General Procedure for the synthesis of Intermediates

Scheme 23. Synthesis of mixed aldol condensation product from unsymmetrical ketones

1.5. General Procedure for the synthesis of Intermediates

General procedure for the preparation of Polymer bound 3-(4-Hydroxy-3- nitrobenzamido)-4-(substituted amino) carboxylates 18.

O O

NH R₁

O NO₂

2 PEG

To a solution of N, N’- dicyclohexylcarbodiimide (DCC) (139 mg, 0.67 mmol, 3.0 equiv) in N, N’-dimethylformamide (DMF) was added 4-hydroxy-3-nitrobenzoic acid 17 (122 g, 0.67 mmol, 3 equiv) and 1-hydroxybenzotriazole (HOBt) (91 mg, 0.67 mmol, 3.0 equiv) in a sequential order. The resulting slurry was stirred for 5 minutes at room temperature and then added polymer (PEG 4000) anchored o-phenylene diammine 16 (1.0 g, 0.22 mmol, 1.0 equiv) in DMF (5 mL). The reaction mixtures were subsequently heated with stirring in a 10 mL microwave process vial for 25 minutes in the appropriate mode of pressure and temperature to obtain the polymer conjugate 18. After completion of the reaction, the suspensible byproducts were filtered through filter paper. The reaction mixtures were precipitated by slow addition of cold ether and precipitated amide conjugates 18 were filtered through fritted funnel. The crude product was washed in succession with ether (100 mL×3) to remove the undesired impurity and dried for further steps.

General procedure for the preparation of Polymer bound 2-(4-Hydroxy-3-nitrophenyl)- 1-alkyl-1H-benzo[d]imidazole carboxylates 19.

O O

N N

R₁

NO₂ OH

2 PEG

To a solution of Polymer bound 3-(4-Hydroxy-3-nitrobenzamido)-4-(substituted amino) carboxylates 18 in 1,2-dichloroethane, trifluoroacetic acid (0.5 mL) and MgSO4 (500 mg) was added and the mixture was subsequently heated with stirring in a 10 mL microwave process vial for 8 minutes in the appropriate mode of pressure and temperature. After completion of the reaction, MgSO4 was removed through celite. The reaction mixtures were precipitated by slow addition of excess of cold ether (100 mL) and filtered through a fritted funnel to obtain the polymer bound 2-(4-Hydroxy-3-nitrophenyl)-1-alkyl-1H-benzo[d]imidazole carboxylates 19 in high purity.

General procedure for the preparation of Polymer bound 2-(3-Amino-4-hydroxyphenyl) -1-alkyl-1H-benzo[d]imidazole carboxylates 20.

O O

N N

R₁

NH₂ OH

2 20

PEG

To a solution of 19 in methanol, Pd on charcoal (48 mg, 0.45 mmol, 1.0 equiv.) and ammonium formate (132 mg, 2.10 mmol, 10.0 equiv) were added. The reaction mixtures was subsequently heated with stirring in a 10 mL microwave process vial for 10 minutes in the appropriate mode of pressure and temperature to complete reduction of nitro group which was evident from color change (yellow to greenish blue) upon spotting on a TLC plate. After completion, the reaction mixtures were then subjected to centrifugation for

removal of Pd on charcoal and the supernatant liquid was concentrated by rotary evaporation to remove methanol. Dichloromethane (10 mL) was then added to salt out ammonium formate. The reaction mixtures were filtered through fritted funnel to remove ammonium formate to obtain the polymer bound 2-(3-Amino-4-hydroxyphenyl)-1-alkyl-1H-benzo[d]imidazole carboxylates 20.

General procedure for the preparation of Polymer bound 2-(2-(Substituted amino) benzo[d]oxazol-5-yl)-1-alkyl-1H-benzo[d]imidazole carboxylates 21.

O O

N N

N H

N R₂

2 21

PEG

To a stirred solution of polymer bound 2-(3-Amino-4-hydroxyphenyl)-1-alkyl-1H-benzo[d]imidazole carboxylates conjugates 20 in CH3CN (5 mL), various isothiocyanates (1.05 mmol, 5.0 equiv) and N-3(dimethylaminopropyl)-3-ethyl carbodiimide (EDC) (163 mg, 1.05 mmol, 5.0 equiv) as an activating agent were added. The reaction mixtures were exposed under pressured microwave irradiation for 10 minutes. Upon completion of cyclization by checking the NMR, the crude product mixtures were purified by precipitation with cold ether (100 mL×3) and dried to obtain the conjugate 21 in high purity.

General procedure for the cleavage of Polymer bound substituted benzimidazolylbenzoxazoles 22.

O O

N N

N H

NR₂

To a solution of polymer conjugates 21 in methanol (20 mL), KCN (100 mg) was added and stirred for 12 hours at room temperature. After completion of the reaction, the crude product was precipitated with excess of cold ether (100 mL), the polymer was filtered off and subjected to evaporation. 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 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 22 in 77-96 % overall yields.

General Procedure for the Preparation of Polymer Bound 3-(4-Fluoro-3-nitrobenzamido)-4-(substituted amino) carboxylates 24.

O O

PEG NH

NH O

NO₂

2 24

Polymer bound o-phenylene diamine 16 (PEG 4000) (1.0 g, 0.25 mmol, 1.0 equiv) dissolved in (5 mL) of dichloromethane was added to a solution of 4-Fluoro-3-nitrobenzoic acid 23 (0.11 g, 0.60 mmol, 2.4 equiv) in dichloromethane (5 mL) in the presence of N,N’–dicyclohexylcarbodiimide (DCC) (0.144 g, 0.70 mmol, 2.4 equiv.) and N,N’- dimethylamino pyridine (DMAP) (3 mg). The reaction mixture was stirred at room temperature and subsequently irradiated microwave for 10 minutes to obtain the polymer bound amide conjugate 24. After completion of the reaction, the suspensible dicyclohexyl urea (DCU) was filtered through filter paper. The reaction mixtures were

precipitated by slow addition of cold ether and precipitated amide conjugate 3 was filtered through fritted funnel. The crude product was washed successively with ether to remove the undesired impurity and dried for further steps.

General Procedure for the Preparation of Polymer Bound Benzimidazole Derivatives 25.

O O PEG

N N

2 25

NO₂ R₁

To a solution of 24 in 1,2-dichloroethane, trifluoroacetic acid (0.5 mL) and of MgSO₄ (0.5 g) was added and irradiated under microwave condition for 5 minutes. After completion of the reaction, MgSO4 was removed through celite. The reaction mixtures were precipitated by slow addition of excess of cold ether (100 mL) and filtered through fritted funnel to obtain the compound 25 in high purity.

General Procedure for the Preparation of Polymer Bound Substituted Benzimidazole Derivatives 26.

O O PEG

2 26

N N

NO₂ NH

O O R₂

The polymer bound benzimidazole derivative 25 was treated with various chiral amino esters (5 equiv.) and Et₃N (3 equiv.) in 1,2-dichloroethane (5 mL). The reaction mixtures were irradiated under microwave condition for 10 minutes to complete SNAr reaction and

the reaction mixtures were washed with cold ether (100 mL), dried to obtain the conjugate 26 in quantitative yields.

General Procedure for the Preparation of Polymer Bound Substituted Benzimidazolylquinoxalinone Derivatives 28.

PEG O

N N

NH HN

O R₂

R₁

To a solution of 26 in methanol, Zn (0.5 g, 7.5 mmol, 30 equiv.) and ammonium formate (0.24 g, 3.75 mmol, 15.0 equiv) were added. The crude mixtures were stirred for 30 minutes for complete reduction of nitro group which was evident from color change from yellow to colorless. The reaction mixtures were then subjected to centrifugation for removal of Zn and the supernatant liquid was concentrated by rotary evaporation to remove methanol. Dichloromethane (10 mL) was then added to salt out ammonium formate. The reaction mixtures were filtered through filter paper to remove ammonium formate to obtain the conjugate 28.

General Procedure for the Cleavage of Polymer Bound Substituted Benzimidazolylquinoxalinone Derivatives 29.

O O

N N

NH HN

O R₂

R₁ 29

To a solution of conjugates 28 in methanol (30 mL), KCN (0.1 g) was added and stirred for 18 hours. After completion of the reaction, the crude product was precipitated with excess of cold ether (100 mL), the polymer was filtered off and subjected to rotavapor.

