3.95 (d, J = 3.9 Hz, 1H), 3.90 (s, 3H), 3.70 (dd, J

= 38.1, 13.5 Hz, 2H) ; ¹³C-NMR (75 MHz, CDCl₃) δ 167.3, 159.9, 148.4, 142.4, 137.3, 129.6, 127.9, 126.7, 125.9, 125.2, 123.2, 122.4, 119.1, 115.7, 114.6, 72.1, 69.3, 52.0, 50.7, 47.1 ； MS (EI) m/z 365 (M⁺) . HRMS (ESI) calcd for: C20H19NO2S ： m/z 365.1198.Found 365.1201

Methyl 2-(phenyl)-3-[2-(pyridin-2-yl)ethyl]-1,2,3,4-tetrahydroquinazoline-7-carboxylate(13p)

N HN O

N F

N HN O

NO₂

1H NMR (300MHz, CDCl₃) δ 8.49 (d, J = 4.8 Hz, 1H), 8.09 (dd, J = 9.3, 1.8 Hz, 1H), 7.60 (td, J = 7.5, 1.8 Hz, 1H), 7.35-7.31(m, 3H), 7.18-7.11(m, 2H), 6.91 (d, J = 7.5 Hz, 1H), 5.27 (d, J = 2.4 Hz, 2H), 4.78 (d, J = 8.7 Hz, 1H), 4.73 (d, J = 3.9 Hz, 1H), 3.87 (s, 3H), 3.15-2.89 (m, 4H); ¹³C-NMR (75 MHz, CDCl₃) δ 167.2, 159.6, 149.6, 148.5, 147.4, 141.2, 137.0, 129.6, 128.1, 127.7, 123.7, 123.6, 121.6, 119.1, 115.2, 71.3, 52.3, 52.0, 48.1, 36.7 ppm; MS(ESI) m/z 419 (M+1) . HRMS (ESI) calcd for: C₂₃H₂₃N₄O₂: m/z 419.1719.Found 419.1717. IR(KBr): 2925, 1712, 1294 cm^-1.

Methyl 2-(2-fluorophenyl)-3-[2-(pyridin-2-yl)ethyl]-1,2,3,4-tetrahydroquinazoline-7-carboxylate(13q)

1H NMR (300MHz, CDCl₃) δ 8.45 (dd, J = 4.2, 0.9 Hz, 1H), 7.56 (td, J = 4.2, 1.8 Hz, 1H), 7.35-7.17 (m, 4H), 7.16 (d, J = 8.4 Hz, 1H), 7.06-6.95 (m, 4H), 5.58 (d, J = 2.4 Hz, 1H), 4.54 (s, 1H), 3.96 (d, J = 4.2 Hz, 1H); 3.90-3.47(m, 6H); ¹³CNMR (75 MHz, CDCl₃) δ 167.3, 159.9, 149.0, 142.3, 136.4, 129.7, 129.1, 128.4, 128.3, 127.4, 123.7, 123.4, 121.2, 118.6, 115.8, 115.5, 114.4, 66.7, 53.4, 52.0, 49.0, 36.9. MS (ESI) m/z 392 (MH⁺) HRMS (ESI) calcd for: C₂₃H₂₃FN₃O₂：m/z 392.1774. Found 392.1775

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Chapter Two

Novel Approach Toward Synthesis of Skeletally Diverse Benzimidazole-pyrrolo[1,2-a]quinoxaline by S

Ar/Pictet-Spengler Reaction and Benzimidazole-(alkyloxy)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin by

S

Ar/Partial Nitro Group Reduction Reaction

2.0 Introduction

As it has been perceived that cells are the fundamental building blocks human body and of all living organism. In our living body cancer develops out of normal cells. As the requirement of the body, normal cells reproduce and die when the body doesn't need them. It has been observed that cancer happens to occur when the growth of cells in the body is out of control and cells separate very rapidly as shown in Figure 2.0. In normal tissues, the rates of growth of new cell and death of old cells are always reserved in balance. In cancer cell, this balance is disorder.¹

Figure 2.0. Defination of Cancers. Courtesy

“http://www.cancer.gov/cancertopics/cancerlibrary/what-is-cancer”

2.1. Different Causes Cancer?^2-3

2.1.1 There are numerous causes of cancers, including:

 Drinking excess alcohol

 Carcinogenic chemicals

 Environmental toxins, such as certain toxic mushrooms and a kind of poison that can grow on peanut plants (aflatoxins)

 Genetic problems

 Extreme sunlight exposure

 Obesity

 Viruses

 Radiation

2.1.2. Genetic Factor Leads to Cancer

 Anti-oncogenes

 Activation Of Proto-oncogenes

 Insensitivity to growth-inhibitory

 Irregular signaling pathway

 Apoptosis

 Abnormal cell cycle regulation

 Metastasis

 Angiogenesis

2.2. Metastatic Cancer

It has been perceived that most of the cancer mortality arises form the effect of Metastasis. Metastasis, normally occurs when the cancer cell penetrate into lymphatic and blood vessels, distributed through the bloodflow, which then occupy and promote in normal tissues. In broader concept, Metastasis has the ability to permeate to other tissues and organs that makes cancer a potentially life-threatening disease. Metastasis concept has been shown in Figure 2.1.⁴

Figure 2.1. Malignant Vs Benign tumors, courtesy from

„http://www.cancer.gov/cancertopics/understandingcancer/angiogenesis/page1‟

2.3. What is tumor angiogenesis?

Normally the emergence of new capillaries from pre-existing blood vessels is called angiogenesis. To grow beyod normal limit the tumor cells need independent blood supply, neutients and oxygen. The propagation of blood vessels which can penetrates into

cancerous growths, supplying nutrients and oxygen and removing waste products is called the tumor angiogenesis as shown in Figure 2.2. ^5-8

Figure 2.2. Tumor Angiogenesis, courtesy from

„http://www.cancer.gov/cancertopics/understandingcancer/angiogenesis/page1‟

2.4. The angiogenesis signaling cascade

The gowth factor VEGF and bFGF has been produced by the tumor cells. As soon as they meet endothelial cells surface, they bind to sequence specific proteins, called receptors, which is located on the outer surface of the cells. When VEGF or bFGF binds to its appropriate receptor it activates a relay proteins that further transmits a signal into the nucleus of the endothelial cells. The nuclear signal directs a group of genes to further generate products which could be needed for new endothelial cell growth as shown in Figure 2.3.^9-1

Figure 2.3. The angiogenesis signaling cascade, courtesy from

„http://www.cancer.gov/cancertopics/understandingcancer/angiogenesis/page13‟

2.5. The VEGF ligand is the predominant regulator of tumor angiogenesis

For the tumor angiogenesis, VEGF ligand has been identified as the most prominent regulator. VEGF help to creat new vasculature establish for very beginning stage of tumor development. It has well established fact that, VEGF may stimulate tumor growth at both primary and metastatic sites that form the building blocks of a new vascular network. VEGF help to creat existing vasculature survive, allowing tumors to sustain

在文檔中研究對合成熔融，線性和角雜環可溶性小分子庫的支持，新的癌症治療 (頁 95-0)