The residue was dried under vacuum, and subjected to crude HPLC analysis (HPLC 254 nm). The residue was dissolved in dichloromethane (5 mL) and again subjected to evaporation. The slurry obtained was loaded on neutral silica gel column and eluted with a mixture of ethyl acetate and hexane (2:1) to get the title compounds 29 in good yields and subjected to chiral HPLC analysis using chiral column (Daicel Chiralcel OD) employing 2-propanol: n-hexane (1:9) as the eluent ratio.

General Procedure for the Preparation of Polymer Bound Substituted Benzimidazole Derivatives 36.

N N

R₁ O

O NH₂

F PEG

2 36

To a solution of 25 in methanol, Zn (0.5 g, 7.5 mmol, 30 equiv.) and ammonium formate (0.24 g, 3.75 mmol, 15.0 equiv) were added. The crude mixtures were stirred for 30 minutes for complete reduction of nitro group which was evident from color change from yellow to colorless. The reaction mixtures were then subjected to centrifugation for removal of Zn and the supernatant liquid was concentrated by rotary evaporation to remove methanol. Dichloromethane (10 mL) was then added to salt out ammonium formate. The reaction mixtures were filtered through filter paper to remove ammonium formate to obtain the conjugate 36.

General Procedure for the Preparation of Polymer Bound Substituted 2, 4-Diaryl-3H-(benzo[b]azepin-8-yl)-1H-benzo[d]imidazole-5- carboxylates Derivatives 44.

N N

R₁ O

O PEG

N R₂

R₂

2 38

A solution of enone 37 (5.0 equiv), polymer bound substituted benzimidazole derivatives 36 (1 equiv) and p-TsOH monohydrate (20 mg) in toluene (25 mL) was refluxed under N2 for 18 h using sealed tube apparatus. Upon completion of the reaction time, solution was cooled to room temp. The solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (50 mL). The reaction mixtures were precipitated by slow addition of excess of cold ether (100 mL) and filtered through fritted funnel to obtain the compound 38 in high purity.

General Procedure for the Cleavage of Polymer Bound Substituted 2, 4-diaryl-3H-(benzo[b]azepin-8-yl)-1H-benzo[d]imidazole-5-carboxylates Derivatives 44.

N N

R₁ O

O N

R₂

To a solution of conjugates 38 in methanol (30 mL), KCN (0.1 g) was added and stirred for 12 hours. After completion of the reaction, the crude product was precipitated with excess of cold ether (100 mL), the polymer was filtered off and subjected to rotavapor.

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 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 44 in 72-91 % overall yields.

2-(2-(4-Fluorophenylamino)benzo[d]oxazol-5-yl)-1-isobutyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 22a.

N O N

O N

22a

1H NMR (300 MHz, CDCl3) δ 8.56 (d, J = 1.5 Hz, 1H), 8.07 (dd, J = 8.5, 1.5 Hz, 1H), 7.98 (brs, 1H), 7.71 (d, J = 1.5 Hz, 1H), 7.64 (dd, J = 9.0 Hz, JHF = 4.6 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.45 (dd, J = 8.2, 1.5 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.08 (dd, J_HF = 8.8 Hz, J = 7.4 Hz, 2H), 4.13 (d, J = 7.5 Hz, 2H), 3.98 (s, 3H), 2.11 (sept, J = 6.6 Hz, 1H), 0.74 (d, J = 6.6 Hz, 6H); ¹³C NMR (75 MHz, CDCl3) δ 168.0, 159.8, 159.4 (d, ¹JCF = 252.9 Hz), 156.5, 149.2, 143.2, 142.7, 139.3, 134.3, 126.7, 125.0, 124.7, 124.1, 122.4, 120.8 (d, ³J_CF = 7.8 Hz), 118.1, 116.4 (d, ²J_CF = 26.1 Hz), 110.7, 109.8, 52.5, 52.4, 29.4, 20.5, 20.4; IR (cm^-1, KBr): 3303, 1708; MS (ESI) m/z 459 (MH⁺); HRMS (ESI, m/z) calcd for C26H23FN4O3: m/z 459.1832; Found 459.1834.

1-Isobutyl-2-(2-(phenylamino)benzo[d]oxazol-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 22b.

N O N

N H

22b

100

1H NMR (300 MHz, CDCl3) δ 8.57 (d, J = 1.5 Hz, 1H), 8.07 (dd, J = 8.5, 1.5 Hz, 1H), 7.97 (brs, 1H), 7.74 (d, J = 1.4 Hz, 1H), 7.67 (dd, J = 8.7, 1.2 Hz, 2H), 7.48 (dd, J = 8.3, 1.4 Hz, 1H), 7.47-7.39 (m, 4H), 7.14 (t, J = 7.4 Hz, 1H), 4.13 (d, J = 6.6 Hz, 2H), 3.98 (s, 3H), 2.13 (sext, J = 6.6 Hz, 1H), 0.73 (d, J = 6.6 Hz, 6H); ¹³C NMR (75 MHz, CDCl3) δ 168.1, 159.4, 156.5, 149.2, 145.4, 143.4, 142.9, 139.4, 138.0, 129.8, 126.9, 124.8, 124.3, 123.9, 122.6, 118.9, 118.3, 110.6, 109.9, 53.2, 52.5, 29.2, 20.5, 20.4; IR (cm^-1, KBr):

3434, 1712; MS (ESI) m/z 441 (MH⁺); HRMS (ESI, m/z) calcd for C26H24N4O3: m/z 441.1927; Found 441.1925.

1-Butyl-2-(2-(phenylamino)benzo[d]oxazol-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 22c.

N O N

O N

22c

1H NMR (300 MHz, CDCl3) δ 9.48 (s, 1H), 8.58 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H), 7.66 (d, J = 7.8 Hz, 2H), 7.46 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.37-7.29 (m, 3H), 7.07 (t, J = 7.2 Hz, 1H), 4.27 (t, J = 7.1 Hz, 2H), 3.97 (s, 3H), 1.74 (quint, J

= 7.1 Hz, 2H), 1.27-1.22 (m, 2H), 0.83 (t, J = 7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl3) δ 168.1, 159.9, 156.3, 149.3, 143.4, 142.8, 139.1, 138.4, 129.7, 126.2, 124.7, 123.9, 123.7, 123.2, 122.4, 119.1, 117.8, 110.4, 109.8, 52.6, 45.1, 32.1, 20.3, 13.9; IR (cm^-1, KBr):

3436, 1714; MS (ESI) m/z 441 (MH⁺); HRMS (ESI, m/z) calcd for C₂₆H₂₄N₄O₃: m/z 441.1927; Found 441.1924

1-Butyl-2-(2-(4-fluorophenylamino)benzo[d]oxazol-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 22d.

101

N O N

N H

22d

1H NMR (300 MHz, CDCl3) δ 9.25 (s, 1H), 8.57 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.63 (dd, J = 8.5 Hz, JHF = 4.6 Hz, 2H), 7.47 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 7.05 (dd, J = 8.5 Hz, J_HF = 8.4 Hz, 2H), 4.27 (t, J = 7.2 Hz, 2H), 3.98 (s, 3H), 1.78 (quint, J = 7.2 Hz, 1H), 1.26-1.19 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H); ¹⁹F NMR (282.4 MHz, CDCl3) δ -119.0; ¹³C NMR (75 MHz, CDCl3) δ 168.1, 160.9, 159.9 (d, ¹J_CF = 260.6 Hz), 156.2, 149.3, 143.3, 142.7, 139.1, 134.5, 126.1, 125.1, 125.0, 124.6, 122.3, 120.9 (d, ³J_CF = 4.0 Hz), 118.1, 116.5 (d, ²J_CF = 23.1 Hz), 111.5, 110.4, 52.6, 45.1, 32.1, 20.3, 13.9; IR (cm^-1, KBr): 3303, 1709; MS (ESI) m/z 459 (MH⁺); HRMS (ESI, m/z) calcd for C26H23FN4O3: m/z 459.1832; Found 459.1831.

1-(2-Cyclohexenylethyl)-2-(2-(4-fluorophenylamino)benzo[d]oxazol-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 22e.

N O N

O N

22e

1H NMR (300 MHz, CDCl3) δ 8.56 (brs, 2H), 8.08 (d, J = 8.5 Hz, 1H), 7.72 (s, 1H), 7.62 (dd, J = 8.6 Hz, JHF = 4.5 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.2 Hz, 1H), 7.09 (dd, J = 8.6 Hz, J_HF = 8.5 Hz, 2H), 5.19 (m, 1H), 4.39 (t, J = 7.2 Hz, 2H), 3.99 (s, 3H), 2.35 (t, J = 7.2 Hz, 2H), 1.83-1.75 (m, 4H), 1.44-1.34 (m, 4H); ¹⁹F NMR (282.4

102

MHz, CDCl3) δ -118.9; ¹³C NMR (75 MHz, CDCl3) δ 168.1, 161.1, 159.7, 159.4 (d, ¹JCF

= 262.2 Hz), 156.2, 149.3, 143.3, 142.8, 139.2, 134.2, 133.4, 126.5, 125.1, 124.9, 124.7, 124.2, 122.5, 120.9 (d, ³JCF = 7.5 Hz), 118.0, 116.4 (d, ²JCF = 30.0 Hz), 110.4, 109.8, 52.6, 44.2, 38.1, 28.6, 25.5, 22.9, 22.3; IR (cm^-1, KBr): 3446, 1716; MS (ESI) m/z 511 (MH⁺);

HRMS (ESI, m/z) calcd for C₃₀H₂₇FN₄O₃: m/z 511.2145; Found 511.2142.

1-(2-Cyclohexenylethyl)-2-(2-(phenylamino)benzo[d]oxazol-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 22f.

N O N

N H

22f

1H NMR (300 MHz, CDCl₃) δ 9.00 (brs, 1H), 8.57 (d, J = 1.5 Hz, 1H), 8.08 (dd, J = 8.5, 1.5 Hz, 1H), 7.73 (s, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 7.44-7.30 (m, 3H), 7.10 (t, J = 8.2 Hz, 1H), 5.18 (m, 1H), 4.37 (t, J = 7.2 Hz, 2H), 3.98 (s, 3H), 2.34 (t, J = 7.2 Hz, 2H), 1.81-1.73 (m, 4H), 1.44-1.41 (m, 4H); ¹³C NMR (75 MHz, CDCl3) δ 168.1, 159.8, 156.3, 149.2, 143.3, 142.8, 139.2, 138.3, 133.4, 129.7, 126.4, 125.1, 124.9, 124.7, 123.8, 123.6, 122.4, 119.0, 117.9, 110.5, 109.8, 52.6, 43.1, 38.1, 28.6, 25.5, 22.9, 21.8; IR (cm^-1, KBr): 3421, 1712; MS (ESI) m/z 493 (MH⁺); HRMS (ESI, m/z) calcd for C₃₀H₂₈N₄O₃: m/z 493.2240; Found 493.2242.

1-Butyl-2-(2-(3-chlorophenylamino)benzo[d]oxazol-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 22g.

103

N O N

N H

N Cl

22g

1H NMR (300 MHz, CDCl3) δ 9.20 (brs, NH), 8.56 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.80 (s, 1H), 7.72 (s, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 8.2, 1H), 7.30-7.25 (m, 2H), 7.05 (d, J = 7.8 Hz, 1H), 4.29 (t, J = 7.4 Hz, 2H), 3.99 (s, 3H), 1.80 (quint, J = 7.4 Hz, 2H), 1.30-1.22 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H); ¹³C NMR (75 MHz, CDCl3) δ 168.0, 159.1, 156.2, 149.2, 143.2, 142.7, 139.6, 139.1, 135.3, 130.7, 126.2, 125.1, 124.8, 124.3, 123.6, 122.3, 118.8, 118.2, 116.8, 110.4, 109.9, 52.6, 45.1, 32.1, 20.3, 13.9; IR (cm^-1, KBr): 3399, 1747; MS (EI) m/z 474 (M⁺); HRMS (ESI, m/z) calcd for C26H23ClN4O3: m/z 475.1537; Found 475.1533.

2-(2-(Allylamino)benzo[d]oxazol-5-yl)-1-isobutyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 22h.

N O N

O N

22h

1H NMR (300 MHz, CDCl₃) δ 8.54 (d, J = 1.4 Hz, 1H), 8.04 (dd, J = 8.5, 1.4 Hz, 1H), 7.60 (s, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.38-7.34 (m, 2H), 6.11 (brs, 1H), 5.99 (m, 1H), 5.33 (dd, J = 17.0, 1.1 Hz, 1H), 5.22 (dd, J = 10.1, 1.1 Hz, 1H), 4.12 (m, 4H), 3.96 (s, 3H), 2.10 (sept, J = 6.6 Hz, 1H), 0.71 (d, J = 6.6 Hz, 6H); ¹³C NMR (75 MHz, CDCl3) δ 168.1, 163.3, 156.6, 149.9, 143.8, 142.9, 139.4, 133.9, 126.6, 124.8, 124.5, 123.3, 122.6, 117.6, 117.4, 110.6, 109.6, 52.5, 52.4, 45.8, 29.1, 20.3; IR (cm^-1, KBr): 3278, 1710; MS

104

(ESI) m/z 405 (MH⁺); HRMS (ESI, m/z) calcd for C23H24N4O3: m/z 405.1927; Found 405.1929.

2-(2-(Benzylamino)benzo[d]oxazol-5-yl)-1-isobutyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 22i.

N O N

N H

22i

1H NMR (300 MHz, CDCl₃) δ 8.53 (d, J = 1.6 Hz, 1H), 8.04 (dd, J = 8.5, 1.6 Hz, 1H), 7.56 (d, J = 1.1 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.42-7.30 (m, 7H), 5.97 (t, J = 6.0 Hz, 1H), 4.72 (d, J = 6.0 Hz, 2H), 4.13 (d, J = 7.5 Hz, 2H), 3.97 (s, 3H), 2.10 (sept, J = 6.6 Hz, 1H), 0.73 (d, J = 6.6 Hz, 6H); ¹³C NMR (75 MHz, CDCl3) δ 168.1, 163.2, 156.5, 149.9, 143.8, 142.9, 139.4, 137.8, 129.3, 128.4, 128.1, 126.8, 124.8, 124.5, 123.5, 122.6, 117.6, 110.6, 109.0, 52.5, 52.4, 47.6, 29.2, 20.3; IR (cm^-1, KBr): 3210, 1705; MS (ESI) m/z 455 (MH⁺); HRMS (ESI, m/z) calcd for C27H26N4O3: m/z 455.2083; Found 455.2085.

2-(2-(Allylamino)benzo[d]oxazol-5-yl)-1-(2-Cyclohexenylethyl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 22j.

N O N

N H

22j

1H NMR (300 MHz, CDCl₃) δ 8.53 (d, J = 1.5 Hz, 1H), 8.05 (dd, J = 8.5, 1.5 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.46 (dd, J = 8.2, 1.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 6.00 (m, 1H), 5.86 (m, 1H), 5.35 (dd, J = 17.1, 1.3 Hz, 1H), 5.24 (dd, J =

105

10.3, 1.3 Hz, 1H), 5.18 (m, 1H), 4.36 (t, J = 7.2 Hz, 2H), 4.17-4.14 (m, 2H), 3.97 (s, 3H), 2.33 (t, J = 7.2 Hz, 2H), 1.81-1.74 (m, 4H), 1.45-1.43 (m, 4H); ¹³C NMR (75 MHz, CDCl3) δ 168.1, 163.2, 156.3, 150.1, 143.9, 142.9, 139.3, 133.9, 133.4, 126.4, 124.9, 124.8, 124.5, 123.3, 122.6, 117.4, 117.3, 110.3, 109.6, 52.5, 45.8, 44.1, 38.1, 28.6, 25.5, 22.9, 22.3; IR (cm^-1, KBr): 3424, 1714; MS (ESI) m/z 457 (MH⁺); HRMS (ESI, m/z) calcd for C₂₇H₂₈N₄O₃: m/z 457.2240; Found 457.2239.

2-(2-(Benzylamino)benzo[d]oxazol-5-yl)-1-(2-Cyclohexenylethyl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 22k.

N O N

N H

22k

1H NMR (300 MHz, CDCl3) δ 8.51 (d, J = 1.4 Hz, 1H), 8.05 (dd, J = 8.5, 1.4 Hz, 1H), 7.54 (d, J = 1.3 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.40-7.23 (m, 7H), 6.65 (m, 1H), 5.18 (m, 1H), 4.68 (d, J = 4.9 Hz, 2H), 4.34 (t, J = 7.2 Hz, 2H), 3.96 (s, 3H), 2.32 (t, J = 7.2 Hz, 2H), 1.81-1.73 (m, 4H), 1.45-1.42 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 168.2, 163.4, 156.3, 150.1, 143.9, 142.9, 139.3, 137.9, 133.4, 129.2, 128.2, 128.0, 126.3, 125.0, 124.8, 124.5, 123.2, 122.5, 117.2, 110.3, 109.6, 52.5, 47.5, 44.1, 38.1, 28.6, 25.5, 23.0, 22.3; IR (cm^-1, KBr): 3209, 1714; MS (ESI) m/z 507 (MH⁺); HRMS (ESI, m/z) calcd for C₃₁H₃₀N₄O₃: m/z 507.2396; Found 507.2395.

1-Cyclopentyl-2-(2-(furan-2-ylmethylamino)benzo[d]oxazol-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 22l.

106

N O N

N H

N O

22l

1H NMR (300 MHz, CDCl3) δ 8.54 (s, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.61 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.45-7.39 (m, 3H), 6.42-6.32 (m, 2H), 5.62 (t, J = 5.5 Hz, 1H), 4.99 (quint, J = 8.9 Hz, 1H), 4.71 (d, J = 5.5 Hz, 2H), 3.98 (s, 3H), 2.36-2.29 (m, 2H), 2.14-2.06 (m, 4H), 1.75-1.73 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 168.0, 163.0, 156.7, 150.9, 150.1, 143.6, 143.0, 142.9, 136.9, 126.6, 124.6, 124.0, 123.6, 122.9, 117.5, 111.9, 110.9, 109.7, 108.4, 58.1, 52.5, 40.4, 30.8, 25.6; IR (cm^-1, KBr): 3423, 1714; MS (ESI) m/z 457 (MH⁺); HRMS (ESI, m/z) calcd for C26H24N4O4: m/z 457.1876; Found 457.1878.

2-(2-(furan-2-ylmethylamino)benzo[d]oxazol-5-yl)-1-(3-methoxypropyl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 15m.

N O N

O N

HN O

O 22m

1H NMR (300 MHz, CDCl₃) δ 8.54 (d, J = 1.5 Hz, 1H), 8.05 (dd, J = 8.5, 1.5 Hz, 1H), 7.67 (d, J = 1.4 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.46-7.36 (m, 3H), 6.35 (dd, J = 5.6, 4.9 Hz, 2H), 6.13 (brs, 1H), 4.70 (s, 2H), 4.42 (t, J = 7.1 Hz, 2H), 3.97 (s, 3H), 3.24 (t, J

= 6.0 Hz, 2H), 3.21 (s, 3H), 1.99 (quint, J = 6.2 Hz, 2H); ¹³C NMR (75 MHz, CDCl3) δ 168.1, 162.9, 156.1, 150.9, 150.1, 143.7, 143.0, 142.8, 139.4, 125.3, 124.7, 124.6, 123.4, 122.5, 117.4, 110.9, 110.3, 109.7, 108.5, 69.1, 59.0, 52.5, 42.2, 40.4, 30.4; IR (cm^-1, KBr):

107

3211, 1708; MS (ESI) m/z 461 (MH⁺); HRMS (ESI, m/z) calcd for C25H24N4O5: m/z 461.1825; Found 461.1822.

2-(2-(Benzylamino)benzo[d]oxazol-5-yl)-1-Cyclopentyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 22n.

N O N

N H

22n

1H NMR (300 MHz, CDCl3) δ 8.51 (d, J = 1.5 Hz, 1H), 8.00 (dd, J = 8.6, 1.5 Hz, 1H), 7.54 (d, J = 1.0 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.42-7.34 (m, 7H), 6.16 (t, J = 5.4 Hz, 1H), 4.98 (quint, J = 8.5 Hz, 1H), 4.71 (d, J = 5.4 Hz, 2H), 3.97 (s, 3H), 2.35-2.26 (m, 2H), 2.13-2.03 (m, 4H), 1.77-1.73 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 168.1, 163.3, 156.7, 150.1, 143.7, 143.6, 137.8, 136.9, 129.3, 128.3, 128.0, 126.6, 124.5, 124.0, 123.5, 122.9, 117.4, 111.9, 109.6, 58.1, 52.5, 47.5, 30.8, 25.6; IR (cm^-1, KBr): 3266, 1712; MS (ESI) m/z 467 (MH⁺); HRMS (ESI, m/z) calcd for C₂₈H₂₆N₄O₃: m/z 467.2083; Found 467.2080.

2-(2-(Isobutylamino)benzo[d]oxazol-5-yl)-1-(3-methoxypropyl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 22o.

N O N

O N

22o

1H NMR (300 MHz, CDCl3) δ 8.54 (d, J = 1.5 Hz, 1H), 8.05 (dd, J = 8.5, 1.5 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.47 (dd, J = 8.2, 1.5 Hz, 1H), 7.38 (d,

108

J = 8.2 Hz, 1H), 5.50 (m, 1H), 4.42 (t, J = 6.9 Hz, 2H), 3.95 (s, 3H), 3.34 (m, 2H), 3.27 (t, J = 6.2 Hz, 2H), 3.21 (s, 3H), 2.18 (m, 1H), 2.02-1.97 (m, 2H), 1.03 (d, J = 6.7 Hz, 6H);

13C NMR (75 MHz, CDCl3) δ 168.2, 163.5, 156.2, 150.0, 145.4, 144.0, 142.9, 139.5, 124.9, 124.6, 123.1, 122.5, 117.1, 110.2, 109.5, 69.2, 59.0, 52.5, 51.0, 42.2, 30.3, 28.9, 20.4; IR (cm^-1, KBr): 3426, 1712; MS (ESI) m/z 437 (MH⁺); HRMS (ESI, m/z) calcd for C₂₄H₂₈N₄O₄: m/z 437.2189; Found 437.2190.

2-(2-(Allylamino)benzo[d]oxazol-5-yl)-1-Cyclopentyl-1H-benzo[d]imidazole-5-carboxylic Acid Methyl Ester 15p.

N O N

N H

22p

1H NMR (300 MHz, CDCl3) δ 8.54 (d, J = 1.5 Hz, 1H), 8.00 (dd, J = 8.6, 1.5 Hz, 1H), 7.58 (d, J = 1.0 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.42-7.37 (m, 2H), 6.01 (m, 1H), 5.64 (m, 1H), 5.36 (dd, J = 17.1, 1.2 Hz, 1H), 5.26 (dd, J = 10.3, 1.2 Hz, 1H), 4.98 (quint, J = 8.5 Hz, 1H), 4.16 (t, J = 5.5 Hz, 2H), 3.97 (s, 3H), 2.39-2.26 (m, 2H), 2.14-2.06 (m, 4H), 1.77-1.73 (m, 2H); ¹³C NMR (75 MHz, CDCl3) δ 168.1, 163.1, 156.7, 150.0, 143.8, 143.7, 136.9, 133.9, 126.7, 125.0, 124.0, 123.6, 122.9, 117.5, 117.4, 111.9, 109.7, 58.1, 52.5, 45.8, 30.8, 25.6; IR (cm^-1, KBr): 3413, 1714; MS (ESI) m/z 417 (MH⁺); HRMS (ESI, m/z) calcd for C24H24N4O3: m/z 417.1927; Found 417.1926.

109

1-Butyl-2-[2-(1H-indol-2-ylmethyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl]-1H benzoimidazole-5-carboxylic acid methyl ester (29h):

1H NMR (300 MHz, CDCl3) δ 8.85 (s, 1H), 8.60 (s, 1H), 8.49 (s, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 8.1, 2H), 7.23 - 7.08 (m, 5H), 6.60 (d, J = 8.1 Hz, 1H), 4.30-4.19 (m, 4H), 3.95 (s, 3H), 3.47 (dd, J = 14.1, 3.0 Hz, 1H), 3.08 (dd, J = 14.1, 10.5 Hz, 1H), 1.81 (m, 2H), 1.28 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H);¹³C NMR (75 MHz, CDCl3) δ 168.6, 168.1, 155.7, 142.4, 139.2, 136.8, 135.1, 127.6, 125.9, 125.0, 124.9, 124.6, 123.9, 122.8, 122.5, 120.1, 119.1, 118.7, 116.8, 114.4, 111.9, 110.6, 110.5, 110.2, 57.0, 52.6, 45.3, 32.2, 28.8, 13.9; MS (EI) m/z: 507 (M+); HRMS (EI, m/z) calcd for C₃₀H₂₉N₅O₃: m/z 507.2270; Found 507.2272; [α]_D²⁰ = -79.8(c 0.8 , CH₂Cl₂) for 82

% ee ; IR (cm^-1, neat): 1720, 1683.

1Isobutyl2(2secbutyl3oxo1,2,3,4tetrahydroquinoxalin6yl)1HBenzoimida -zole-5-carboxylic acid methyl ester (29i):

1H NMR (300 MHz, CDCl₃) δ 8.46 (s, 1H), 8.42 (s, 1H), 8.04 (dd, J = 8.6, 1.6 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.19 - 7.13 (m, 2H), 6.75 (d, J = 8.1 Hz, 1H), 4.30 (s, 1H), 4.15-4.10 (m, 2H), 3.93 (s, 3H), 2.13 (m, 1H), 1.64 - 1.55 (m, 2H), 1.05 (d, J = 6.9 Hz, 2H), 0.80 (m, 6H), 0.79 (d, J = 6.6 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 167.7, 167.5, 155.4, 138.9, 135.2, 125.4, 124.7, 124.5, 124.0, 121.7, 118.9, 116.2, 112.9, 109.9, 109.7, 61.1, 52.1, 44.8, 38.6, 31.9, 24.5, 19.9, 15.3, 13.2, 12.1; MS (EI) m/z: 434 (M+); HRMS (EI, m/z) calcd for C25H30N4O3: m/z 434.2318; Found 434.2331; [α]D20 = -45.0 (c 0.1 , CH₂Cl₂) for 97% ee; IR (cm^-1, neat): 1715, 1661.

1-Butyl-2-(2-methyl-3-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl)-1H-benzoimidazole-5-carboxylic acid methyl ester (29j):

110

1H NMR (300 MHz, CDCl3): δ 8.48 (s, 1H), 8.21 (s, 1H), 8.04 (dd, J = 8.5, 1.4 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.24 - 7.20 (m, 2H), 6.81 (d, J = 7.9 Hz, 1H), 4.23 (t, J= 7.9 Hz, 2H), 4.11-4.15 (m, 2H), 3.36 (s, 3H), 1.78-1.88 (m, 2H), 1.53 (d, J = 6.6 Hz, 3H), 1.37-1.28 (m, 2H), 0.92 (t, J = 7.5 Hz, 3H); ¹³C NMR (75 MHz, CDCl3): δ 168.8, 168.1, 155.5, 142.9, 139.3, 135.5, 126.2, 124.9, 124.5, 122.3, 116.8, 114.2, 110.0, 96.5, 52.5, 52.3, 45.2, 32.3, 21.2, 20.4, 18.7, 14.0; MS (EI) m/z: 392 (M+); HRMS (EI, m/z) calcd for C22H24N4O3:m/z 392.1848; Found 392.1843; [α]D20 = -44.0 (c 0.1 , CH2Cl2) for 99 % ee;

IR (cm^-1, neat): 1714, 1666.

1-Butyl-2-(2-isopropyl-3-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl)-1H-benzoimidazole -5-carboxylic acid methyl ester (29k)

1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 8.04 (dd, J = 8.5, 1.5 Hz, 1H), 7.80 (s, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.26-7.13 (m, 2H), 6.76 (d, J = 8.0 Hz, 1H), 4.24-4.29 (m, 3H), 3.97 (s, 3H), 3.92 (m, 1H), 2.27 (m, 1H), 1.78-1.89 (m, 2H), 1.37-1.25 (m, 2H), 1.09 (d, J

= 6.8 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 0.90 (t, J = 6.0 Hz, 3H); ¹³C NMR (75 MHz, CDCl3): δ 168.0, 167.3, 155.6, 143.0, 139.4, 135.5, 125.3, 125.0, 124.5, 122.3, 120.5, 116.5, 113.4, 109.9, 62.1, 52.5, 45.2, 37.0, 32.2, 25.1, 20.4, 19.3, 17.7, 13.9; MS (EI) m/z:

420 (M+); HRMS (EI, m/z) calcd for C₂₄H₂₈N₄O₃: m/z 420.2161; Found 420.2155; [α]_D²⁰

= -67.0 (c 1.1 , CH₂Cl₂) for 95 % ee ; IR (cm^-1, neat): 1716, 1633.

1-Cyclopentyl-2-(2-methyl-3-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl)-1H benzoimida -zole-5-carboxylic acid methyl ester (29l):

1H NMR (300 MHz, CDCl₃) δ 8.48 (s, 1H), 8.38 (s, 1H), 7.98 (dd, J = 8.6, 1.5 Hz, 1H), 7.54 (d, J = 7.4 Hz, 1H), 7.17-7.15 (m, 2H), 6.80 (d, J = 8.5 Hz, 1H), 4.98 (m, 1H), 4.16-4.12 (m, 2H), 3.97 (s, 3H), 2.31 - 2.23 (m, 2H), 2.10-2.06 (m, 6H), 1.53 (d, J = 6.6 Hz,

111

3H); ¹³C NMR (75 MHz, CDCl3) δ 168.9, 167.6, 155.8, 136.3, 135.3, 128.7, 125.8, 124.8, 124.3, 123.6, 121.9, 116.6, 113.6, 111.5, 57.8, 52.0, 51.7, 30.5, 28.9, 25.2, 23.7, 22.9, 18.4; MS (EI) m/z: 404 (M+); HRMS (EI, m/z) calcd for C23H24N4O3: m/z 404.1848;

Found 404.1856; [α]D20 = -69.0 (c 1.0, CH2Cl2) for 98 % ee; IR (cm^-1, neat): 1716, 1674.

1-Cyclopentyl-2-(2-isopropyl-3-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl)-1H-benzoimi -dazole-5-carboxylic acid methyl ester (29m):

1H NMR (300 MHz, CDCl3) δ 10.15 (s, 1H), 8.46 (s, 1H), 7.95 (dd, J = 8.5, 1.5 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.15-7.08 (m, 2H), 6.70 (d, J = 8.1 Hz, 1H), 4.97 (m, 1H), 4.61 (m, 1H), 3.96 (s, 3H), 3.88 (m, 1H), 2.30-2.23 (m, 3H), 2.08-2.05 (m, 5H), 1.04 (d, J = 7.0 Hz, 3H), 0.99 (d, J = 7.0 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 168.3, 168.1, 156.6, 143.6, 136.9, 135.6, 125.6, 124.9, 124.1, 122.9, 119.9, 116.8, 113.3, 111.8, 61.8, 58.3, 52.5, 32.0, 30.8, 25.7, 23.0, 20.6, 19.3, 17.6; MS (EI) m/z: 432 (M+); HRMS (EI, m/z) calcd for C₂₅H₂₈N₄O₃: m/z 432.2161; Found 432.2163; [α]_D²⁰ = -74.0 (c 1.1, CH₂Cl₂) for 80 % ee; IR (cm^-1, neat ): 1715, 1667.

1-Isobutyl-2-(3-sec-butyl-2-oxo-1,2-dihydro-quinoxalin-6-yl)-1H-Benzoimidazole-5-carboxylic acid methyl ester (30i):

1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.11 (d, J = 7.5 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.80 (s, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 4.21 (d, J = 7.4 Hz, 2H), 3.98 (s, 3H), 3.50 (m, 1H), 2.15 (m, 1H), 1.68-1.62 (m, 2H), 1.33 (d, J = 6.8 Hz, 3H), 1.00-0.97 (m, 3H), 0.80 (d, J = 6.5 Hz, 6H); MS (ESI) m/z: 433 (MH+).

1-Butyl-2-(3-methyl-2-oxo-1,2-dihydro-quinoxalin-6-yl)-1H-benzoimidazole-5 carboxylic acid methyl ester (30j):

112

1H NMR (300 MHz, CDCl3) δ 11.3 (s, 1H), 8.55 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 4.32 (t, J

= 7.5 Hz, 2H), 3.97 (s, 3H), 2.65 (s, 3H), 1.90-1.82 (m, 2H), 1.36-1.29 (m, 2H), 0.90 (t, J

= 7.3 Hz, 3H); MS (ESI) m/z: 391 (MH+).

1-Butyl-2-(3-isopropyl-2-oxo-1,2-dihydro-quinoxalin-6-yl)-1H-benzoimidazole-5- carboxylic acid methyl ester (30k):

1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 7.9 Hz, 2H), 7.63-7.54 (m, 2H), 4.48-4.43 (m, 2H), 3.99 (s, 3H), 3.60 (m, 1H), 1.78-1.70 (m, 2H), 1.17-1.10 (m, 8H), 0.89 (t, J = 7.1 Hz, 3H); MS (ESI) m/z: 419 (MH+).

1-Cyclopentyl-2-(3-methyl-2-oxo-1,2-dihydro-quinoxalin-6-yl)-1H-benzoimidazole-5-carboxylic acid methyl ester (30l):

1H NMR (300 MHz, CDCl3) δ 12.04 (s, 1H), 8.55 (s, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.82 (s, 1H), 7.58 (d, J = 8.5 Hz, 2H), 5.00 (m, 1H), 3.97 (s, 3H), 2.65 (s, 3H), 2.35-2.33 (m, 2H), 2.19-2.06 (m, 3H), 1.80-1.71(m, 3H); MS (ESI) m/z: 403 (MH+).

1-Cyclopentyl-2-(3-isopropyl-2-oxo-1,2-dihydro-quinoxalin-6-yl)-1H-benzoimidazole-5-carboxylic acid methyl ester (30m):

1H NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 8.19 (d, J = 8.6 Hz, 1H), 8.00-7.97 (m, 2H), 7.70 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 5.03 (m, 1H), 3.99 (s, 3H), 3.53 (m, 1H), 2.32-2.30 (m, 3H), 2.19-1.83 (m, 5H), 1.33 (d, J = 6.2 Hz, 6H); MS (ESI) m/z: 431 (MH+).

113

1-(2-Cyclohexenylethyl)-2-((1E,4E)-2,4-diphenyl-3H-benzo[b]azepin-8-yl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 44a.

N O N

O N

1H NMR (300 MHz, CDCl3) δ 8.57 (d, J = 1.4 Hz, 1H), 8.09 (dd, J = 8.5, 1.4 Hz, 1H), 7.98 (d, J = 1.4 Hz, 1H), 7.90 (dd, J = 7.6, 1.4 Hz, 2H), 7.66-7.63 (m, 4H), 7.50 (d, J = 8.5 Hz, 1H), 7.52-7.35 (m, 6H), 7.17 (s, 1H), 5.28 (m, 1H), 4.49 (t, J = 7.3 Hz, 2H), 3.98 (s, 3H), 3.48 (brs, 2H), 2.47 (t, J = 7.3 Hz, 2H), 1.86-1.81 (m, 4H), 1.48-1.44 (m, 4H);

13C NMR (75 MHz, CDCl3) δ 168.1, 158.6, 155.4, 147.1, 142.8, 139.9, 139.3, 138.2, 136.8, 133.4, 131.7, 131.0, 130.9, 129.3, 129.1, 129.0, 128.7, 128.6, 128.5, 128.4, 127.4, 125.4, 124.9, 124.8, 124.5, 122.6, 110.4, 52.5, 44.5, 38.4, 34.5, 28.7, 25.5, 25.9, 22.3; IR (cm^-1, KBr): 1714, 1612; MS (ESI) m/z 578 (MH⁺); HRMS (ESI, m/z) calcd for C39H36N3O2: m/z 578.2807; Found 578.2808.

1-Butyl-2-((1E, 4E)-2, 4-diphenyl-3H-benzo[b]azepin-8-yl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 44b.

N O N

O N

1H NMR (300 MHz, CDCl3) δ 8.58 (d, J = 1.4 Hz, 1H), 8.09 (dd, J = 8.5, 1.4 Hz, 1H), 7.96 (d, J = 1.1 Hz, 1H), 7.91 (dd, J = 7.6, 1.4 Hz, 2H), 7.68-7.60 (m, 4H), 7.52 (d, J =

114

8.5 Hz, 1H), 7.50-7.33 (m, 6H), 7.17 (s, 1H), 4.41 (t, J = 7.5 Hz, 2H), 3.98 (s, 3H), 3.49 (brs, 2H), 1.90 (quint, J = 7.5 Hz, 2H), 1.32 (sext, J = 7.5 Hz, 2H), 0.91 (t, J = 7.5 Hz, 3H); ¹³C NMR (75 MHz, CDCl3) δ 168.1, 158.7, 155.4, 147.2, 142.9, 139.9, 139.3, 138.3, 136.9, 131.7, 131.2, 130.9, 129.3, 129.2, 129.0, 128.6, 128.5, 128.4, 127.4, 125.1, 124.9, 124.8, 124.7, 122.6, 110.4, 52.5, 45.3, 34.6, 32.2, 20.4, 13.9; IR (cm^-1, KBr): 1707, 1612;

MS (ESI) m/z 526 (MH⁺); HRMS (ESI, m/z) calcd for C₃₅H₃₁N₃O₂: m/z 526.2494;

Found 526.2491.

1-Cyclopentyl-2-((1E, 4E)-2, 4-diphenyl-3H-benzo[b]azepin-8-yl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 44c.

N O N

O N

1H NMR (300 MHz, CDCl₃) δ 8.58 (s, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.92 (d, J = 1.3 Hz, 1H), 7.91-7.90 (m, 2H), 7.66 (d, J = 8.1 Hz, 1H), 7.62-7.57 (m, 4H), 7.49-7.34 (m, 6H), 7.17 (s, 1H), 5.28 (quint, J = 8.9 Hz, 1H), 3.98 (s, 3H), 3.49 (brs, 2H), 2.37-2.34 (m, 2H), 2.23-2.07 (m, 4H), 1.84-1.80 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 168.0, 158.7, 156.0, 147.1, 143.5, 139.5, 138.2, 136.9, 136.8, 136.0, 131.6, 131.4, 130.9, 129.5, 129.3, 129.0, 128.7, 128.5, 127.3, 126.6, 125.0, 124.8, 124.3, 122.9, 112.0, 58.3, 52.5, 34.6, 30.9, 25.8;

IR (cm^-1, KBr): 1714, 1614; MS (ESI) m/z 537 (MH⁺); HRMS (ESI, m/z) calcd for C₃₆H₃₂N₃O₂: m/z 538.2494; Found 526.2492.

2-((1E,4E)-2,4-diphenyl-3H-benzo[b]azepin-8-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 44d.

115

N O N

O N

1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 1.4 Hz, 1H), 7.88 (dd, J = 7.0, 1.7 Hz, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.61 (dd, J = 7.0, 1.1 Hz, 2H), 7.55 (dd, J = 8.0, 1.7 Hz, 1H), 7.48-7.34 (m, 6H), 7.17 (s, 1H), 5.07 (sept, J = 7.0 Hz, 1H), 3.98 (s, 3H), 3.49 (brs, 2H), 1.74 (d, J = 7.0 Hz, 6H);

13C NMR (75 MHz, CDCl3) δ 167.8, 159.0, 154.6, 147.1, 143.1, 139.9, 138.1, 137.3, 136.8, 136.0, 132.6, 131.9, 131.0, 129.5, 129.3, 129.2, 128.7, 128.5, 127.4, 126.6, 125.1, 124.7, 124.3, 122.1, 112.6, 52.6, 50.0, 34.6, 21.9; IR (cm^-1, KBr): 1714, 1614; MS (ESI) m/z 512 (MH⁺); HRMS (ESI, m/z) calcd for C₃₄H₃₀N₃O₂: m/z 512.2338; Found 512.2336.

2-((1E, 4E)-2, 4-diphenyl-3H-benzo[b]azepin-8-yl)-1-isobutyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 44e.

N O N

O N

1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.94 (s, 1H), 7.90 (dd, J = 7.1, 1.0 Hz, 2H), 7.65 (d, J = 8.1 Hz, 1H), 7.62-7.58 (m, 3H), 7.51 (d, J = 8.5 Hz, 1H), 7.46-7.35 (m, 6H), 7.17 (s, 1H), 4.25 (d, J = 7.2 Hz, 2H), 3.98 (s, 3H), 3.48 (brs, 2H), 2.20 (sext, J = 6.6 Hz, 1H), 0.80 (d, J = 6.6 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ

116

168.0, 158.8, 155.9, 147.2, 143.1, 139.9, 139.6, 138.3, 136.9, 131.6, 131.3, 130.9, 129.3, 129.2, 129.1, 129.0, 128.7, 128.4, 127.3, 126.7, 124.9, 124.7, 124.6, 122.7, 110.6, 52.6, 52.5, 34.6, 29.4, 20.5; IR (cm^-1, KBr): 1712, 1612; MS (ESI) m/z 526 (MH⁺); HRMS (ESI, m/z) calcd for C35H32N3O2: m/z 526.2494; Found 526.2495.

2-((1E, 4E)-2, 4-dip-tolyl-3H-benzo[b]azepin-8-yl)-1-isobutyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 44f.

N O N

O N

1H NMR (300 MHz, CDCl3) δ 8.57 (d, J = 1.3 Hz, 1H), 8.07 (dd, J = 8.6, 1.3 Hz, 1H), 7.92 (d, J = 1.4 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 8.1 Hz, 1H), 7.57 (dd, J = 8.2, 1.4 Hz, 1H), 7.52-7.46 (m, 4H), 7.24 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 1H), 7.14 (s, 1H), 4.26 (d, J = 7.2 Hz, 2H), 3.99 (s, 3H), 3.44 (brs, 2H), 2.41 (s, 3H), 2.36 (s, 3H), 2.20 (sext, J = 6.6 Hz, 1H), 0.80 (d, J = 6.6 Hz, 6H); ¹³C NMR (75 MHz, CDCl3) δ 168.1, 158.6, 155.9, 147.2, 142.9, 141.2, 139.5, 138.6, 137.1, 136.8, 135.5, 131.6, 131.5, 129.7, 129.6, 128.8, 128.6, 128.5, 127.3, 125.8, 124.9, 124.7, 124.6, 122.7, 110.6, 52.6, 52.5, 34.6, 29.4, 21.7, 21.6, 20.5; IR (cm^-1, KBr): 1712, 1610; MS (ESI) m/z 554 (MH⁺);

HRMS (ESI, m/z) calcd for C37H36N3O2: m/z 554.2807; Found 554.2805.

2-((1E,4E)-2,4-dip-tolyl-3H-benzo[b]azepin-8-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 44g.

117

N O N

O N

1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.86 (s, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 8.6 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.55-7.50 (m, 3H), 7.24 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.14 (s, 1H), 5.07 (sept, J = 7.0 Hz, 1H), 3.98 (s, 3H), 3.46 (brs, 2H), 2.41 (s, 3H), 2.36 (s, 3H), 1.74 (d, J = 7.0 Hz, 6H); ¹³C NMR (75 MHz, CDCl3) δ 167.9, 158.6, 155.3, 147.1, 141.3, 138.7, 137.1, 136.9, 135.4, 131.7, 131.6, 129.9, 129.7, 129.4, 129.3, 129.0, 128.7, 128.5, 127.8, 127.2, 125.8, 124.8, 124.4, 122.7, 112.4, 52.5, 49.7, 34.4, 21.9, 21.8, 21.6; IR (cm^-1, KBr): 1716, 1612; MS (ESI) m/z 540 (MH⁺); HRMS (ESI, m/z) calcd for C₃₆H₃₄N₃O₂: m/z 540.2651; Found 540.2648.

2-((1E, 4E)-2,4-bis(4-chlorophenyl)-3H-benzo[b]azepin-8-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 44h.

N O N

O N

1H NMR (300 MHz, CDCl3) δ 8.56 (d, J = 1.5 Hz, 1H), 8.04 (dd, J = 8.6, 1.5 Hz, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.82 (dd, J = 7.0, 1.6 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.37 (dd, J = 8.6, 1.8 Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.15 (s, 1H), 5.04 (sept, J = 7.0 Hz, 1H), 3.98 (s, 3H), 3.42 (brs, 2H), 1.67 (d, J

118

= 7.0 Hz, 6H); ¹³C NMR (75 MHz, CDCl3) δ 167.9, 156.9, 155.0, 146.9, 138.2, 137.3, 137.2, 136.4, 135.3, 134.8, 131.7, 131.5, 129.7, 129.6, 129.4, 129.3, 129.1, 128.6, 127.3, 127.0, 125.2, 125.1, 124.4, 122.8, 112.4, 52.5, 49.7, 34.3, 21.9; IR (cm^-1, KBr): 1714, 1612; MS (ESI) m/z 580 (MH⁺); HRMS (ESI, m/z) calcd for C34H28Cl2N3O2: m/z 580.1558; Found 580.1550.

2-((1E, 4E)-2,4-bis(4-chlorophenyl)-3H-benzo[b]azepin-8-yl)-1-phenethyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 44i.

N O N

O N

1H NMR (300 MHz, CDCl3) δ 8.57 (d, J = 1.4 Hz, 1H), 8.08 (dd, J = 8.5, 1.4 Hz, 1H), 7.85 (d, J = 8.6 Hz, 2H), 7.76 (d, J = 1.4 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.51-7.49 (m, 2H), 7.46 (dd, J = 8.2, 1.5 Hz, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 7.19-7.16 (m, 4H), 7.13 (s, 1H), 6.99-6.97 (m, 2H), 4.63 (t, J = 7.3 Hz, 2H), 3.99 (s, 3H), 3.40 (brs, 2H), 3.16 (t, J = 7.3 Hz, 2H); ¹³C NMR (75 MHz, CDCl3) δ 168.0, 156.8, 155.3, 146.8, 142.9, 139.0, 138.2, 137.4, 137.3, 136.4, 135.1, 135.0, 131.6, 130.9, 129.9, 129.7, 129.6, 129.2, 129.1, 129.0, 128.9, 128.6, 127.5, 127.3, 125.1, 125.0, 124.9, 122.7, 110.3, 52.6, 47.0, 36.4, 34.1; IR (cm^-1, KBr): 1712, 1612; MS (ESI) m/z 642 (MH⁺); HRMS (ESI, m/z) calcd for C39H30Cl2N3O2: m/z 642.1715; Found 642.1709.

2-((1E, 4E)-2,4-bis(3-methoxyphenyl)-3H-benzo[b]azepin-8-yl)-1-phenethyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 44j.

119

N O N

O N

O O

1H NMR (300 MHz, CDCl₃) δ 8.57 (d, J = 1.4 Hz, 1H), 8.08 (dd, J = 8.6, 1.4 Hz, 1H), 7.80 (d, J = 1.7 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.52-7.40 (m, 3H), 7.38 (dd, J = 8.2, 1.7 Hz, 2H), 7.34 (d, J = 8.6 Hz, 1H), 7.26-7.19 (m, 4H), 7.16 (s, 1H), 7.11 (t, J = 2.2 Hz, 1H), 6.94-6.92 (m, 4H), 4.63 (t, J = 7.3 Hz, 2H), 3.99 (s, 3H), 3.84 (s, 3H), 3.74 (s, 3H), 3.44 (brs, 2H), 3.16 (t, J = 7.3 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 168.1, 160.3, 160.2, 158.4, 155.6, 147.0, 143.0, 141.4, 139.7, 139.1, 137.4, 136.7, 131.6, 131.3, 130.3, 130.0, 129.2, 129.1, 128.9, 128.5, 127.5, 126.6, 125.0, 124.9, 124.9, 122.7, 120.8, 119.9, 117.8, 114.4, 112.9, 112.8, 110.2, 55.7, 55.6, 52.6, 47.0, 36.4, 34.9; IR (cm^-1, KBr): 1712, 1608;

MS (ESI) m/z 634 (MH⁺); HRMS (ESI, m/z) calcd for C₄₁H₃₆N₃O₄: m/z 634.2706; Found 634.2711.

2-((1E, 4E)-2,4-bis(3-methoxyphenyl)-3H-benzo[b]azepin-8-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 44k.

N O N

O N

O O

1H NMR (300 MHz, CDCl₃) δ 8.56 (d, J = 1.4 Hz, 1H), 8.03 (dd, J = 8.6, 1.4 Hz, 1H), 7.88 (d, J = 1.6 Hz, 1H), 7.68 (t, J = 8.6 Hz, 2H), 7.54 (d, J = 1.6 Hz, 1H), 7.50 (dd, J = 8.2, 1.6 Hz, 1H), 7.45 (t, J = 2.4 Hz, 1H), 7.39-7.25 (m, 3H), 7.17 (s, 1H), 7.10 (t, J = 2.4

120

Hz, 1H), 6.94 (ddd, J = 6.2, 1.6, 0.6 Hz, 2H), 5.05 (sept, J = 7.0 Hz, 1H), 3.98 (s, 3H), 3.87 (s, 3H), 3.77 (s, 3H), 3.46 (brs, 2H), 1.68 (d, J = 7.0 Hz, 6H); ¹³C NMR (75 MHz, CDCl3) δ 168.0, 160.3, 160.1, 158.5, 155.4, 147.1, 143.7, 141.4, 139.7, 137.3, 136.8, 131.6, 131.3, 130.3, 130.0, 129.4, 129.1, 126.6, 124.9, 124.7, 124.3, 122.9, 120.9, 119.9, 117.8, 114.3, 112.9, 112.7, 112.4, 55.7, 55.6, 52.5, 49.6, 35.0, 21.9; IR (cm^-1, KBr): 1712, 1606; MS (EI) m/z 572 (MH⁺); HRMS (ESI, m/z) calcd for C₃₆H₃₄N₃O₄: m/z 572.2549;

Found 572.2546.

2-((1E, 4E)-2,4-bis(3-methoxyphenyl)-3H-benzo[b]azepin-8-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 44l.

N O N

O N

O O

1H NMR (300 MHz, CDCl3) δ 8.56 (d, J = 1.5 Hz, 1H), 8.07 (dd, J = 8.0, 1.5 Hz, 1H), 7.95 (d, J = 1.5 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.59 (dd, J = 8.2, 1.7 Hz, 1H), 7.50-7.46 (m, 3H), 7.38 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 7.25-7.22 (m, 1H), 7.17 (s, 1H), 7.13 (t, J = 2.4 Hz, 1H), 6.95 (ddd, J = 6.2, 1.7, 0.6 Hz, 2H), 4.26 (d, J = 7.5 Hz, 2H), 3.98 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H), 3.45 (brs, 2H), 2.19 (sext, J = 6.7 Hz, 1H), 0.83 (d, J = 6.7 Hz, 6H); ¹³C NMR (75 MHz, CDCl3) δ 168.1, 160.3, 160.2, 158.6, 155.8, 147.2, 143.1, 141.5, 139.8, 139.6, 136.7, 131.6, 131.2, 130.3, 130.0, 129.3, 129.2, 126.7, 125.0, 124.9, 124.7, 122.7, 120.8, 119.9, 117.8, 114.3, 112.9, 112.7, 110.7, 55.7, 55.6, 52.7, 52.5, 35.1, 29.4, 20.4; IR (cm^-1, KBr): 1712, 1606; MS (EI) m/z 585 (M⁺); HRMS (EI, m/z) calcd for C37H35N3O4: m/z 585.2628; Found 585.2623.

121 1.6. VEGFR-3 inhibitory activity

After the successful synthesis of benzoxazole bis-heterocyclic library, our attention for biological evaluation of these compounds was deviated towards the VEGFR inhibitors due to their structural resemblance with the potent KDR inhibitor and potential VEGFR-3 inhibitor. It is a well established fact in cancer biology that the tumor growth depends on the expression of various growth factors associated with angiogenesis and lymphangiogenesis. Recently, more advanced studies on the identification of roles of various VEGFR investigated that the VEGFR-3 has been implicated as key mediator of lymphangiogenesis in both normal biology and tumors. Consequently as an novel VEGFR target, we are intriguing to examine the new bis-heterocyclic scaffold for the inhibition of VEGFR-3.

Accordingly, the new benzimidazolyl linked benzoxazole derivatives 22a-p were examined with in vitro inhibition of VEGFR-3 kinase cell based assay in the concentration of 3 μM on H928 cell lines. Interestingly, after preliminary screening it has been found that all the compounds have shown moderate to high inhibition from 15 % to 87 % (Table 6). Gratifyingly, compounds namely 22c, 22f, 22h-k, 22m and 22n shows higher inhibitory activity against VEGFR-3. These selective compounds were further studied for the IC50 values and respective data was specified in Table 6. The comparative biological studies points to compound 22c, 22m and 22n as the prominent compounds that inhibits receptor tyrosine kinase VEGFR-3. A generalization of this study suggests that the new benzimidazole linked benzoxazole bis-heterocyclic scaffold possess potential to inhibit receptor tyrosine kinase VEGFR-3 and further extension of this study can defiantly aid the development of novel cancer therapeutics.

122

Inhibition(%)^a LRMS^c

Table 6. Percent inhibition of VEGFR-3 and IC50 (µM) value for selected compounds.

123

a Results are expressed as the mean percent inhibition at 3μM level. ^b For the selective compounds having inhibition is more than 60%; values are an average of three individual determinations.

KIRA ELISA Assay (In vitro method for detecting VEGF R3 activity):

H928 cells (2X10⁵) in 100 μl medium were added to each well in a flat bottom 24-well culture plate and cultured overnight at 37°C in 5% CO2. After the supernatants were removed, the cells were serum-starved for 24h. A medium containing a test compound was added into each well and the cell culture was incubated for 30 minutes before it was stimulated by recombinant VEGF-C for 15 minutes. After the supernatants were removed, 100 μl of a lysis buffer were added into each well to lyse the cells and solubilize the VEGFR3. The lysis buffer included 150 mM NaCl containing 50 mM Hepes (Genentech media prep), 0.5% Triton-X100 (Genentech media prep), 0.01%

thimerosol, 30 kIU/ml aprotinin (ICN Biochemicals, Aurora, Ohio), 1 mM 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF; ICN Biochemicals), and 2 mM sodium orthovanadate. The plate was then put on a plate shaker (Bellco Instruments Vineland, N.J.) and the substance in each well of the plate underwent mixing for 6o minutes at room temperature. While the cells were being solubilized, an ELISA microtiter plate (Nunc Maxisorp, Inter Med, Denmark) coated overnight at 4°C with the affinity-purified polyclonal anti-VEGFR3 (2.5 μg/well block buffer (PBS containing 0.5% BSA and 0.01% thimerosol) for 60 minutes at room temperature with gentle agitation. The anti-VEGFR3 coated plate was subsequently washed twice with a wash buffer (PBS containing 0.05% Tween 20 and 0.01% thimerosol). The lysate containing

124

solubilized VEGFR3 from the cell culture microtiter well were transferred (85 μl/well) to the anti-VEGFR3 coated ELISA plate and incubated for 2 h at room temperature with gentle agitation. The unbound receptors were removed by washing with a wash buffer.

100 μl of biotinylated 4G10 (antiphosphotyrosine) diluted to 0.2 μg/ml in dilution buffer (PBS containing 0.5% BSA, 0.05% Tween 20, 5 mM EDTA, and 0.01% thimerosol) were added into each well. After incubation for 2 h at room temperature, the plate were washed and 100 μl HRP-conjugated streptavidin (Zymed Laboratories, S.San Francisco, Calif.) diluted 1:2000 in dilution buffer will be further added. After the free avidin conjugate were washed away, 100 μl freshly prepared substrate solution (tetramethyl benzidine, TMB) was added to each well. The reaction was allowed to proceed for 10 minutes and the color development was stopped by the addition of 100 μl/well 1.0 M H3PO4. The absorbance at 450 nm and the absorbance at a reference wavelength of 650 nm (A_450/650) were measured using an ELISA reader and the data were repeated 3 times.

The inhibition efficacy of each test compound is expressed as an inhibition percentage calculated according to following formula: 1-[(C-A)/(B-A)] X 100. In this formula, A is the basal amount of phosphotyrosine detected in a blank control, B is the amount of phosphotyrosine detected with VEGFR-C only, and C is the amount of phosphotyrosine detected with a test compound and VEGF-C. For IC₅₀ generation, the final compound concentrations ranged from 0.1 μM to 10 μM.

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